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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. 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

  3. 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

  4. 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…

  5. KRAS Mutation

    PubMed Central

    Franklin, Wilbur A.; Haney, Jerry; Sugita, Michio; Bemis, Lynne; Jimeno, Antonio; Messersmith, Wells A.

    2010-01-01

    Treatment of colon carcinoma with the anti-epidermal growth factor receptor antibody Cetuximab is reported to be ineffective in KRAS-mutant tumors. Mutation testing techniques have therefore become an urgent concern. We have compared three methods for detecting KRAS mutations in 59 cases of colon carcinoma: 1) high resolution melting, 2) the amplification refractory mutation system using a bifunctional self-probing primer (ARMS/Scorpion, ARMS/S), and 3) direct sequencing. We also evaluated the effects of the methods of sectioning and coring of paraffin blocks to obtain tumor DNA on assay sensitivity and specificity. The most sensitive and specific combination of block sampling and mutational analysis was ARMS/S performed on DNA derived from 1-mm paraffin cores. This combination of tissue sampling and testing method detected KRAS mutations in 46% of colon tumors. Four samples were positive by ARMS/S, but initially negative by direct sequencing. Cloned DNA samples were retested by direct sequencing, and in all four cases KRAS mutations were identified in the DNA. In six cases, high resolution melting abnormalities could not be confirmed as specific mutations either by ARMS/S or direct sequencing. We conclude that coring of the paraffin blocks and testing by ARMS/S is a sensitive, specific, and efficient method for KRAS testing. PMID:20007845

  6. 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

  7. Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation.

    PubMed

    Micalizzi, Alessia; Moroni, Isabella; Ginevrino, Monia; Biagini, Tommaso; Mazza, Tommaso; Romani, Marta; Valente, Enza Maria

    2016-07-01

    Dysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function. PMID:27251579

  8. Estimating mutation rate: how to count mutations?

    PubMed Central

    Fu, Yun-Xin; Huai, Haying

    2003-01-01

    Mutation rate is an essential parameter in genetic research. Counting the number of mutant individuals provides information for a direct estimate of mutation rate. However, mutant individuals in the same family can share the same mutations due to premeiotic mutation events, so that the number of mutant individuals can be significantly larger than the number of mutation events observed. Since mutation rate is more closely related to the number of mutation events, whether one should count only independent mutation events or the number of mutants remains controversial. We show in this article that counting mutant individuals is a correct approach for estimating mutation rate, while counting only mutation events will result in underestimation. We also derived the variance of the mutation-rate estimate, which allows us to examine a number of important issues about the design of such experiments. The general strategy of such an experiment should be to sample as many families as possible and not to sample much more offspring per family than the reciprocal of the pairwise correlation coefficient within each family. To obtain a reasonably accurate estimate of mutation rate, the number of sampled families needs to be in the same or higher order of magnitude as the reciprocal of the mutation rate. PMID:12807798

  9. 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.

  10. Amputation des quatre membres

    PubMed Central

    Feruzi, Maruis Kitembo; Milindi, Cédrick Sangwa; Zabibu, Mireille Kakinga; Mulefu, Jules Panda; Katombe, Francois Tshilombo

    2014-01-01

    Les auteurs présentent les cas d'amputation des quatre membres réalisée chez trois patients différents. Ce sont des amputations réalisées pour chaque patient au cours d'une seule hospitalisation et en un seul temps opératoire. Deux patients pour gangrène sèche infectée et un pour amputation traumatique des quatre membres. L'amputation d'urgence a été pratiquée en premier temps suivie de remodelage des moignons d'amputation en second temps. L’évolution de tous les patients a été bonne. PMID:25469177

  11. Mutation and the environment

    SciTech Connect

    Mendelsohn, M.L. ); Albertini, R.J. )

    1990-01-01

    This book is organized under the following headings: Plenary lectures; Brook mutational mechanisms; Adduction and DNA damage; Recombination and gene conversion; Repair: Prokoyote mechanisms and induction; Repair: Lower eukaryote and plant mechanisms; Repair: Higher eukaryote mechanisms and selectivity; Repair: Human genes and mechanisms; Mutation: Spectra and mechanisms; Mutation: Shuttle vectors; Mutation: Transgenic animals; New methods: Polymerase chain reaction.

  12. Two Desmin Gene Mutations Associated with Myofibrillar Myopathies in Polish Families

    PubMed Central

    Berdynski, Mariusz; Sikorska, Agata; Filipek, Slawomir; Redowicz, Maria Jolanta; Kaminska, Anna; Zekanowski, Cezary

    2014-01-01

    Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization. PMID:25541946

  13. CF Mutation Panel

    MedlinePlus

    ... page: Was this page helpful? Also known as: Cystic Fibrosis Genotyping; CF DNA Analysis; CF Gene Mutation Panel; CF Molecular Genetic Testing Formal name: Cystic Fibrosis Gene Mutation Panel Related tests: Sweat Test ; Trypsinogen ; ...

  14. Colorectal cancer prognosis: is it all mutation, mutation, mutation?

    PubMed Central

    Hassan, A B; Paraskeva, C

    2005-01-01

    For the 500 000 new cases of colorectal cancer in the world each year, identification of patients with a worse prognosis and those who are more likely to respond to treatment is a challenge. There is an increasing body of evidence correlating genetic mutations with outcome in tumours derived from human colorectal cancer cohorts. K-ras, but not p53 or APC, mutations appear to be associated with poorer overall survival in colorectal cancer patients. PMID:16099785

  15. 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

  16. 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

  17. UV signature mutations.

    PubMed

    Brash, Douglas E

    2015-01-01

    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 nontranscribed 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; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  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. Stationary mutation models.

    PubMed

    Simonsson, Ivar; Mostad, Petter

    2016-07-01

    Probability calculations for relationship inference based on DNA tests are often performed with computer packages such as Familias. When mutations are assumed to be a possibility, one may notice a curious and problematic effect of including untested parents: results tend to change slightly. In this paper, we trace this effect back to fundamental model-formulating issues which can only be resolved by using stationary mutation models. We present several methods for obtaining such stationary mutation matrices from original mutation matrices, and evaluate essential properties of these methods. Our conclusion is that typically, stationary mutation models can be obtained, but for many types of markers, it may be impossible to combine specific biologically reasonable requirements for a mutation matrix with the requirement of stationarity. PMID:27231805

  20. 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.

  1. Effective Temperature of Mutations

    NASA Astrophysics Data System (ADS)

    Derényi, Imre; Szöllősi, Gergely J.

    2015-02-01

    Biological macromolecules experience two seemingly very different types of noise acting on different time scales: (i) point mutations corresponding to changes in molecular sequence and (ii) thermal fluctuations. Examining the secondary structures of a large number of microRNA precursor sequences and model lattice proteins, we show that the effects of single point mutations are statistically indistinguishable from those of an increase in temperature by a few tens of kelvins. The existence of such an effective mutational temperature establishes a quantitative connection between robustness to genetic (mutational) and environmental (thermal) perturbations.

  2. Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy

    PubMed Central

    ZHAO, YUE; FENG, YUE; ZHANG, YUN-MEI; DING, XIAO-XUE; SONG, YU-ZHU; ZHANG, A-MEI; LIU, LI; ZHANG, HONG; DING, JIA-HUAN; XIA, XUE-SHAN

    2015-01-01

    Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death and heart failure, and it is characterized by genetic and clinical heterogeneity, even for some patients with a very poor clinical prognosis; in the majority of cases, DCM necessitates a heart transplant. Genetic mutations have long been considered to be associated with this disease. At present, mutations in over 50 genes related to DCM have been documented. This study was carried out to elucidate the characteristics of gene mutations in patients with DCM. The candidate genes that may cause DCM include MYBPC3, MYH6, MYH7, LMNA, TNNT2, TNNI3, MYPN, MYL3, TPM1, SCN5A, DES, ACTC1 and RBM20. Using next-generation sequencing (NGS) and subsequent mutation confirmation with traditional capillary Sanger sequencing analysis, possible causative non-synonymous mutations were identified in ~57% (12/21) of patients with DCM. As a result, 7 novel mutations (MYPN, p.E630K; TNNT2, p.G180A; MYH6, p.R1047C; TNNC1, p.D3V; DES, p.R386H; MYBPC3, p.C1124F; and MYL3, p.D126G), 3 variants of uncertain significance (RBM20, p.R1182H; MYH6, p.T1253M; and VCL, p.M209L), and 2 known mutations (MYH7, p.A26V and MYBPC3, p.R160W) were revealed to be associated with DCM. The mutations were most frequently found in the sarcomere (MYH6, MYBPC3, MYH7, TNNC1, TNNT2 and MYL3) and cytoskeletal (MYPN, DES and VCL) genes. As genetic testing is a useful tool in the clinical management of disease, testing for pathogenic mutations is beneficial to the treatment of patients with DCM and may assist in predicting disease risk for their family members before the onset of symptoms. PMID:26458567

  3. 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.

  4. 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

  5. Mutations in Lettuce Improvement.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations can make profound impact on the evolution and improvement of a self-pollinated crop such as lettuce. Since it is nontransgenic, mutation breeding is more acceptable to consumers. Combined with genomic advances in new technologies like TILLING, mutagenesis is becoming an even more powerfu...

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. Towards a Dynamic DES model

    NASA Astrophysics Data System (ADS)

    Subbareddy, Pramod; Candler, Graham

    2009-11-01

    Hybrid RANS/LES methods are being increasingly used for turbulent flow simulations in complex geometries. Spalart's detached eddy simulation (DES) model is one of the more popular ones. We are interested in examining the behavior of the Spalart-Allmaras (S-A) Detached Eddy Simulation (DES) model in its ``LES mode.'' The role of the near-wall functions present in the equations is analyzed and an explicit analogy between the S-A and a one-equation LES model based on the sub-grid kinetic energy is presented. A dynamic version of the S-A DES model is proposed based on this connection. Validation studies and results from DES and LES applications will be presented and the effect of the proposed modification will be discussed.

  13. Vecteurs Singuliers des Theories des Champs Conformes Minimales

    NASA Astrophysics Data System (ADS)

    Benoit, Louis

    En 1984 Belavin, Polyakov et Zamolodchikov revolutionnent la theorie des champs en explicitant une nouvelle gamme de theories, les theories quantiques des champs bidimensionnelles invariantes sous les transformations conformes. L'algebre des transformations conformes de l'espace-temps presente une caracteristique remarquable: en deux dimensions elle possede un nombre infini de generateurs. Cette propriete impose de telles conditions aux fonctions de correlations qu'il est possible de les evaluer sans aucune approximation. Les champs des theories conformes appartiennent a des representations de plus haut poids de l'algebre de Virasoro, une extension centrale de l'algebre conforme du plan. Ces representations sont etiquetees par h, le poids conforme de leur vecteur de plus haut poids, et par la charge centrale c, le facteur de l'extension centrale, commune a toutes les representations d'une meme theorie. Les theories conformes minimales sont constituees d'un nombre fini de representations. Parmi celles-ci se trouvent des theories unitaires dont les representation forment la serie discrete de l'algebre de Virasoro; leur poids h a la forme h_{p,q}(m)=[ (p(m+1) -qm)^2-1] (4m(m+1)), ou p,q et m sont des entiers positifs et p+q<= m+1. L'entier m parametrise la charge centrale: c(m)=1 -{6over m(m+1)} avec n>= 2. Ces representations possedent un sous-espace invariant engendre par deux sous-representations avec h_1=h_{p,q} + pq et h_2=h_{p,q} + (m-p)(m+1-q) dont chacun des vecteurs de plus haut poids portent le nom de vecteur singulier et sont notes respectivement |Psi _{p,q}> et |Psi_{m-p,m+1-q}>. . Les theories super-conformes sont une version super-symetrique des theories conformes. Leurs champs appartiennent a des representation de plus haut poids de l'algebre de Neveu-Schwarz, une des deux extensions super -symetriques de l'algebre de Virasoro. Les theories super -conformes minimales possedent la meme structure que les theories conformes minimales. Les representations

  14. 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

  15. Mutations in lettuce improvement.

    PubMed

    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

  16. 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

  17. 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).

  18. Classification of 15 DES supernovae by OzDES

    NASA Astrophysics Data System (ADS)

    Yuan, F.; Tucker, B. E.; Lidman, C.; Martini, P.; Gshwend, Julia; Moller, A.; Zhang, B.; 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.; 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.

    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).

  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 4 DES supernovae by OzDES

    NASA Astrophysics Data System (ADS)

    Glazebrook, K.; Amon, A.; Lidman, C.; Martini, P.; Tucker, B. E.; Yuan, F.; 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.; 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.

    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).

  1. Classification of 6 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Lewis, G. F.; Mould, J.; Lidman, C.; Tucker, B. E.; Sharp, R.; Yuan, F.; Martini, P.; Kessler, R.; Scolnic, D.; Covarrubias, R. A.; Brout, D. J.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; D'Andrea, C.; Smith, M.; Sullivan, M.; Childress, 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.

    2015-10-01

    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).

  2. Classification of 14 DES Supernova with OzDES

    NASA Astrophysics Data System (ADS)

    Tucker, B. E.; Sharp, R.; Yuan, F.; Zhang, B.; Lidman, C.; Davis, T. M.; Hinton, S.; Mould, J.; Smith, R. C.; Schubnell, M.; Kessler, R.; Scolnic, D.; Covarrubias, R. A.; Brout, D. J.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.; Wolf, R. C.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; Nichol, R.; Papadopoulos, A.; D'Andrea, C.; Smith, M.; Sullivan, M.; Childress, 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.; Castander, F. J.; Desai, S.; Paech, K.

    2015-10-01

    We report new spectroscopic classifications by OzDES of supernovae discovered by the Dark Energy Survey. 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).

  3. 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

  4. Mutation detection by chemical cleavage.

    PubMed

    Cotton, R G

    1999-02-01

    Detection and amplification of mutations in genes in a cheap, 100% effective manner is a major objective in modern molecular genetics. This ideal is some way away and many methods are used each of which have their own particular advantages and disadvantages. Sequencing is often thought of as the 'gold standard' for mutation detection. This perception is distorted due to the fact that this is the ONLY method of mutation identification but this does not mean it is the best for mutation detection. The fact that many scanning methods detect 5-10% of mutant molecules in a wild type environment immediately indicates these methods are advantageous over sequencing. One such method, the Chemical Cleavage method, is able to cut the costs of detecting a mutation on order of magnitude and guarantees mutation detection as evidenced by track record and the fact that each mutation has two chances of being detected. PMID:10084109

  5. 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

  6. Calreticulin mutations in myeloproliferative neoplasms.

    PubMed

    Lavi, Noa

    2014-10-01

    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

  7. Two new Gaucher disease mutations.

    PubMed

    Beutler, E; Gelbart, T

    1994-02-01

    Recently, a mutation at nucleotide 1193 of the glucocerebrosidase gene was described in a patient with type 1 Gaucher disease. This mutation destroys a TaqI site in a polymerase chain reaction (PCR)-amplified fragment. We used digestion with this enzyme to screen DNA samples from Gaucher disease patients representing 23 previously unidentified alleles and discovered that this site had been destroyed in three samples. However, the mutation that caused this change proved to be a CT substitution at cDNA nucleotide 1192 (Genomic 5408; 359Arg-->End). Fortuitously, another TaqI site was destroyed by a different mutation, a GA mutation at nt 1312 (Genomic 5927; 399AspAsn). Both of these mutations were functionally severe in that they were associated with type 2 (acute neuronopathic) Gaucher disease. PMID:8112750

  8. Annuaire du Bureau des longitudes - 2006

    NASA Astrophysics Data System (ADS)

    Imcce; Bureau Des Longitudes

    2005-07-01

    This annual publication provides ephemerides and data to the use of professionnal and amateur astronomers. Divided in 11 chapters it covers concordance of various calendars, explanation of fondamental astronomy and various time scales, explanation for the use of ephemerides; tables provide ephemerides (positions, rise/set/passage) of the Sun and the Moon, planets, planetary satellites, asteroids, comets, bright stars; data and explanation for the physical observation of the surface of the Sun, the Moon, and planets; chart of the sky and a list of constellations and galaxies; prediction and ephemerides for astronomical phenomenon: occultation by the moon, stellar occultations by asteroids and appulses, solar eclipses and lunar eclipses; and an additional review about a hot scientific topic, this year: "Legendre et le méridien terrestre, 200 ans après". Cette publication annuelle fournit des éphémérides et des données à l'usage des astronomes professionnels et des astronomes amateurs. Composée de 11 chapitres elle comprend les rubriques sur les différents calendriers et leurs concordance, les fêtes légales en France, les dates et décrets sur les heures légales en France métropolitaine ; une introduction à l'astronomie fondamentale et aux différentes échelles de temps, des explications sur l'utilisation des éphémérides ; des tables fournissent les éphémérides (positions, heures de lever/coucher/passage) du Soleil et de la Lune, de planètes, de satellites naturels, d'astéroïdes, de comètes, d'étoiles brillantes ; des données pour l'observation de la surface du Soleil, de la Lune, et des planètes ; des cartes du ciel ainsi qu'une liste de constellations et de galaxies ; des prédictions des phénomènes astronomiques : occultation par la Lune, occultation stellaires par des astéroïdes et appulses, éclipses de Soleil et de la Lune; la liste et les coordonnées des observatoires astronomiques les plus connus ; et enfin un cahier th

  9. BRAF Mutations in Canine Cancers

    PubMed Central

    Mochizuki, Hiroyuki; Kennedy, Katherine; Shapiro, Susan G.; Breen, Matthew

    2015-01-01

    Activating mutations of the BRAF gene lead to constitutive activation of the MAPK pathway. Although many human cancers carry the mutated BRAF gene, this mutation has not yet been characterized in canine cancers. As human and canine cancers share molecular abnormalities, we hypothesized that BRAF gene mutations also exist in canine cancers. To test this hypothesis, we sequenced the exon 15 of BRAF, mutation hot spot of the gene, in 667 canine primary tumors and 38 control tissues. Sequencing analysis revealed that a single nucleotide T to A transversion at nucleotide 1349 occurred in 64 primary tumors (9.6%), with particularly high frequency in prostatic carcinoma (20/25, 80%) and urothelial carcinoma (30/45, 67%). This mutation results in the amino acid substitution of glutamic acid for valine at codon 450 (V450E) of canine BRAF, corresponding to the most common BRAF mutation in human cancer, V600E. The evolutional conservation of the BRAF V600E mutation highlights the importance of MAPK pathway activation in neoplasia and may offer opportunity for molecular diagnostics and targeted therapeutics for dogs bearing BRAF-mutated cancers. PMID:26053201

  10. 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.

  11. Driver Mutations in Uveal Melanoma

    PubMed Central

    Decatur, Christina L.; Ong, Erin; Garg, Nisha; Anbunathan, Hima; Bowcock, Anne M.; Field, Matthew G.; Harbour, J. William

    2016-01-01

    IMPORTANCE Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. OBJECTIVE To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. MAIN OUTCOMES AND MEASURES Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. RESULTS The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1–28.5) and

  12. 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

  13. 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

  14. 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.

  15. Mutation breeding by ion implantation

    NASA Astrophysics Data System (ADS)

    Yu, Zengliang; Deng, Jianguo; He, Jianjun; Huo, Yuping; Wu, Yuejin; Wang, Xuedong; Lui, Guifu

    1991-07-01

    Ion implantation as a new mutagenic method has been used in the rice breeding program since 1986, and for mutation breeding of other crops later. It has been shown, in principle and in practice, that this method has many outstanding advantages: lower damage rate; higher mutation rate and wider mutational spectrum. Many new lines of rice with higher yield rate; broader disease resistance; shorter growing period but higher quality have been bred from ion beam induced mutants. Some of these lines have been utilized for the intersubspecies hybridization. Several new lines of cotton, wheat and other crops are now in breeding. Some biophysical effects of ion implantation for crop seeds have been studied.

  16. 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

  17. Glucocerebrosidase mutations in Gaucher disease.

    PubMed Central

    Beutler, E.; Demina, A.; Gelbart, T.

    1994-01-01

    BACKGROUND: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling. MATERIALS AND METHODS: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected. RESULTS: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-->A transversion at cDNA nt 644 (Ala176-->Asp), a C-->A transversion at cDNA nt 661 that resulted in a (Pro182-->Thr), and a G-->A transition at cDNA nt 721 (Gly202-->Arg). Two missense mutations were found in exon 7: a G-->A transition at cDNA nt 887 (Arg257-->Gln) and a C-->T at cDNA nt 970 (Arg285-->Cys). Two missense mutations were found in exon 9: a T-->G at cDNA nt 1249 (Trp378-->Gly) and a G-->A at cDNA nt 1255 (Asp380-->Asn). In addition to these disease-producing mutations, a silent C-->G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family. CONCLUSIONS: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature. PMID:8790604

  18. Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

    PubMed Central

    2014-01-01

    Background Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). Conclusions We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of

  19. 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

  20. Les complications abdominales associées à la chirurgie cardiaque : à propos d'une expérience chirurgicale contemporaine et examen d'une population opérée sans circulation extracorporelle

    PubMed Central

    Poirier, Brigitte; Baillot, Richard; Bauset, Richard; Dagenais, François; Mathieu, Patrick; Simard, Serge; Dionne, Brigitte; Caouette, Manon; Hould, Frédéric-Simon; Doyle, Daniel; Poirier, Paul

    2003-01-01

    Introduction Pour évaluer l'incidence, les facteurs de risque et la morbidité associés aux complications gastro-intestinales (GI) suite à une chirurgie cardiaque avec ou sans circulation extra-corporelle (CEC), nous avons effectué une étude rétrospective de cohortes dans un hôpital universitaire. Méthodes 11 405 patients adultes répartis en 2 groupes : groupe A (de janvier 1992 à juin 1996, 4657 patients) et groupe B (de juillet 1996 à décembre 2000, 6748 patients). Résultats 134 patients (1,2 %) ont présenté 147 complications. Le pourcentage des événements GI fut identique pour les 2 groupes (groupe A, n = 59/4657 [1,2 %]; groupe B, n = 75/6748 [1,1 %]). Le groupe B était composé de patients plus âgés, obèses, diabétiques ayant une maladie vasculaire cérébrale et périphérique. Les complications les plus fréquentes sont associées à l'œsophage et l'estomac, n = 67/147 (45,5 %). Nous identifions à la suite 10 (6,8 %) cholécystites, 13 (8,8 %) pancréatites, 17 (11,6 %) atteintes ischémiques du grêle et du colon, 12 (8,2 %) colites pseudomembraneuses et 5 (3,4 %) diverticulites. L'ischémie mésentérique est responsable de 11 (37,9 %) des 29 décès; 293 patients ont subi une revascularisation myocardique à cœur battant. Cinq patients (1,7 %) ont présenté des complications GI dont trois avec ischémie viscérale. L'analyse multivariée démontre que l'insuffisance rénale, l'intubation prolongée et l'infection sont associées aux complications GI dans les deux groupes alors que le score de Parsonnet et l'accident vasculaire cérébral apparaissent prédictifs dans le second groupe. Conclusions Ces résultats démontent que le nombre de patients qui présentent des complications GI lors d'une chirurgie cardiaque n'augmente pas malgré le caractère sénescent et la co-morbidité. La chirurgie coronarienne pratiquée sans CEC ne semble pas diminuer l'incidence des complications GI. PMID:12812238

  1. 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

  2. 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.

  3. Copernic: la piste des influences arabes

    NASA Astrophysics Data System (ADS)

    Khalatbari, A.; Bonnet-Bidaud, J. M.

    2004-10-01

    Copernic a-t-il connu le travail des astronomes du Moyen-Orient ? S'en est-il inspiré pour élaborer sa théorie de l'héliocentrisme ? C'est l'hypothèse avancée par certains historiens des sciences pour comprendre le génie de celui qui, le premier, a placé le Soleil au centre du monde. Enquête.

  4. 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

  5. Diffusion des Metaux et Evolution Stellaire

    NASA Astrophysics Data System (ADS)

    Turcotte, Sylvain

    Nous presentons dans cette these des modeles d'evolution stellaire incorporant la diffusion microscopique de maniere consistante. Pour la premiere fois, on a calcule l'evolution d'etoiles en tenant compte en detail de l'impact des variations d'abondances sur leur structure. Nous utilisons des spectres monochromatiques pour chacun des elements les plus abondants dans un melange solaire pour recalculer l'opacite pour les abondances et les conditions locales dans l'interieur d'une etoile au cours de son evolution. Nos modeles montrent que la diffusion atomique des metaux a un effet important sur les opacites dan les etoiles de plus de 1.3Msolar ou l'abondance du fer et des autres elements du pic du fer varient substantiellement. Ces etoiles, sans rotation ou champ magnetique, sont proches des etoiles de type Fm-Am dans lesquelles on observe une legere surabondance d'elements du pic du fer en plus d'une sous-abondance de calcium, sous-abondance que l'on obtient egalement. Nous obtenons cependant des surabondances depassant un facteur 10 pour les etoiles de plus de 1.4Msolar ce qui suggere qu'il existe un ou plusieurs mecanismes limitant la diffusion microscopique. La surabondance du fer en surface cause une augmentation, qui peut atteindre un facteur sept, de l'opacite a la limite de la zone convective. Ceci cause un accroissement de la temperature effective et de la masse de la zone convective comparativement aux modeles n'incluant que la diffusion de l'helium. Il s'agit la du principal effet de la diffusion sur la structure interne de ces etoiles. La diffusions n'a pas d'influence sur l'evolution de coeur stellaire dans les etoiles significativement plus massives quie le Soleil. Nous avons verife que l'utilisation de modeles consistants avec diffusion n'apporte pas d'amelioration sensible aux modeles solaires. Les forces radiatives calculees a partir des spectres d'OPAL pour les elements du pic du fer representent une fraction importante de la gravite. On obtient des

  6. SQSTM1 Mutations and Glaucoma

    PubMed Central

    Scheetz, Todd E.; Roos, Ben R.; Solivan-Timpe, Frances; Miller, Kathy; DeLuca, Adam P.; Stone, Edwin M.; Kwon, Young H.; Alward, Wallace L. M.; Wang, Kai; Fingert, John H.

    2016-01-01

    Glaucoma is the most common cause of irreversible blindness worldwide. One subset of glaucoma, normal tension glaucoma (NTG) occurs in the absence of high intraocular pressure. Mutations in two genes, optineurin (OPTN) and TANK binding kinase 1 (TBK1), cause familial NTG and have known roles in the catabolic cellular process autophagy. TKB1 encodes a kinase that phosphorylates OPTN, an autophagy receptor, which ultimately activates autophagy. The sequestosome (SQSTM1) gene also encodes an autophagy receptor and also is a target of TBK1 phosphorylation. Consequently, we hypothesized that mutations in SQSTM1 may also cause NTG. We tested this hypothesis by searching for glaucoma-causing mutations in a cohort of NTG patients (n = 308) and matched controls (n = 157) using Sanger sequencing. An additional 1098 population control samples were also analyzed using whole exome sequencing. A total of 17 non-synonymous mutations were detected which were not significantly skewed between cases and controls when analyzed separately, or as a group (p > 0.05). These data suggest that SQSTM1 mutations are not a common cause of NTG. PMID:27275741

  7. [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. PMID:27295708

  8. Driver mutations of cancer epigenomes.

    PubMed

    Roy, David M; Walsh, Logan A; Chan, Timothy A

    2014-04-01

    Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies. PMID:24622842

  9. 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

  10. 33 CFR 117.439 - Des Allemands Bayou.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 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...

  11. 33 CFR 117.439 - Des Allemands Bayou.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 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...

  12. 33 CFR 117.439 - Des Allemands Bayou.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 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...

  13. 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.

  14. 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

  15. Mutational Heterogeneity in Melanoma: An Inconvenient Truth.

    PubMed

    Chang, Gregory A; Polsky, David

    2015-12-01

    Identification of oncogenic BRAF mutations in primary and metastatic melanomas supports a linear model of clonal evolution in cancer. Some mutational studies, however, have failed to identify BRAF mutations in metastatic tumors from patients with BRAFmutant primary melanomas. Using a combination of methods, Riveiro-Falkenbach et al. (2015) assert that technical issues, and not clonal heterogeneity, may explain prior discordant mutational results. PMID:26569584

  16. 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

  17. 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

  18. 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

  19. 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. PMID:26774059

  20. The GBT-SerDes ASIC prototype

    NASA Astrophysics Data System (ADS)

    Moreira, P.; Baron, S.; Bonacini, S.; Cobanoglu, O.; Faccio, F.; Feger, S.; Francisco, R.; Gui, P.; Li, J.; Marchioro, A.; Paillard, C.; Porret, D.; Wyllie, K.

    2010-11-01

    In the framework of the GigaBit Transceiver project (GBT), a prototype, the GBT-SerDes ASIC, was developed, fabricated and tested. To sustain high radiation doses while operating at 4.8Gb/s, the ASIC was fabricated in a commercial 130 nm CMOS technology employing radiation tolerant techniques and circuits. The transceiver serializes-deserializes the data, Reed-Solomon encodes and decodes the data and scrambles and descrambles the data for transmission over optical fibre links. This paper describes the GBT-SerDes architecture, and presents the test results.

  1. Genetic Analysis of 63 Mutations Affecting Maize Kernel Development Isolated from Mutator Stocks

    PubMed Central

    Scanlon, M. J.; Stinard, P. S.; James, M. G.; Myers, A. M.; Robertson, D. S.

    1994-01-01

    Sixty-three mutations affecting development of the maize kernel were isolated from active Robertson's Mutator (Mu) stocks. At least 14 previously undescribed maize gene loci were defined by mutations in this collection. Genetic mapping located 53 of these defective kernel (dek) mutations to particular chromosome arms, and more precise map determinations were made for 21 of the mutations. Genetic analyses identified 20 instances of allelism between one of the novel mutations and a previously described dek mutation, or between new dek mutations identified in this study; phenotypic variability was observed in three of the allelic series. Viability testing of homozygous mutant kernels identified numerous dek mutations with various pleiotropic effects on seedling and plant development. The mutations described here presumably arose by insertion of a Mu transposon within a dek gene; thus, many of the affected loci are expected to be accessible to molecular cloning via transposon-tagging. PMID:8138165

  2. 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.

  3. [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

  4. 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

  5. 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

  6. Mutational patterns in oncogenes and tumour suppressors.

    PubMed

    Baeissa, Hanadi M; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

    2016-06-15

    All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer. PMID:27284061

  7. TCF12 is mutated in anaplastic oligodendroglioma.

    PubMed

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G; Sanson, Marc; Houlston, Richard S

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  8. TCF12 is mutated in anaplastic oligodendroglioma

    PubMed Central

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E.; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P.; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G.; Sanson, Marc; Houlston, Richard S.; Adam, Clovis; Andraud, Marie; Aubriot-Lorton, Marie-Hélène; Bauchet, Luc; Beauchesne, Patrick; Blechet, Claire; Campone, Mario; Carpentier, Antoine; Carpentier, Catherine; Carpiuc, Ioana; Chenard, Marie-Pierre; Chiforeanu, Danchristian; Chinot, Olivier; Cohen-Moyal, Elisabeth; Colin, Philippe; Dam-Hieu, Phong; Desenclos, Christine; Desse, Nicolas; Dhermain, Frederic; Diebold, Marie-Danièle; Eimer, Sandrine; Faillot, Thierry; Fesneau, Mélanie; Fontaine, Denys; Gaillard, Stéphane; Gauchotte, Guillaume; Gaultier, Claude; Ghiringhelli, Francois; Godard, Joel; Marcel Gueye, Edouard; Sebastien Guillamo, Jean; Hamdi-Elouadhani, Selma; Honnorat, Jerome; Louis Kemeny, Jean; Khallil, Toufik; Jouvet, Anne; Labrousse, Francois; Langlois, Olivier; Laquerriere, Annie; Lechapt-Zalcman, Emmanuelle; Le Guérinel, Caroline; Levillain, Pierre-Marie; Loiseau, Hugues; Loussouarn, Delphine; Maurage, Claude-Alain; Menei, Philippe; Janette Motsuo Fotso, Marie; Noel, Georges; Parker, Fabrice; Peoc'h, Michel; Polivka, Marc; Quintin-Roué, Isabelle; Ramirez, Carole; Ricard, Damien; Richard, Pomone; Rigau, Valérie; Rousseau, Audrey; Runavot, Gwenaelle; Sevestre, Henri; Christine Tortel, Marie; Uro-Coste, Emmanuelle; Burel-Vandenbos, Fanny; Vauleon, Elodie; Viennet, Gabriel; Villa, Chiara; Wager, Michel

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  9. Digenic mutations in severe congenital neutropenia

    PubMed Central

    Germeshausen, Manuela; Zeidler, Cornelia; Stuhrmann, Manfred; Lanciotti, Marina; Ballmaier, Matthias; Welte, Karl

    2010-01-01

    Severe congenital neutropenia a clinically and genetically heterogeneous disorder. Mutations in different genes have been described as causative for severe neutropenia, e.g. ELANE, HAX1 and G6PC3. Although congenital neutropenia is considered to be a group of monogenic disorders, the phenotypic heterogeneity even within the yet defined genetic subtypes points to additional genetic and/or epigenetic influences on the disease phenotype. We describe congenital neutropenia patients with mutations in two candidate genes each, including 6 novel mutations. Two of them had a heterozygous ELANE mutation combined with a homozygous mutation in G6PC3 or HAX1, respectively. The other 2 patients combined homozygous or compound heterozygous mutations in G6PC3 or HAX1 with a heterozygous mutation in the respective other gene. Our results suggest that digenicity may underlie this disorder of myelopoiesis at least in some congenital neutropenia patients. PMID:20220065

  10. 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

  11. 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

  12. 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…

  13. 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.

  14. 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

  15. Use of mutation spectra analysis software.

    PubMed

    Rogozin, I; Kondrashov, F; Glazko, G

    2001-02-01

    The study and comparison of mutation(al) spectra is an important problem in molecular biology, because these spectra often reflect on important features of mutations and their fixation. Such features include the interaction of DNA with various mutagens, the function of repair/replication enzymes, and properties of target proteins. It is known that mutability varies significantly along nucleotide sequences, such that mutations often concentrate at certain positions, called "hotspots," in a sequence. In this paper, we discuss in detail two approaches for mutation spectra analysis: the comparison of mutation spectra with a HG-PUBL program, (FTP: sunsite.unc.edu/pub/academic/biology/dna-mutations/hyperg) and hotspot prediction with the CLUSTERM program (www.itba.mi.cnr.it/webmutation; ftp.bionet.nsc.ru/pub/biology/dbms/clusterm.zip). Several other approaches for mutational spectra analysis, such as the analysis of a target protein structure, hotspot context revealing, multiple spectra comparisons, as well as a number of mutation databases are briefly described. Mutation spectra in the lacI gene of E. coli and the human p53 gene are used for illustration of various difficulties of such analysis. PMID:11180592

  16. Profil epidemiologique des brulures d'enfants admis au Centre National des Brules, Maroc

    PubMed Central

    Zahid, A.; Atannaz, J.; Alaoui, M.; Rafik, A.; Ezzoubi, M.; Diouri, M.; Chlihi, A.; Bahechar, N.; Boukind, E.H.

    2011-01-01

    Summary Ce travail rétrospectif analyse les particularités épidémiologiques de 543 cas de brûlures d'enfants, représentant 45,7% des admissions de notre centre, en vue de déterminer les éléments pouvant contribuer à renforcer la prévention, qui reste le traitement de choix de cette pathologie. La moyenne d'âge est de 4,25 ans avec une prédilection pour la tranche d'âge d'un à cinq ans, avec 42,5% des cas. Une atteinte masculine est retrouvée dans 63,5% des cas. La brûlure survient à domicile dans 85,1% et accidentellement dans 95% des cas. Les brûlures thermiques représentent 96,5% des causes dominées par les liquides dans 69,3% des cas. La surface cutanée brûlée est ≥ 20% dans 52,3%. La brûlure intéresse essentiellement les membres supérieurs (79,1%). 56,8% des enfants sont transférés par d'autres hôpitaux et le délai de prise en charge hospitalière est supérieur à 6 heures dans 65,5%. Le taux de mortalité a été de 13,2%. PMID:22639559

  17. Les effets des interfaces sur les proprietes magnetiques et de transport des multicouches nickel/iron et cobalt/silver

    NASA Astrophysics Data System (ADS)

    Veres, Teodor

    Cette these est consacree a l'etude de l'evolution structurale des proprietes magnetiques et de transport des multicouches Ni/Fe et nanostructures a base de Co et de l'Ag. Dans une premiere partie, essentiellement bibliographique, nous introduisons quelques concepts de base relies aux proprietes magnetiques et de transport des multicouches metalliques. Ensuite, nous presentons une breve description des methodes d'analyse des resultats. La deuxieme partie est consacree a l'etude des proprietes magnetiques et de transport des multicouches ferromagnetiques/ferromagnetiques Ni/Fe. Nous montrerons qu'une interpretation coherente de ces proprietes necessite la prise en consideration des effets des interfaces. Nous nous attacherons a mettre en evidence, a evaluer et a etudier les effets de ces interfaces ainsi que leur evolution, et ce, suite a des traitements thermiques tel que le depot a temperature elevee et l'irradiation ionique. Les analyses correlees de la structure et de la magnetoresistance nous permettront d'emettre des conclusions sur l'influence des couches tampons entre l'interface et le substrat ainsi qu'entre les couches elles-memes sur le comportement magnetique des couches F/F. La troisieme partie est consacree aux systemes a Magneto-Resistance Geante (MRG) a base de Co et Ag. Nous allons etudier l'evolution de la microstructure suite a l'irradiation avec des ions Si+ ayant une energie de 1 MeV, ainsi que les effets de ces changements sur le comportement magnetique. Cette partie debutera par l'analyse des proprietes d'une multicouche hybride, intermediaire entre les multicouches et les materiaux granulaires. Nous analyserons a l'aide des mesures de diffraction, de relaxation superparamagnetique et de magnetoresistance, les evolutions structurales produites par l'irradiation ionique. Nous etablirons des modeles qui nous aideront a interpreter les resultats pour une serie des multicouches qui couvrent un large eventail de differents comportements magnetiques

  18. 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

  19. Mutation, Witten index, and quiver invariant

    NASA Astrophysics Data System (ADS)

    Kim, Heeyeon; Lee, Seung-Joo; Yi, Piljin

    2015-07-01

    We explore Seiberg-like dualities, or mutations, for quiver quantum mechanics in the context of wall-crossing. In contrast to higher dimensions, the 1d Seiberg-duality must be performed with much care. With fixed Fayet-Iliopoulos constants, at most two nodes can be mutated, one left and the other right, mapping a chamber of a quiver into a chamber of a mutated quiver. We delineate this complex pattern for triangle quivers and show how the Witten indices are preserved under such finely chosen mutations. On the other hand, the quiver invariants, or wall-crossing-safe part of supersymmetric spectra, mutate more straightforwardly, whereby a quiver is mapped to a quiver. The mutation rule that preserves the quiver invariant is different from the usual one, however, which we explore and confirm numerically.

  20. 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

  1. 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

  2. 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.

  3. Determination of a mutational spectrum

    SciTech Connect

    Thilly, W.G.; Keohavong, P.

    1991-09-03

    A method is disclosed of resolving (physically separating) mutant DNA from nonmutant DNA. A method is also described 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. 3 figures.

  4. 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.

  5. Community Environmental Response Facilitation Act (CERFA) report. Fort Des Moines, Des Moines, Iowa. Final report

    SciTech Connect

    Young, B.; Rausch, K.; Kang, J.

    1994-04-01

    This report presents the results of the Community Environmental Response Facilitation Act (CERFA) investigation conducted by The Earth Technology Corporation (TETC) at the Fort Des Moines, a U.S. Government property selected for closure by the Base Realignment and Closure (BRAC) Commission. Under CERFA Federal agencies are required to identify real property that can be immediately reused and redeveloped. Satisfying this objective requires the identification of real property where no hazardous substances or petroleum products, regulated by the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), were stored for one year or more, known to have been released, or disposed. Fort Des Moines is a 53.28-acre site located in Polk County, Iowa, within the city limits of Des Moines. The installation's primary mission is to provide support and shelter for the U.S. Army Reserve. Activities associated with the property that have environmental significance are photographic processing, vehicle maintenance, printing, and fuel storage. TETC reviewed existing investigation documents; U.S. Environmental Protection Agency (USEPA), State, and county regulatory records; environmental data bases; and title documents pertaining to Fort Des Moines during this investigation. In addition, TETC conducted interviews and visual inspections of Fort Des Moines as well as visual inspections and data base searches for the surrounding properties. Information in this CERFA Report was current as of April 1994.

  6. Haplotypes and mutations in Wilson disease

    SciTech Connect

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

    1995-06-01

    Wilson disease is a disorder of copper transport, resulting in neurological and hepatic damage due to copper toxicity. We have recently identified >20 mutations in the copper-transporting ATPase defective in this disease. Given the difficulties of searching for mutations in a gene spanning >80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Here we examine the haplotypes associated with specific mutations. We have extended previous studies of DNA haplotypes of dinucleotide-repeat polymorphisms (CA repeats) in the Wilson disease region to include an additional marker, in 58 families. These haplotypes, combining three markers (D13S314, D12S316, and D13S301), are usually specific for each different mutation, even though highly polymorphic CA repeat markers have been used. Haplotypes, as well as their accompanying mutations, differ between populations. In the patients whom we have studied, the haplotype data indicate that as many as 20 mutations may still be unidentified. The use of the haplotypes that we have identified provides an important guide for the identification of known mutations and can facilitate future mutation searches. 15 refs., 1 fig., 2 tabs.

  7. 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

  8. 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.

  9. Three Turkish families with different transthyretin mutations.

    PubMed

    Bekircan-Kurt, Can Ebru; Güneş, Nalan; Yılmaz, Arda; Erdem-Özdamar, Sevim; Tan, Ersin

    2015-09-01

    Transthyretin (TTR)-related hereditary amyloidosis, also called familial amyloid polyneuropathy (FAP), is a rare autosomal dominant systemic disorder that presents with progressive axonal sensory, autonomic and/or motor neuropathies. The present report describes three families with three different TTR mutations who were followed from 1995 to 2014. Only one of these families expressed the Val30Met mutation, which is the most common mutation in endemic regions; all members of this family had late disease onset but varied severities and clinical presentations of the disease. The second family expressed the Thr49Ser mutation, which has not been well documented previously. Our limited experience obtained from these patients indicates that this mutation presents with autonomic neuropathy but a greater degree of cardiac involvement, especially fatal heart failure. The third mutation, Glu54Lys, has been identified as a cause of severe familial amyloid polyneuropathy; the family members with this mutation exhibited severe motor and autonomic neuropathy, early vitreous opacity, and fatal heart failure. Three of the patients with the Val30Met mutation were treated with tafamidis for longer than one year and cessation of the polyneuropathy resulted. However, a short trial of tafamidis in two patients with the Glu54Lys mutation, who showed severe systemic and neurological involvement, did not gain any clinical benefits. PMID:26115788

  10. Compensating the Fitness Costs of Synonymous Mutations.

    PubMed

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

    2016-06-01

    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

  11. 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

  12. 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.

  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. Etude des phenomenes de penetration des especes chimiques dans les revetements cathodiques des cuves d'electrolyse de l'aluminium

    NASA Astrophysics Data System (ADS)

    Brisson, Pierre-Yves

    Cette these decrit l'etude effectuee sur les phenomenes d'insertion du sodium et de penetration du bain electrolytique dans les revetements cathodiques des cuves d'electrolyse de l'aluminium. L'etude fut effectuee a l'aide d'un montage permettant d'effectuer l'electrolyse en laboratoire. Trois types de revetement cathodiques furent etudies : des blocs semi-graphitique, des blocs graphitiques et des blocs graphitises. L'insertion du sodium dans les trois differents types de blocs fut etudiee a l'aide de la spectrometrie des photoelectrons X (XPS). L'analyse a permis de mettre en evidence deux formes de sodium dans l'anthracite et la phase liante des materiaux semi-graphitiques et graphitiques, indiquant qu'une fraction du sodium se retrouve sous forme adsorbee dans les micropores des materiaux alors que l'autre fraction est inseree dans la structure cristalline du carbone. Dans les phases graphitiques (materiaux graphitises et graphitiques), seuls les micropores sont occupes par le sodium Ce resultat explique la tendance observee selon laquelle l'ajout de graphite dans les blocs permet d'abaisser le gonflement sodique. Les mecanismes de penetration du bain dans le reseau poreux des materiaux furent etudies en microscopie electronique et en diffraction des rayons X sur des echantillons apres differents temps d'electrolyses et en variant l'atmosphere (soit sous argon ou sous azote). Ces analyses ont permis d'identifier le mecanisme conduisant a la mouillabilite du bain sur le carbone en fonction de l'atmosphere entourant l'electrolyse. Ainsi, sous azote, la formation de NaCN dans les pores des materiaux par reactions entre le sodium et l'azote permet une mouillabilite accrue du bain alors qu'en absence d'azote (sous argon), le carbure d'aluminium, formes a la surface des pores, joue un role similaire. Dans ce dernier cas, la penetration du bain est moins rapide etant donnee la necessite de toujours amener des especes contenant de l'aluminium en tete du front de

  15. 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

  16. 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.

  17. Early Results from the DES SN Survey

    NASA Astrophysics Data System (ADS)

    Scolnic, Daniel; Dark Energy Survey

    2016-01-01

    The Dark Energy Survey Supernova program (DES SN) has already discovered over 1000 Type Ia supernovae with well-sampled multi-color light curves in the redshift range 0.1 < z < 1.2. I will present an overview of the survey and show recent advances in our detection, photometry, calibration and spectroscopic follow-up pipelines. I will go over initial results from photometric classification of our sample and discuss methods used to reach measurements of cosmological parameters.

  18. A Magellanic Origin of the DES Dwarfs

    NASA Astrophysics Data System (ADS)

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

    2016-06-01

    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 subhaloes in ΛCDM, we further demonstrate that, of 14 observed satellites, the MW halo contributes fewer than 4(8) of these with 68(95)% confidence and that 7(12) DES dwarfs have probabilities greater than 0.7(0.5) of belonging to the LMC. Marginalising 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 1011M⊙. 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.

  19. Sonderverfahren des Spritzgießens

    NASA Astrophysics Data System (ADS)

    Michaeli, Walther; Lettowsky, Christoph

    Das Spritzgießen ist neben der Extrusion das wichtigste Verarbeitungsverfahren für Kunststoffe [1]. Das Verfahren hat sich seit seinen Ursprüngen Ende des 19. Jahrhunderts bis heute stetig weiterentwickelt [2]. In neuerer Zeit steigt die Anzahl komplexer Anwendungen, die die gezielte Kombination verschiedener Funktionalitäten in einem Formteil erfordern. Das Standard-Spritzgießen kann diese Anforderungen immer weniger befriedigen. Daher gewinnen die Sonderverfahren des Spritzgießens zunehmend an Bedeutung [3]. Ihre Anzahl beträgt inzwischen über 100. Die Aufgabe des Anwenders ist es, aus der Vielzahl der möglichen Verfahren, ein anforderungsgerechtes auszuwählen, das sowohl unter technischen wie wirtschaftlichen Gesichtspunkten die optimale Lösung darstellt. Dies setzt die ständige Auseinandersetzung mit Entwicklungstendenzen im Bereich der Spritzgießtechnologie voraus. Daher soll im folgenden Abschnitt ein Überblick über die wichtigsten Spritzgieß-Sonderverfahren gegeben werden.

  20. 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

  1. 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.

  2. 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).

  3. Choice of DES: is there a difference?

    PubMed Central

    Kaul, U; Bhatia, V

    2009-01-01

    Restenosis after percutaneous coronary interventions has been a major limitation of this otherwise very well-accepted method of coronary revascularisation. Coronary stents work by scaffolding the intimal flaps and preventing elastic recoil, which was a major problem after balloon angioplasty. The neointimal growth response to stenting contributes significantly to the restenotic process. Randomised studies comparing coronary artery bypass surgery with coronary stenting especially in multivessel disease clearly highlighted this problem. The problem has been greater in magnitude in special subgroups: diabetics, patients with small vessels (≤2.5 mm in diameter), long segments of disease (≥20 mm in length), etc. These limitations of Bare metal stents have been addressed by drug-eluting stents (DESs). Third-generation stents with bioabsorbable polymers like the Biolimus releasing Biomatrix stent have already become available in Europe and parts of Asia. A longer follow-up will prove their long-term safety vis-à-vis first-generation DES. The polymer-free stent with capability of using more than one drug, though very attractive, needs larger multicentric studies before gaining wider acceptance. The fully bioabsorbable stent is yet another promising concept. The feasibility has already been demonstrated, and finer refinements are under way. The future of newer DES thus is very promising, and most of the issues related to first-generation DES are at the threshold of being solved.

  4. 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

  5. Sécurité au-delà des mythes et des croyances

    ScienceCinema

    None

    2011-10-06

    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 ?

  6. 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.

  7. 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

  8. TERT Promoter Mutations in Thyroid Cancer.

    PubMed

    Alzahrani, Ali S; Alsaadi, Rawan; Murugan, Avaniyapuram Kannan; Sadiq, Bakr Bin

    2016-06-01

    Two mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) have recently been described in different types of cancer including follicular cell-derived thyroid cancer (TC). In this paper, we reviewed the rates of these mutations in different types and subtypes of TC, their association with a number of clinical and histopathological features and outcome of TC, and their potential diagnostic and prognostic roles in TC. The overall rate of these mutations in TC is about 14 % with least prevalence in the well-differentiated subtypes of papillary thyroid cancer (10-13 %). Their rates increase significantly with increasing aggressiveness of TC reaching about 40 % in the undifferentiated and anaplastic thyroid cancers. There is also clear association with increasing age of patients at the time of diagnosis of TC. The evidence is compelling but with some conflicting results for associations between TERT promoter mutations and tumor size, extrathyroidal invasion, distant metastases, high tumor TNM stage, BRAF (V600E) mutation, recurrence, and mortality. A couple of studies reported a potential diagnostic role for TERT promoter mutations in thyroid nodules with indeterminate cytology of fine needle aspiration biopsy. These studies showed 100 % specificity but very low sensitivity of 7-10 %. The sensitivity increases significantly when TERT promoter mutation testing is combined with other gene mutations, particularly BRAF (V600E) and RAS mutations. Although TERT promoter mutations seem to play significant roles in the pathogenesis of TC, the mechanisms by which they contribute to carcinogenesis remain elusive and future work is needed to fully assess the roles, interactions, and impact of these mutations on the pathogenesis, diagnosis, prognosis, and therapeutics of TC. PMID:26902827

  9. 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

  10. 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

  11. Traitement des fractures des plateaux externes par vissage percutané assisté par arthroscopie

    PubMed Central

    Abouchane, Merouane; Belmoubarik, Amine; Benameur, Hamza; Haddoun, Ahmed Reda; Nechad, Mohammed

    2015-01-01

    Le but de notre étude est d'évaluer les résultats de fractures des plateaux tibiaux externes traitées par ostéosynthèse percutanée assistée par arthroscopie. Dix patients (8 hommes et 2 femmes) de 32 ans en moyenne ont subi cette intervention afin de réparer des fractures des plateaux tibiaux Schatzker I-III. Après avoir appliqué un garrot pneumatique, nous avons réduit et fixé la fracture au moyen de vis cannelées souschondrales. Lésions associées retrouvent deux lésions partielles du ménisque externe ont été retrouvé, traitées par résection partielle. Une orthèse de genou été de mise à but antalgique et protectrice pendant six semaines avec béquillage et interdiction de l'appui pour une durée de douze semaines avec reprise d'appui partiel au delà. La durée d'hospitalisation été d'une moyenne de cinq jours. La rééducation passive a été commence le lendemain de l'intervention et continuait dans chez un kinésithérapeute à la sortie du patient du service. Le suivi été à J7, J15, 1mois, 3mois, 6 mois puis tous les 6 mois. Neuf de nos patients ont été revu régulièrement sauf un perdu de vue. Le recul moyen de notre série été de 16 mois (10 et 24 mois). Le score de Lysholm a été utilisé pour évaluer les résultats cliniques chez nos neuf patients: excellent chez trois patients bons chez trois moyen chez un seul et mauvais chez deux patients. Tous nos neuf patients ont consolidé (figure 10 contrôle scopique d un article). Aucune gonarthrose n'a été note chez nos neuf patients due essentiellement au recul moyen faible de 16 mois. Le traitement des fractures des plateaux tibiaux externes assisté par arthroscopie produit des résultats satisfaisants et peut être accepté comme solution de rechange efficace au traitement des fractures des plateaux tibiaux causées par un choc de faible énergie. PMID:26587137

  12. 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.

  13. Spectrum of mutations in alpha-mannosidosis.

    PubMed Central

    Berg, T; Riise, H M; Hansen, G M; Malm, D; Tranebjaerg, L; Tollersrud, O K; Nilssen, O

    1999-01-01

    alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first alpha-mannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident. PMID:9915946

  14. Significance of duon mutations in cancer genomes.

    PubMed

    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

  15. Analyzing effects of naturally occurring missense mutations.

    PubMed

    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. Model for Mutation in Bacterial Populations

    NASA Astrophysics Data System (ADS)

    Donangelo, R.; Fort, H.

    2002-07-01

    We describe the evolution of E. coli populations through a Bak-Sneppen-type model which incorporates random mutations. We show that, for a value of the mutation level which coincides with the one estimated from experiments, this model reproduces the measures of mean fitness relative to that of a common ancestor, performed for over 10 000 bacterial generations.

  17. 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. PMID:23934111

  18. 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

  19. 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

  20. Somatic Mutation Favors the Evolution of Diploidy

    PubMed Central

    Orr, H. A.

    1995-01-01

    Explanations of diploidy have focused on advantages gained from masking deleterious mutations that are inherited. Recent theory has shown that these explanations are flawed. Indeed, we still lack any satisfactory explanation of diploidy in species that are asexual or that recombine only rarely. Here I consider a possibility first suggested by EFROIMSON in 1932, by MULLER in 1964 and by CROW and KIMURA in 1965: diploidy may provide protection against somatic, not inherited, mutations. I both compare the mean fitness of haploid and diploid populations that are asexual and investigate the invasion of ``diploidy'' alleles in sexual populations. When deleterious mutations are partially recessive and somatic mutation is sufficiently common, somatic mutation provides a clear advantage to diploidy in both asexual and sexual species. PMID:7768451

  1. Elevated germline mutation rate in teenage fathers.

    PubMed

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

    2015-03-22

    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

  2. Evolution on a Lattice under Strong Mutation

    NASA Astrophysics Data System (ADS)

    Otwinowski, Jakub; Boettcher, Stefan

    2011-03-01

    The most common approach to study biological evolution in a population considers mutations to arise one at a time, and spread to the whole population. However, recent experimental work has shown that under conditions of strong mutation and strong selection, multiple mutations may arise simultaneously. Such overlapping mutations compete with each other and make the results difficult to analyse. Theorists are working on understanding the relationships between different parameters such as population size, mutation rate, and selection coefficients, in the way they affect observables such as the speed of evolution, and the probability of fixation. We have shown with simulations that under additional spatial constraints the dynamics are very different compared to well-mixed populations. A surface in fitness space evolves, akin to surface growth phenomena, with non-trivial power-law exponents. The result is that the speed of evolution is restricted and the probability of fixation is reduced. With support from the NSF through grant DMR-0812204.

  3. The mutation spectrum in RECQL4 diseases

    PubMed Central

    Siitonen, H Annika; Sotkasiira, Jenni; Biervliet, Martine; Benmansour, Abdelmadjid; Capri, Yline; Cormier-Daire, Valerie; Crandall, Barbara; Hannula-Jouppi, Katariina; Hennekam, Raoul; Herzog, Denise; Keymolen, Kathelijn; Lipsanen-Nyman, Marita; Miny, Peter; Plon, Sharon E; Riedl, Stefan; Sarkar, Ajoy; Vargas, Fernando R; Verloes, Alain; Wang, Lisa L; Kääriäinen, Helena; Kestilä, Marjo

    2009-01-01

    Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund–Thomson (RTS), RAPADILINO and Baller–Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data. PMID:18716613

  4. The mutation spectrum in RECQL4 diseases.

    PubMed

    Siitonen, H Annika; Sotkasiira, Jenni; Biervliet, Martine; Benmansour, Abdelmadjid; Capri, Yline; Cormier-Daire, Valerie; Crandall, Barbara; Hannula-Jouppi, Katariina; Hennekam, Raoul; Herzog, Denise; Keymolen, Kathelijn; Lipsanen-Nyman, Marita; Miny, Peter; Plon, Sharon E; Riedl, Stefan; Sarkar, Ajoy; Vargas, Fernando R; Verloes, Alain; Wang, Lisa L; Kääriäinen, Helena; Kestilä, Marjo

    2009-02-01

    Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data. PMID:18716613

  5. On the Specificity of Adaptive Mutations

    PubMed Central

    Hall, B. G.

    1997-01-01

    Adaptive mutations are mutations that occur in nondividing or slowly dividing cells during prolonged nonlethal selection, and that appear to be specific to the challenge of the selection in the sense that the only mutations that arise are those that provide a growth advantage to the cell. The issue of the specificity has been controversial because it violates our most basic assumptions about the randomness of mutations with respect to their effect on the cell. Although a variety of experiments in several systems in both bacteria and yeast have claimed to demonstrate that specificity, those experiments have been subjected to a variety of technical criticisms suggesting that the specificity may not be real. Here I use the ebg system to provide evidence that when selection is applied to one specific nucleotide site within a gene, mutation occurs at that site but not at an alternative and equally mutable site within the same gene. PMID:9017388

  6. 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

  7. 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

  8. 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/ . PMID:26503432

  9. The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: a New Online Resource

    PubMed Central

    Payne, Amanda B.; Miller, Connie H.; Kelly, Fiona M.; Soucie, J. Michael; Hooper, W. Craig

    2015-01-01

    Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports. PMID:23280990

  10. 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

  11. The missing puzzle piece: splicing mutations

    PubMed Central

    Lewandowska, Marzena A

    2013-01-01

    Proper gene splicing is highly dependent on the correct recognition of exons. Among the elements allowing this process are the “cis” (conserved sequences) and “trans” (snRNP, splicing factors) elements. Splicing mutations are related with a number of genetic disorders and usually induce exon skipping, form new exon/intron boundaries or activate new cryptic exons as a result of alterations at donor/acceptor sites. They constitute more than 9% of the currently published mutations, but this value is highly underestimated as many of the potential mutations are located in the “cis” elements and should be confirmed experimentally. The most commonly detected splicing mutations are located at donor (5’) and acceptor (3’) sites. Mutations at the branch point are rare (only over a dozen are known to date), and are mostly searched and detected when no alteration has been detected in the sequenced exons and UTRs. Polypyrimidine tract mutations are equally rare. High throughput technologies, as well as traditional Sanger sequencing, allow detection of many changes in intronic sequences and intron/exon boundaries. However, the assessment whether a mutation affects exon recognition and results in a genetic disorder has to be conducted using molecular biology methods: in vitro transcription of the sequence of interest cloned into a plasmid, with and without alterations, or mutation analysis via a hybrid minigene system. Even though microarrays and new generation sequencing methods pose difficulties in detecting novel branch point mutations, these tools seem appropriate to expand the mutation detection panel especially for diagnostic purposes. PMID:24294354

  12. Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations

    PubMed Central

    Wetterskog, Daniel; Wilkerson, Paul M; Rodrigues, Daniel N; Lambros, Maryou B; Fritchie, Karen; Andersson, Mattias K; Natrajan, Rachael; Gauthier, Arnaud; Di Palma, Silvana; Shousha, Sami; Gatalica, Zoran; Töpfer, Chantal; Vukovic, Vesna; A’Hern, Roger; Weigelt, Britta; Vincent-Salomon, Anne; Stenman, Göran; Rubin, Brian P; Reis-Filho, Jorge S

    2016-01-01

    Aims The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB–NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs. Methods and results DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.0. Genes found to be mutated in any of the breast AdCCs and genes related to the same canonical molecular pathways, as well as KIT, a proto-oncogene whose protein product is expressed in AdCCs, were sequenced in an additional 68 AdCCs from various anatomical sites by Sanger sequencing. Using the Sequenom MassARRAY platform and Sanger sequencing, mutations in BRAF and HRAS were identified in three and one cases, respectively (breast, and head and neck). KIT, which has previously been reported to be mutated in AdCCs, was also investigated, but no mutations were identified. Conclusions Our results demonstrate that mutations in genes pertaining to the canonical RAS pathway are found in a minority of AdCCs, and that activating KIT mutations are either absent or remarkably rare in these cancers, and unlikely to constitute a driver and therapeutic target for patients with AdCC. PMID:23398044

  13. Novel EGFR mutation specific antibodies for NSCLC: Immunohistochemistry as a possible screening method for EGFR mutations

    PubMed Central

    Kato, Yasufumi; Peled, Nir; Wynes, Murry W.; Yoshida, Koichi; Pardo, Marta; Mascaux, Celine; Ohira, Tatsuo; Tsuboi, Masahiro; Matsubayashi, Jun; Nagao, Toshitaka; Ikeda, Norihiko; Hirsch, Fred R.

    2010-01-01

    Background Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors (TKIs). The most common mutations are exon 19 deletions (most frequently E746-A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation specific antibodies in a Japanese cohort with NSCLC and compared to direct DNA sequencing and clinical outcome. Materials and methods Immunohistochemistry (IHC) using antibodies specific for the E746-A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results DNA sequencing showed EGFR mutations in 41 patients (58.6%), and exon 19 deletions in 18 patients (25.7%), 61% (11/18) had a deletion in the range of E746-A750) and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746-A750 and L858R mutations, sensitivity (81.8% and 75%), specificity (100%, 96.6%), PPV (100%, 81.8%) and NPV (96.7%, 94.9%). Analysis for objective response rates (ORR) and survival were not correlated to IHC staining, although the combined staining showed non-significant trends towards better overall survival for patients with EGFR mutations. Conclusions The mutation specific IHC antibodies have high sensitivity and specificity for pre-defined EFGR mutations and may be suitable for screening for these pre-defined mutations. However, negative IHC results require further mutation analyses prior to excluding EGFR-targeted therapy. PMID:20697298

  14. 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.

  15. 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.

  16. Peste des Petits Ruminants Virus in Heilongjiang Province, China, 2014

    PubMed Central

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

    2015-01-01

    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

  17. Seventeen novel mutations that cause profound biotinidase deficiency.

    PubMed

    Wolf, B; Jensen, K; Hüner, G; Demirkol, M; Baykal, T; Divry, P; Rolland, M-O; Perez-Cerdá, C; Ugarte, M; Straussberg, R; Basel-Vanagaite, L; Baumgartner, E R; Suormala, T; Scholl, S; Das, A M; Schweitzer, S; Pronicka, E; Sykut-Cegielska, J

    2002-01-01

    We report 17 novel mutations that cause profound biotinidase deficiency. Six of the mutations are due to deletions, whereas the remaining 11 mutations are missense mutations located throughout the gene and encode amino acids that are conserved in mammals. Our results increase the total number of different mutations that cause biotinidase deficiency to 79. These additional mutations will undoubtedly be helpful in identifying structure/function relationships once the three-dimensional structure of biotinidase is determined. PMID:12359137

  18. Altération des sulfures des granulats dans les chaussées

    NASA Astrophysics Data System (ADS)

    Jigorel, A.; Jauberthie, R.

    2002-07-01

    Sulfides present in hornsfeld aggregates, used in light pavanent construction in contact with humid air alter rapidly. Crystallisation of sulfates at the interface of bitumastic material and sub-base creates serious problems (intumescence and crazing) that can lead to a total reconstruction of the project (roads, sidewalks, sports areas, etc). The sulfides in the aggregates and the sulfates produced due to alteration are studied by SEM and XRD. The results show that the intensity of this phenomenon is linked to the nature and the crystallinity of the sulfides. The evolution of the sulfates formed during this alteration process is slow and complex. In new pavements (3 years) the sulfates have a pulverised appearance and consist mostly of epsomite, associated with pickeringite and halotrichite. In older pavements (20 years) the sulfates form a fibrous concretion consisting of pickeringite and small quantities of halotrichite. Les sulfures présents dans les granulats élaborés à partir de cornéen nes s'altèrent rapidement dans les chaussées légères en présence d'air humide. La cristallisation des sulfates à l'interface enrobé-couche de fondation crée des désordres si importants (intumescences, faiençage) qu'il est bien souvent nécessaire d'assurer la réfection totale des ouvrages (routes, trottoirs, plateaux sportifs...). Les sulfures des granulats et les sulfates issus du processus d'altération ont été étudiés par diffractométrie X et examen su Microscope Electronique à Balayage équipé de microanalyse X. Les résultats montrent que !intensité des désordres est liée à la nature et à la cristallinité des sulfures. Les sulfates formés évoluent su cours du processus d'altération qui est long et complexe. Dans les chaussées récentes (3 ans) ils ont un aspect pulvérulent et sont constitués d'epsomite dominante associée à de la pickeringite et à de l'halotrichite. Dans les chaussées plus anciennes (20 ans) ils forment des concr

  19. Benchmarking infrastructure for mutation text mining

    PubMed Central

    2014-01-01

    Background Experimental research on the automatic extraction of information about mutations from texts is greatly hindered by the lack of consensus evaluation infrastructure for the testing and benchmarking of mutation text mining systems. Results We propose a community-oriented annotation and benchmarking infrastructure to support development, testing, benchmarking, and comparison of mutation text mining systems. The design is based on semantic standards, where RDF is used to represent annotations, an OWL ontology provides an extensible schema for the data and SPARQL is used to compute various performance metrics, so that in many cases no programming is needed to analyze results from a text mining system. While large benchmark corpora for biological entity and relation extraction are focused mostly on genes, proteins, diseases, and species, our benchmarking infrastructure fills the gap for mutation information. The core infrastructure comprises (1) an ontology for modelling annotations, (2) SPARQL queries for computing performance metrics, and (3) a sizeable collection of manually curated documents, that can support mutation grounding and mutation impact extraction experiments. Conclusion We have developed the principal infrastructure for the benchmarking of mutation text mining tasks. The use of RDF and OWL as the representation for corpora ensures extensibility. The infrastructure is suitable for out-of-the-box use in several important scenarios and is ready, in its current state, for initial community adoption. PMID:24568600

  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. 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.

  2. The mutation process in colored coalescent theory.

    PubMed

    Tian, Jianjun Paul; Lin, Xiao-Song

    2009-11-01

    The mutation process is introduced into the colored coalescent theory. The mutation process can be viewed as an independent Poisson process running on the colored genealogical random tree generated by the colored coalescent process, with the edge lengths of the random tree serving as the time scale for the mutation process. Moving backward along the colored genealogical tree, the color of vertices may change in two ways, when two vertices coalesce, or when a mutation happens. The rule that governs the coalescent change of color involves a parameter x; the rule that governs the mutation involves a parameter micro. Explicit computations of the expectation of the coalescent time (the first hitting time), and the coalescent probabilities (the first hitting probabilities) are carried out. For example, our calculation shows that when x = 1/2, for a sample of n colored individuals, the expected time for the colored coalescent process with the mutation process superimposed to first reach a black MRCA or a white MRCA, respectively, is 3 -- 2/n with probability 1/2 for any value of the parameter micro. On the other hand, the expected time for the colored coalescent process with mutation to first reach a MRCA, either black or white, is 2 -- 2/n for any values of the parameters micro and x, which is the same as that for the standard Kingman coalescent process. PMID:19462210

  3. 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

  4. 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.

  5. Mutational Analysis of TARDBP in Neurodegenerative Diseases

    PubMed Central

    Ticozzi, Nicola; LeClerc, Ashley Lyn; Van-Blitterswijk, Marka; Keagle, Pamela; McKenna-Yasek, Diane M.; Sapp, Peter C.; Silani, Vincenzo; Wills, Anne-Marie; Brown, Robert H.; Landers, John E.

    2010-01-01

    Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in Amyotrophic Lateral Sclerosis (ALS), but has also been observed in Alzheimer's (AD) and Parkinson's Diseases (PD). In addition, mutations in the TARDBP gene, encoding TDP-43, have been found to be a significant cause of familial ALS (FALS). All mutations, except for one, have been found in exon 6. To confirm this observation in ALS and to investigate whether TARDBP may play a role in the pathogenesis of AD and PD, we screened for mutations in exon 6 of the TARDBP gene in three cohorts composed of 376 AD, 463 PD (18% familial PD) and 376 ALS patients (50% FALS). We found mutations in ∼7% of FALS and ∼0.5% of sporadic ALS (SALS) patients, including two novel mutations, p.N352T and p.G384R. In contrast, we did not find TARDBP mutations in our cohort of AD and PD patients. These results suggest that mutations in TARDBP are not a significant cause of AD and PD. PMID:20031275

  6. 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. PMID:25256313

  7. 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

  8. Hemophilia B: Molecular Pathogenesis and Mutation Analysis

    PubMed Central

    Goodeve, Anne C.

    2015-01-01

    Summary Hemophilia B is an X-chromosome-linked inherited bleeding disorder primarily affecting males, while those carrier females having reduced factor IX:C levels may also experience some bleeding issues. Genetic analysis has been undertaken for hemophilia B since the mid-1980s, both through linkage analysis to track inheritance of an affected allele and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in more than 97% of hemophila B patients. Risk of inhibitory antibodies, reported in ~2% of hemophilia B patients can be predicted, especially in patients with large deletions and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally with small insertions/deletions, splice mutations and rarely with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently "silent" changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders including hemophilia B are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity whilst a growing range of algorithms is available to help predict pathogenicity for previously unreported variants. PMID:25851415

  9. The mutational landscape of adenoid cystic carcinoma.

    PubMed

    Ho, Allen S; Kannan, Kasthuri; Roy, David M; Morris, Luc G T; Ganly, Ian; Katabi, Nora; Ramaswami, Deepa; Walsh, Logan A; Eng, Stephanie; Huse, Jason T; Zhang, Jianan; Dolgalev, Igor; Huberman, Kety; Heguy, Adriana; Viale, Agnes; Drobnjak, Marija; Leversha, Margaret A; Rice, Christine E; Singh, Bhuvanesh; Iyer, N Gopalakrishna; Leemans, C Rene; Bloemena, Elisabeth; Ferris, Robert L; Seethala, Raja R; Gross, Benjamin E; Liang, Yupu; Sinha, Rileen; Peng, Luke; Raphael, Benjamin J; Turcan, Sevin; Gong, Yongxing; Schultz, Nikolaus; Kim, Seungwon; Chiosea, Simion; Shah, Jatin P; Sander, Chris; Lee, William; Chan, Timothy A

    2013-07-01

    Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC. PMID:23685749

  10. Mitochondrial DNA mutations and breast tumorigenesis

    PubMed Central

    Yadav, Neelu; Chandra, Dhyan

    2013-01-01

    Breast cancer is a heterogeneous disease and genetic factors play an important role in its genesis. Although mutations in tumor suppressors and oncogenes encoded by the nuclear genome are known to play a critical role in breast tumorigenesis, the contribution of the mitochondrial genome to this process is unclear. Like the nuclear genome, the mitochondrial genome also encodes proteins critical for mitochondria functions such as oxidative phosphorylation (OXPHOS), which is known to be defective in cancer including breast cancer. Due to limited repair mechanisms compared to that for nuclear DNA (nDNA), mitochondrial DNA (mtDNA) is more susceptible to mutations. Thus changes in mitochondrial genes could also contribute to the development of breast cancer. In this review we discuss mtDNA mutations that affect OXPHOS. Continuous acquisition of mtDNA mutations and selection of advantageous mutations ultimately leads to generation of cells that propagate uncontrollably to form tumors. Since irreversible damage to OXPHOS leads to a shift in energy metabolism towards enhanced aerobic glycolysis in most cancers, mutations in mtDNA represent an early event during breast tumorigenesis, and thus may serve as potential biomarkers for early detection and prognosis of breast cancer. Because mtDNA mutations lead to defective OXPHOS, development of agents that target OXPHOS will provide specificity for preventative and therapeutic agents against breast cancer with minimal toxicity. PMID:24140413

  11. Inherited cardiomyopathies caused by troponin mutations

    PubMed Central

    Lu, Qun-Wei; Wu, Xiao-Yan; Morimoto, Sachio

    2013-01-01

    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy. PMID:23610579

  12. CFTR mutations in the Algerian population.

    PubMed

    Loumi, O; Ferec, C; Mercier, B; Creff, J; Fercot, B; Denine, R; Grangaud, J P

    2008-01-01

    The nature and frequency of the major CFTR mutations in the North African population remain unclear, although a small number of CFTR mutation detection studies have been done in Algeria and Tunisia, showing largely European mutations such as F508del, G542X and N1303K, albeit at different frequencies, which presumably emerged via population admixture with Caucasians. Some unique mutations were identified in these populations. This is the first study that includes a genetic and clinical evaluation of CF patients living in Algeria. In order to offer an effective diagnostic service and to make accurate risk estimates, we decided to identify the CFTR mutations in 81 Algerian patients. We carried out D-HPLC, chemical-clamp denaturing gradient gel electrophoresis, multiplex amplification analysis of the CFTR gene and automated direct DNA sequencing. We identified 15 different mutations which account for 58.5% of the CF chromosomes. We used a quantitative PCR technique (quantitative multiplex PCR short fragment fluorescence analysis) to screen for deletion/duplication in the 27 exons of the gene. Taking advantage of the homogeneity of the sample, we report clinical features of homozygous CF patients. As CFTR mutations have been detected in males with infertility, 46 unrelated Algerian individuals with obstructive azoospermia were also investigated. PMID:17572159

  13. Mutational Robustness of Gene Regulatory Networks

    PubMed Central

    van Dijk, Aalt D. J.; van Mourik, Simon; van Ham, Roeland C. H. J.

    2012-01-01

    Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor – target gene interactions) but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive). In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence. PMID:22295094

  14. 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

  15. 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.

  16. Fissuration en relaxation des aciers inoxydables austénitiques au voisinage des soudures

    NASA Astrophysics Data System (ADS)

    Auzoux, Q.; Allais, L.; Gourgues, A. F.; Pineau, A.

    2003-03-01

    Des fissures intergranulaires peuvent se développer au voisinage des soudures des aciers inoxydables austénitiques lorsqu'ils sont réchauffés dans le domaine de température compris entre 500^{circ}C et 700^{circ}C. A ces températures, les contraintes résiduelles post-soudage se relaxent par déformation viscoplastique. Il peut arriver que ces zones proches de la soudure soient tellement fragiles, qu'elles ne puissent accommoder cette faible déformation. Afin de préciser quelles peuvent être les modifications microstructurales qui conduisent à une telle fragilisation, on a examiné les microstructures de ces zones et révélé ainsi un écrouissage résiduel, responsable d'une forte élévation de la dureté. On a pu reproduire par hypertrempe puis laminage entre 400^{circ}C et 600^{circ}C une microstructure similaire. Des essais mécaniques (traction, fluage, relaxation, sur éprouvettes lisses et pré-fissurées) ont été réalisés à 550^{circ}C et à 600^{circ}C sur ces zones affectées simulées et sur un état de référence hypertrempé. Ils ont montré que l'écrouissage diminuait la ductilité dans le domaine de rupture intergranulaire, sans modifier qualitativement le mécanisme d'endommagement. Pendant la pré-déformation les incompatibilités de déformation entre grains conduiraient à l'existence de contraintes locales élevées qui favoriseraient la germination des cavités intergranulaires.

  17. TERT promoter mutations in melanoma survival.

    PubMed

    Nagore, Eduardo; Heidenreich, Barbara; Rachakonda, Sívaramakrishna; Garcia-Casado, Zaida; Requena, Celia; Soriano, Virtudes; Frank, Christoph; Traves, Victor; Quecedo, Esther; Sanjuan-Gimenez, Josefa; Hemminki, Kari; Landi, Maria Teresa; Kumar, Rajiv

    2016-07-01

    Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter. PMID:26875008

  18. 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.

  19. 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

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

    PubMed

    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

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. Pharmacogenomics: mapping monogenic mutations to direct therapy.

    PubMed

    Taylor, Palmer

    2012-07-01

    The molecular mapping of mutations that underlie congenital disorders of monogenic origin can result in both a broader understanding of the molecular basis of the disorder and novel therapeutic insights. Indeed, genotyping patients and then replicating the behavior of the mutant gene products in well-defined biochemical or electrophysiological systems will allow tailoring of therapy to be mutation- and protein sequence-dependent. In this issue of the JCI, Shen and colleagues describe such an approach that identified novel mutations in the α subunit of the nicotinic receptor linked to myasthenia gravis. PMID:22728931

  6. Le traitement familial des enfants et des adolescents anorexiques : Des lignes directrices pour le médecin communautaire

    PubMed Central

    Findlay, S; Pinzon, J; Taddeo, D; Katzman, DK

    2010-01-01

    L’anorexie mentale (AM) est une maladie grave qui met la vie en danger et qui fait généralement son apparition pendant l’adolescence. Les données probantes au sujet du traitement optimal de l’AM chez les enfants et les adolescents sont en croissance, mais il reste beaucoup à apprendre. Même si les démarches thérapeutiques actuelles varient au Canada et ailleurs, les données jusqu’à présent indiquent que le traitement familial (TF) est le plus efficace pour les enfants et les adolescents anorexiques. Un élément essentiel du modèle de TF, c’est que les parents sont investis de la responsabilité de rétablir la santé physique de leur enfant et de s’assurer de la reprise complète de son poids. Le médecin qui comprend les principes fondamentaux et la philosophie du TF peut mettre en place les éléments de cette intervention fondée sur des faits probants auprès des jeunes patients anorexiques et de leur famille.

  7. 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.

  8. Ivacaftor: A Novel Mutation Modulating Drug

    PubMed Central

    Koolwal, Astha; Singh, Ankur

    2014-01-01

    Cystic fibrosis (CF) is multisystemic disorder presenting in newborn period to adulthood, predominantly affecting respiratory system. It is caused by mutation in CF transmembrane conductance regulator gene. ΔF508 is the most common mutation seen worldwide. Supportive management with bronchodilators, anti-inflammatory, mucolytics, antibiotics are the corner stone of therapy. Mutation specific drug, Ivacaftor, was recently approved USFDA in January 2012 for patients carrying G551D mutation. It is approved in patients who are six years and older in 150 mg twice daily dosing schedule with fat containing meals. It improves the lung function and other aspects of disease including weight gain. The side effects like upper respiratory infection, headache, rash, diarrhoea, stomach ache and dizziness are mild and self-limiting. This is excellent example of promise of personalised medicine – targeted drug that treat patients with specific genetic makeup. PMID:25584290

  9. IFITM5 mutations and osteogenesis imperfecta.

    PubMed

    Hanagata, Nobutaka

    2016-03-01

    Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed. PMID:26031935

  10. Ribosomal Mutations in Streptococcus pneumoniae Clinical Isolates

    PubMed Central

    Pihlajamäki, Marja; Kataja, Janne; Seppälä, Helena; Elliot, John; Leinonen, Maija; Huovinen, Pentti; Jalava, Jari

    2002-01-01

    Eleven clinical isolates of Streptococcus pneumoniae, isolated in Finland during 1996 to 2000, had an unusual macrolide resistance phenotype. They were resistant to macrolides and streptogramin B but susceptible, intermediate, or low-level resistant to lincosamides. No acquired macrolide resistance genes were detected from the strains. The isolates were found to have mutations in domain V of the 23S rRNA or ribosomal protein L4. Seven isolates had an A2059C mutation in two to four out of the four alleles encoding the 23S rRNA, two isolates had an A2059G mutation in two alleles, one isolate had a C2611G mutation in all four alleles, and one isolate had a 69GTG71-to-69TPS71 substitution in ribosomal protein L4. PMID:11850244

  11. 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 ...

  12. Selection for mutational robustness in finite populations.

    PubMed

    Forster, Robert; Adami, Christoph; Wilke, Claus O

    2006-11-21

    We investigate the evolutionary dynamics of a finite population of RNA sequences replicating on a neutral network. Despite the lack of differential fitness between viable sequences, we observe typical properties of adaptive evolution, such as increase of mean fitness over time and punctuated-equilibrium transitions, after initial mutation-selection balance has been reached. We find that a product of population size and mutation rate of approximately 30 or larger is sufficient to generate selection pressure for mutational robustness, even if the population size is orders of magnitude smaller than the neutral network on which the population resides. Our results show that quasispecies effects and neutral drift can occur concurrently, and that the relative importance of each is determined by the product of population size and mutation rate. PMID:16901510

  13. 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

  14. 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

  15. 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

  16. Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies.

    PubMed

    Bär, Harald; Goudeau, Bertrand; Wälde, Sarah; Casteras-Simon, Monique; Mücke, Norbert; Shatunov, Alexey; Goldberg, Y Paul; Clarke, Charles; Holton, Janice L; Eymard, Bruno; Katus, Hugo A; Fardeau, Michel; Goldfarb, Lev; Vicart, Patrick; Herrmann, Harald

    2007-04-01

    Myofibrillar myopathy (MFM) encompasses a genetically heterogeneous group of human diseases caused by mutations in genes coding for structural proteins of muscle. Mutations in the intermediate filament (IF) protein desmin (DES), a major cytoskeletal component of myocytes, lead to severe forms of "desminopathy," which affects cardiac, skeletal, and smooth muscle. Most mutations described reside in the central alpha-helical rod domain of desmin. Here we report three novel mutations--c.1325C>T (p.T442I), c.1360C>T (p.R454W), and c.1379G>T (p.S460I)--located in desmin's non-alpha-helical carboxy-terminal "tail" domain. We have investigated the impact of these and four--c.1237G>A (p.E413K), c.1346A>C (p.K449T), c.1353C>G (p.I451M), and c.1405G>A (p.V469M)--previously described "tail" mutations on in vitro filament formation and on the generation of ordered cytoskeletal arrays in transfected myoblasts. Although all but two mutants (p.E413K, p.R454W) assembled into IFs in vitro and all except p.E413K were incorporated into IF arrays in transfected C2C12 cells, filament properties differed significantly from wild-type desmin as revealed by viscometric assembly assays. Most notably, when coassembled with wild-type desmin, these mutants revealed a severe disturbance of filament-formation competence and filament-filament interactions, indicating an inherent incompatibility of mutant and wild-type protein to form mixed filaments. The various clinical phenotypes observed may reflect altered interactions of desmin's tail domain with different components of the myoblast cytoskeleton leading to diminished biomechanical properties and/or altered metabolism of the individual myocyte. Our in vitro assembly regimen proved to be a very sensible tool to detect if a particular desmin mutation is able to cause filament abnormalities. PMID:17221859

  17. [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

  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. Mutation specific immunohistochemistry is highly specific for the presence of calreticulin mutations in myeloproliferative neoplasms.

    PubMed

    Andrici, Juliana; Farzin, Mahtab; Clarkson, Adele; Sioson, Loretta; Sheen, Amy; Watson, Nicole; Toon, Christopher W; Koleth, Mary; Stevenson, William; Gill, Anthony J

    2016-06-01

    The identification of somatic calreticulin (CALR) mutations can be used to confirm the diagnosis of a myeloproliferative disorder in Philadelphia chromosome-negative, JAK2 and MPL wild type patients with thrombocytosis. All pathogenic CALR mutations result in an identical C-terminal protein and therefore may be identifiable by immunohistochemistry. We sought to test the sensitivity and specificity of mutation specific immunohistochemistry for pathogenic CALR mutations using a commercially available mouse monoclonal antibody (clone CAL2). Immunohistochemistry for mutant calreticulin was performed on the most recent bone marrow trephine from a cohort of patients enriched for CALR mutations and compared to mutation testing performed by polymerase chain reaction (PCR) amplification followed by fragment length analysis. Twenty-nine patients underwent both immunohistochemistry and molecular testing. Eleven patients had CALR mutation, and immunohistochemistry was positive in nine (82%). One discrepant case appeared to represent genuine false negative immunohistochemistry. The other may be attributable to a 12 year delay between the bone marrow trephine and the specimen which underwent molecular testing, particularly because a liver biopsy performed at the same time as molecular testing demonstrated positive staining in megakaryocytes in extramedullary haematopoiesis. All 18 cases which lacked CALR mutation demonstrated negative staining. In this population enriched for CALR mutations, the specificity was 100%; sensitivity 82-91%, positive predictive value 100% and negative predictive value 90-95%. We conclude that mutation specific immunohistochemistry is highly specific for the presence of CALR mutations. Whilst it may not identify all mutations, it may be very valuable in routine clinical care. PMID:27114372

  20. BRAF MUTATIONS IN HAIRY CELL LEUKEMIA

    PubMed Central

    Tiacci, Enrico; Trifonov, Vladimir; Schiavoni, Gianluca; Holmes, Antony; Kern, Wolfgang; Martelli, Maria Paola; Pucciarini, Alessandra; Bigerna, Barbara; Pacini, Roberta; Wells, Victoria; Sportoletti, Paolo; Pettirossi, Valentina; Mannucci, Roberta; Elliott, Oliver; Liso, Arcangelo; Ambrosetti, Achille; Pulsoni, Alessandro; Forconi, Francesco; Trentin, Livio; Semenzato, Gianpietro; Inghirami, Giorgio; Capponi, Monia; Di Raimondo, Francesco; Patti, Caterina; Arcaini, Luca; Musto, Pellegrino; Pileri, Stefano; Haferlach, Claudia; Schnittger, Susanne; Pizzolo, Giovanni; Foà, Robin; Farinelli, Laurent; Haferlach, Torsten; Pasqualucci, Laura; Rabadan, Raul; Falini, Brunangelo

    2013-01-01

    Background Hairy cell leukemia (HCL) is a well defined clinico-pathological entity whose underlying genetic lesion is still obscure. Methods We searched for HCL-associated mutations by massively parallel sequencing of the whole exome of leukemic and matched normal mononuclear cells purified from the peripheral blood of one patient with HCL. Results Whole exome sequencing identified 5 missense somatic clonal mutations that were confirmed at Sanger sequencing, including a heterozygous V600E mutation involving the BRAF gene. Since the BRAF V600E mutation is oncogenic in other tumors, further analyses were focused on this genetic lesion. Sanger sequencing detected mutated BRAF in 46/46 additional HCL patients (47/47 including the index case; 100%). None of the 193 peripheral B-cell lymphomas/leukemias other than HCL that were investigated carried the BRAF V600E mutation, including 36 cases of splenic marginal zone lymphomas and unclassifiable splenic lymphomas/leukemias. Immunohistological and Western blot studies showed that HCL cells express phospho-MEK and phospho-ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic cells from 5 HCL patients with PLX-4720, a specific inhibitor of active BRAF, led to marked decrease of phosphorylated ERK and MEK. Conclusions The BRAF V600E mutation was present in all HCL patients investigated. This finding may have relevant implications for the pathogenesis, diagnosis and targeted therapy of HCL (Funded by the Associazione Italiana Ricerca Cancro and others). PMID:21663470

  1. 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

  2. (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.

  3. Mutation spectra of complex environmental mixtures

    SciTech Connect

    DeMarini, D.M.

    1997-10-01

    Bioassay-directed chemical analysis of complex environmental mixtures has indicated that much of the genotoxic activity of mixtures is due to the presence of one or a few classes or chemicals within the mixture. We have extended this observation to the molecular level by using colony probe hybridization and PCR/DNA sequence analysis to determine the mutation spectra of {approximately}8,000 revertants induced by a variety of complex mixtures and their chemical fractions in TA100 and TA98 of Salmonella. For urban air, >80% of mutagenic activity was due to a base/neutral fraction that contained primarily PAHs. The mutation spectrum induced by unfractionated urban air was not significantly different from that produced by a model PAH, B(a)P. The mutation spectrum induced by organic extracts of chlorinated drinking water were similar to those produced by the chlorinated furanone MX, which accounted for {approximately}20% of the mutagenic activity of the samples. The base/neutral fraction of municipal waste incinerator emissions accounted for the primary class of mutations induced by the emissions, and a polar neutral fraction accounted for the secondary class of mutations induced by the emissions. The primary class of mutations induced by cigarette smoke condensate in TA100 (GC {yields} TA) is also the primary class of mutations in the p53 gene of lung tumors of cigarette smokers. These results confirm at the molecular level that the mutations induced by a complex mixture reflect the dominance of one or a few classes of chemicals within the mixture.

  4. 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

  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. 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.

  7. GJB2 mutations in deaf population of Ilam (Western Iran): a different pattern of mutation distribution.

    PubMed

    Mahdieh, Nejat; Mahmoudi, Hamdollah; Ahmadzadeh, Soleiman; Bakhtiyari, Salar

    2016-05-01

    Hearing loss is the most common sensory defect caused by heterogeneous factors. Up to now, more than 60 mutations in genes have been documented for nonsyndromic hearing loss. Hence, finding the causal gene in affected families could be a laborious and time-consuming process. GJB2 mutations, here, were investigated among deaf subjects of Ilam for the first time. In this study, we studied 62 unrelated patients with non-syndromic autosomal recessive deafness from 62 families. The most common mutation of GJB2, 35delG was checked, followed by direct sequencing of the GJB2 gene for determination of other mutations. In silico analyses were also performed using available software. In nine families, mutations in the connexin 26 gene were observed. In the studied population, R32H was the most common mutation. 35delG, W24X, and R127H were other mutations found in this study. In silico analyses showed pathogenicity of 35delG, R32H, and W24X but not R127H. Low frequency of GJB2 mutations in this population is probably indicative of the fact that other genes may be involved in nonsyndromic hearing loss in Ilam populations. In the other hand, the vicinity of Ilam and Iraq suggests that GJB2 mutations have likely a low frequency in this population. PMID:26059209

  8. RAD21 Mutations Cause a Human Cohesinopathy

    PubMed Central

    Deardorff, Matthew A.; Wilde, Jonathan J.; Albrecht, Melanie; Dickinson, Emma; Tennstedt, Stephanie; Braunholz, Diana; Mönnich, Maren; Yan, Yuqian; Xu, Weizhen; Gil-Rodríguez, María Concepcion; Clark, Dinah; Hakonarson, Hakon; Halbach, Sara; Michelis, Laura Daniela; Rampuria, Abhinav; Rossier, Eva; Spranger, Stephanie; Van Maldergem, Lionel; Lynch, Sally Ann; Gillessen-Kaesbach, Gabriele; Lüdecke, Hermann-Josef; Ramsay, Robert G.; McKay, Michael J.; Krantz, Ian D.; Xu, Huiling; Horsfield, Julia A.; Kaiser, Frank J.

    2012-01-01

    The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a “cohesinopathy.” Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development. PMID:22633399

  9. Early neuropsychological characteristics of progranulin mutation carriers.

    PubMed

    Hallam, Bradley J; Jacova, Claudia; Hsiung, Ging-Yuek R; Wittenberg, Dana; Sengdy, Pheth; Bouchard-Kerr, Phoenix; Slack, Penny; Rademakers, Rosa; Baker, Matthew; Chow, Tiffany W; Levine, Brian; Feldman, Howard H; Mackenzie, Ian R

    2014-08-01

    Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature. PMID:24993774

  10. KIT mutations are common in testicular seminomas.

    PubMed

    Kemmer, Kathleen; Corless, Christopher L; Fletcher, Jonathan A; McGreevey, Laura; Haley, Andrea; Griffith, Diana; Cummings, Oscar W; Wait, Cecily; Town, Ajia; Heinrich, Michael C

    2004-01-01

    Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations in 54 testicular seminomas, 1 ovarian dysgerminoma and 37 non-seminomatous germ cell tumors (NSGCT). Fourteen seminomas (25.9%) contained exon 17 point mutations including D816V (6 cases), D816H (3 cases), Y823D (2 cases), and single examples of Y823C, N822K, and T801I. No KIT mutations were found in the ovarian dysgerminoma or the NSGCTs. In transient transfection assays, mutant isoforms D816V, D816H, Y823D, and N822K were constitutively phosphorylated in the absence of the natural ligand for KIT, stem cell factor (SCF). In contrast, activation of T801I and wild-type KIT required SCF. Mutants N822K and Y823D were inhibited by imatinib mesylate (Gleevec, previously STI571) whereas D816V and D816H were both resistant to imatinib mesylate. Biochemical evidence of KIT activation, as assessed by KIT phosphorylation and KIT association with phosphatidylinositol (PI) 3-kinase in tumor cell lysates, was largely confined to seminomas with a genomic KIT mutation. These findings suggest that activating KIT mutations may contribute to tumorigenesis in a subset of seminomas, but are not involved in NSGCT. PMID:14695343

  11. 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

  12. 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.

  13. OzDES Spectroscopic Classification of DES13X3woy

    NASA Astrophysics Data System (ADS)

    Yuan, F.; Childress, M.; Sharp, R.; Lidman, C.; Parkinson, D.; Mould, J.; Brown, P. J.; Krisciunas, K.; Suntzeff, N.; D'Andrea, C.; Nichol, R.; Papadopoulos, A.; Sullivan, M.; Maartens, R.; Smith, M.; Barbary, K.; Bernstein, J. P.; Biswas, R.; Gupta, R.; Kovacs, E.; Kuhlmann, S.; Spinka, H.; Ahn, E.; Finley, D.; Frieman, J.; Marriner, J.; Wester, W.; Aldering, G.; Bloom, J. S.; Goldstein, D.; Kim, A.; Nugent, P.; Perlmutter, S.; Thomas, R. C.; Foley, R. J.; Desai, S.; Paech, K.; Smith, R. C.; Schubnell, M.; Kessler, R.; Covarrubias, R. A.; Cane, R.; Fischer, J. A.; Gladney, L.; March, M.; Sako, M.

    2014-01-01

    We report spectroscopic classification by OzDES of a supernova discovered by the Dark Energy Survey (ATel #4668). The spectrum (370-885nm) was obtained with the AAOmega Spectrograph (Saunders et al. 2004, SPIE, 5492, 389) and the 2dF fibre positioner at the Anglo-Australian Telescope (AAT). Object classification was performed using superfit (Howell and Wang, 2002, BAAS, 34, 1256), the details of which are reported in the table below.

  14. Prise en compte des ``courants de London'' dans la modélisation des supraconducteurs

    NASA Astrophysics Data System (ADS)

    Bossavit, Alain

    1997-10-01

    A model is given, in variational form, in which volumic “Bean currents”, ruled by Bean's law, and surface “London currents” coexist. This macroscopic model generalizes Bean's one, by appending to the critical density j_c a second parameter, with the dimension of a length, similar to London's depth λ. The one-dimensional version of the model is investigated, in order to link this parameter with the standard observable H-M characteristics On propose un modèle, sous forme variationnelle, associant des “courants de Bean” volumiques, décrits par la loi de Bean, et des “courants de London”, surfaciques. Ce modèle macroscopique généralise celui de Bean, caractérisé par le courant critique j_c, et fait intervenir un second paramètre, homogène à une longueur, analogue au λ de London. La version unidimensionnelle du modèle est étudiée en détail de manière à relier ce paramètre à l'observation des caractéristiques H-M usuelles.

  15. 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 ...

  16. Suppressors of Recb Mutations in Salmonella Typhimurium

    PubMed Central

    Benson, N. R.; Roth, J.

    1994-01-01

    Using a screen that directly assesses transductional proficiency, we have isolated suppressors of recB mutations in Salmonella typhimurium. The alleles of sbcB reported here are phenotypically distinct from those isolated in Escherichia coli in that they restore recombination proficiency (Rec(+)), resistance to ultraviolet light (UV(R)), and mitomycin C resistance (MC(R)) in the absence of an accompanying sbcCD mutation. In addition the sbcB alleles reported here are co-dominant to sbcB(+). We have also isolated insertion and deletion mutants of the sbcB locus. These null mutations suppress only the UV(S) phenotype of recB mutants. We have also isolated sbcCD mutations, which map near proC. These sbcCD mutations increase the viability, recombination proficiency and MC(R) of both the transductional recombination suppressors (sbcB1 & sbcB6) and the sbcB null mutations. S. typhimurium recB sbcB1 sbcCD8 strains are 15-fold more recombination proficient than wild-type strains. The increase in transductants in these strains is accompanied by a loss of abortive transductants suggesting that these fragments are accessible to the mutant recombination apparatus. Using tandem duplications, we have constructed sbcB merodiploids and found that, in a recB mutant sbcCD(+) genetic background, the sbcB(+) allele is dominant to sbcB1 for transductional recombination but co-dominant for UV(R) and MC(R). However, in a recB sbcCD8 genetic background, the sbcB1 mutation is co-dominant to sbcB(+) for all phenotypes. Our results lead us to suggest that the SbcB and SbcCD proteins have roles in RecBCD-dependent recombination. PMID:8001778

  17. Characterization of the Glycosyltransferase DesVII and Its Auxiliary Partner Protein DesVIII in the Methymycin/Pikromycin Biosynthetic Pathway†

    PubMed Central

    Borisova, Svetlana A.; Liu, Hung-wen

    2010-01-01

    The in vitro characterization of the catalytic activity of DesVII, the glycosyltransferase involved in the biosynthesis of the macrolide antibiotics methymycin, neomethymycin, narbomycin, and pikromycin in Streptomyces venezuelae, is described. DesVII is unique among glycosyltransferases in that it requires an additional protein component, DesVIII, for activity. Characterization of the metabolites produced by a S. venezuelae mutant lacking desVIII gene confirmed that desVIII is important for the biosynthesis of glycosylated macrolides, but can be replaced by at least one of the homologous genes from other pathways. The addition of recombinant DesVIII protein significantly improves the glycosylation efficiency of DesVII in the in vitro assay. When affinity-tagged DesVII and DesVIII proteins were co-produced in E. coli, they formed a tight (αβ)3 complex that is at least 103-fold more active than DesVII alone. The formation of the DesVII/DesVIII complex requires co-expression of both genes in vivo and cannot be fully achieved by mixing the individual protein components in vitro. The ability of DesVII/DesVIII system to catalyze the reverse reaction with the formation of TDP-desosamine was also demonstrated in a transglycosylation experiment. Taken together, our data suggest that DesVIII assists the folding of DesVII during protein production and remains tightly bound during catalysis. This requirement must be taken into consideration in the design of combinatorial biosynthetic experiments of new glycosylated macrolides. PMID:20695498

  18. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi.

    PubMed

    Charbel, Christelle; Fontaine, Romain H; Malouf, Gabriel G; Picard, Arnaud; Kadlub, Natacha; El-Murr, Nizar; How-Kit, Alexandre; Su, Xiaoping; Coulomb-L'Hermine, Aurore; Tost, Jorg; Mourah, Samia; Aractingi, Selim; Guégan, Sarah

    2014-04-01

    Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMNs and compared them with small and medium CMNs using Sanger sequencing, pyrosequencing, high-resolution melting analysis, and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMNs displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be investigated. We therefore performed exome sequencing on five specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMNs was significantly different, with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero. PMID:24129063

  19. 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

  20. Homozygous MAPT R406W mutation causing FTDP phenotype: A unique instance of a unique mutation.

    PubMed

    Behnam, Mahdiyeh; Ghorbani, Fatemeh; Shin, Jin-Hong; Kim, Dae-Seong; Jang, Hojung; Nouri, Narges; Sedghi, Maryam; Salehi, Mansoor; Ansari, Behnaz; Basiri, Keivan

    2015-10-01

    Frontotemporal dementia is a neurodegenerative disorder among adults. An autosomal-dominantly form of frontotemporal dementia and parkinsonism linked to chromosome 17q21.2 (FTDP-17) was defined in 1996. The MAPT gene is responsible for the major cases of FTDP-17, and tau also has a role in Alzheimer's disease. So far, different FTDP-17 causing mutations have been identified in the MAPT gene. Among different MAPT mutations, the R406W mutation has been reported with a phenotype resembling Alzheimer's disease. Nonetheless, in this study we have identified the first homozygous case of R406W mutation in an Iranian family which shows characteristics of FTDP, just like the other heterozygous mutations of MAPT. This study clearly indicates that homozygous R406W mutation could result in FTDP phenotype. Our family confirms heterogeneity in the clinical phenotype of MAPT mutations; moreover, in the R406W mutation, a dosage effect is likely to contribute to this clinical heterogeneity. PMID:26086902

  1. 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

  2. Organisation des gesundheitlichen Verbraucherschutzes auf Bundesebene

    NASA Astrophysics Data System (ADS)

    Tschiersky-Schöneburg, Helmut; Büttner, Antje

    Zahlreiche Krisen wie Dioxin belastete Futtermittel, die missbräuchliche Verwendung von Antibiotika in der Schweinemast und nicht zuletzt das Auftreten von BSE in Deutschland erschütterten Ende der neunziger Jahre das Vertrauen der Bürger in die Sicherheit der Lebensmittel. Mit dem Weißbuch zur Lebensmittelsicherheit, das im Januar 2000 herausgegeben wurde, hatte die Europäische Kommission ihre Erfahrungen aus dem BSE-Geschehen in ein neues Konzept für den Verbraucherschutz eingearbeitet. Kernstücke des Konzepts sind die ganzheitliche Betrachtung der Lebensmittelsicherheit von der landwirtschaftlichen Erzeugung bis zum Verzehr und der Anspruch nach Transparenz und Unabhängigkeit der Risikobewertung.

  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. La détermination des distances: Sol, Hipparcos, GAIA.

    NASA Astrophysics Data System (ADS)

    Turon, C.

    Les parallaxes trigonométriques des étoiles les plus proches du soleil sont la base de la détermination des distances dans l'Univers. Elles permettent, par la calibration en luminosité des différents indicateurs de distance d'étalonner les distances d'abord dans notre Galaxie, puis dans les galaxies du Groupe Local, puis pour les galaxies plus lointaines. Cette base est, actuellement, très mince, et peu de types d'étoiles y sont représentés. Hipparcos va déjà apporter une amélioration sensible. Avec GAIA une révision complète des calibrations de luminosité de tous les indicateurs "primaires" serait directement possible.

  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. A Mutation-Sensitive Switch Assay to Detect Five Clinically Significant Epidermal Growth Factor Receptor Mutations

    PubMed Central

    Liu, Bin; Zhou, Lin; Wang, Qian

    2015-01-01

    Epidermal growth factor receptor (EGFR) mutations can affect the therapeutic efficacy of drugs used to treat nonsmall-cell lung cancer (NSCLC). We aimed to develop methods to detect five common EGFR somatic mutations in tumor tissues from NSCLC patients by using a nanoscale mutation-sensitive switch consisting of a high-fidelity polymerase and phosphorothioate-modified allele-specific primers. The five clinically significant EGFR mutations examined here are S768I, T790M, L858R, and 15- and 18-bp deletion mutations in exon 19. Our assays showed sensitivities of 100 copies and specificities of more than three log scales for matched templates relative to mismatched templates by routine polymerase chain reaction (PCR), real-time PCR, and multiplex PCR. This assay would be superior to DNA sequencing in situations where mutant DNA is not abundant. PMID:25918867

  7. An extreme test of mutational meltdown shows mutational firm up instead.

    PubMed

    Woodruff, R C

    2013-06-01

    Traditionally, the accumulation of new deleterious mutations in populations or species in low numbers is expected to lead to a reduction in fitness and mutational meltdown, but in this study the opposite was observed. Beginning with a highly inbred populations of Drosophila melanogaster, new mutations that accumulated in experiments of two females and two males or of one female and one male each generation for 52 generations did not cause a decline in progeny numbers over time. Only two lines went extinct among 52 tested lines. In three of four experiments there was a significant increase in progeny numbers over time (mutational firm up), which had to be due to new beneficial, compensatory, overdominant, or back mutations. PMID:23543206

  8. 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.

  9. 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.

  10. Multiple dispersed spontaneous mutations: A novel pathway of mutation in a malignant human cell line

    SciTech Connect

    Harwood, J.; Tachibana, Akira; Meuth, M. )

    1991-06-01

    The authors analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in part hemizygotes derived from SW620, largely as a result of base substitutions at G {center dot} C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells.

  11. Frameshift mutation events in beta-glucosidases.

    PubMed

    Rojas, Antonio; Garcia-Vallvé, Santiago; Montero, Miguel A; Arola, Lluís; Romeu, Antoni

    2003-09-18

    Compensated frameshift mutation is a modification of the reading frame of a gene that takes place by way of various molecular events. It appears to be a widespread event that is only observed when homologous amino acid and nucleodotide sequences are compared. To identify these mutation events, the sequence analysis rationale was based on the search for short regions that would have much lower degrees of conservation in protein, but not in DNA, in well-conserved beta-glucosidase families. We have restricted our study to a seed set of sequences of O-glycoside hydrolase families 1 and 3. We found compensated frameshift mutation in the family of 1 beta-glucosidases for the Erwinia herbicola, Cellulomonas fimi, and (non-cyanogenic) Trifolium repens gene sequences, and in the family of 3 beta-glucosidases for the Clostridium thermocellum and Clostridium stercorarium gene sequences. By computational treatment, the observed mutation events in the gene frameshifting sub-sequence have been neutralised. Each nucleotide insertion must be eliminated and each nucleotide deletion must be substituted by the symbol N (any nucleotide). When the frameshifting fragments of the amino acid sequences were substituted by the computationally neutralised subsequences, the beta-glucosidase alignments were improved. We also discuss the structural implications of the compensated frameshift mutations events. PMID:14527732

  12. Epidemic spreading with immunization and mutations

    NASA Astrophysics Data System (ADS)

    Dammer, Stephan M.; Hinrichsen, Haye

    2003-07-01

    The spreading of infectious diseases with and without immunization of individuals can be modeled by stochastic processes that exhibit a transition between an active phase of epidemic spreading and an absorbing phase, where the disease dies out. In nature, however, the transmitted pathogen may also mutate, weakening the effect of immunization. In order to study the influence of mutations, we introduce a model that mimics epidemic spreading with immunization and mutations. The model exhibits a line of continuous phase transitions and includes the general epidemic process (GEP) and directed percolation (DP) as special cases. Restricting to perfect immunization in two spatial dimensions, we analyze the phase diagram and study the scaling behavior along the phase transition line as well as in the vicinity of the GEP point. We show that mutations lead generically to a crossover from the GEP to DP. Using standard scaling arguments, we also predict the form of the phase transition line close to the GEP point. The protection gained by immunization is vitally decreased by the occurrence of mutations.

  13. The new mutation theory of phenotypic evolution

    PubMed Central

    Nei, Masatoshi

    2007-01-01

    Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance. PMID:17640887

  14. [Diseases caused by mutations in mitochondrial DNA].

    PubMed

    Wojewoda, Marta; Zabłocki, Krzysztof; Szczepanowska, Joanna

    2011-01-01

    Mitochondrial diseases associated with mutations within mitochondrial genome are a subgroup of metabolic disorders since their common consequence is reduced metabolic efficiency caused by impaired oxidative phophorylation and shortage of ATP. Although the vast majority of mitochondrial proteins (approximately 1500) is encoded by nuclear genome, mtDNA encodes 11 subunits of respiratory chain complexes, 2 subunits of ATP synthase, 22 tRNAs and 2 rRNAs. Up to now, more than 250 pathogenic mutations have been described within mtDNA. The most common are point mutations in genes encoding mitochondrial tRNAs such as 3243A-->G and 8344T-->G that cause, respectively, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) or MIDD (maternally-inherited diabetes and deafness) and MERRF (myoclonic epilepsy with ragged red fibres) syndromes. There have been also found mutations in genes encoding subunits of ATP synthase such as 8993T-->G substitution associated with NARP (neuropathy, ataxia and retinitis pigmentosa) syndrome. It is worth to note that mitochondrial dysfunction can also be caused by mutations within nuclear genes coding for mitochondrial proteins. PMID:21913424

  15. TERT promoter mutations in primary liver tumors.

    PubMed

    Nault, Jean-Charles; Zucman-Rossi, Jessica

    2016-02-01

    Next-generation sequencing has drawn the genetic landscape of hepatocellular carcinoma and several signaling pathways are altered at the DNA level in tumors: Wnt/β-catenin, cell cycle regulator, epigenetic modifier, histone methyltransferase, oxidative stress, ras/raf/map kinase and akt/mtor pathways. Hepatocarcinogenesis is a multistep process starting with the exposure to different risk factors, followed by the development of a chronic liver disease and cirrhosis precede in the vast majority of the cases the development of HCC. Several lines of evidence have underlined the pivotal role of telomere maintenance in both cirrhosis and HCC pathogenesis. TERT promoter mutations were identified as the most frequent genetic alterations in hepatocellular carcinoma with an overall frequency around 60%. Moreover, in cirrhosis, TERT promoter mutations are observed at the early steps of hepatocarcinogenesis since they are recurrently identified in low-grade and high-grade dysplastic nodules. In contrast, acquisition of genomic diversity through mutations of classical oncogenes and tumor suppressor genes (TP53, CTNNB1, ARID1A…) occurred only in progressed HCC. In normal liver, a subset of HCC can derived from the malignant transformation of hepatocellular adenoma (HCA). In HCA, CTNNB1 mutations predispose to transformation of HCA in HCC and TERT promoter mutations are required in most of the cases as a second hit for a full malignant transformation. All these findings have refined our knowledge of HCC pathogenesis and have pointed telomerase as a target for tailored therapy in the future. PMID:26336998

  16. Urinary tract effects of HPSE2 mutations.

    PubMed

    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; Woolf, Adrian S

    2015-04-01

    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

  17. 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

  18. Mutations in ANTXR1 cause GAPO syndrome.

    PubMed

    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

    2013-05-01

    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

  19. PRRT2 mutations and paroxysmal disorders.

    PubMed

    Méneret, A; Gaudebout, C; Riant, F; Vidailhet, M; Depienne, C; Roze, E

    2013-06-01

    In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders. PMID:23398397

  20. Elevated Levels of Somatic Mutation in a Manifesting BRCA1 Mutation Carrier

    PubMed Central

    GRANT, Stephen G.; DAS, Rubina; CERCEO, Christina M.; RUBINSTEIN, Wendy S.; LATIMER, Jean J.

    2015-01-01

    Homozygous loss of activity at the breast cancer-predisposing genes BRCA1 and BRCA2 (FANCD1) confers increased susceptibility to DNA double strand breaks, but this genotype occurs only in the tumor itself, following loss of heterozygosity at one of these loci. Thus, if these genes play a role in tumor etiology as opposed to tumor progression, they must manifest a heterozygous phenotype at the cellular level. To investigate the potential consequences of somatic heterozygosity for a BRCA1 mutation demonstrably associated with breast carcinogenesis on background somatic mutational burden, we applied the two standard assays of in vivo human somatic mutation to blood samples from a manifesting carrier of the Q1200X mutation in BRCA1 whose tumor was uniquely ascertained through an MRI screening study. The patient had an allele-loss mutation frequency of 19.4 × 10−6 at the autosomal GPA locus in erythrocytes and 17.1 × 10−6 at the X-linked HPRT locus in lymphocytes. Both of these mutation frequencies are significantly higher than expected from age-matched disease-free controls (P < 0.05). Mutation at the HPRT locus was similarly elevated in lymphoblastoid cell lines established from three other BRCA1 mutation carriers with breast cancer. Our patient’s GPA mutation frequency is below the level established for diagnosis of homozygous Fanconi anemia patients, but consistent with data from obligate heterozygotes. The increased HPRT mutation frequency is more reminiscent of data from patients with xeroderma pigmentosum, a disease characterized by UV sensitivity and deficiency in the nucleotide excision pathway of DNA repair. Therefore, this BRCA1-associated breast cancer patient manifests a unique phenotype of increased background mutagenesis that likely contributed to the development of her disease independent of loss of heterozygosity at the susceptibility locus. PMID:18158561

  1. Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations.

    PubMed

    Harms, Paul W; Hovelson, Daniel H; Cani, Andi K; Omata, Kei; Haller, Michaela J; Wang, Michael L; Arps, David; Patel, Rajiv M; Fullen, Douglas R; Wang, Min; Siddiqui, Javed; Andea, Aleodor; Tomlins, Scott A

    2016-05-01

    Porocarcinomas are a rare eccrine carcinoma with significant metastatic potential. Oncogenic drivers of porocarcinomas have been underexplored, with PIK3CA-activating mutation reported in 1 case. We analyzed 5 porocarcinomas by next-generation sequencing using the DNA component of the Oncomine Comprehensive Assay, which provides data on copy number changes and mutational events in 126 cancer-relevant genes through multiplex polymerase chain reaction. We detected an average of 3.3 high-confidence nonsynonymous mutations per tumor (range, 1-6), including a spectrum of oncogenic activation and tumor suppressor inactivation events. Tumor suppressor mutations included TP53 (4/5, 80%), RB1 (3/5, 60%), ATM (2/5, 40%), ARID1A (1/5, 20%), and CDKN2A (1/5, 20%). In 4 (80%) of 5 tumors, at least 1 potential oncogenic driver was identified. Activating HRAS mutations were detected in 2 (40%) of 5, including G13D and Q61L hotspot mutations. Mutations of EGFR were identified in 2 (40%) of 5; these mutations have been previously reported in cancer but did not affect classic activation hotspot sites. EGFR and HRAS mutations were mutually exclusive. HRAS mutations were detected by targeted sequencing in a minority of benign eccrine poromas (2/17; 11.7%), suggesting that HRAS activation may rarely be an early event in sweat gland neoplasia. Together, our data suggest roles for HRAS and EGFR as drivers in a subset of poroma and porocarcinoma. TP53 and RB1 inactivation events are also likely to contribute to tumorigenesis. These findings suggest that porocarcinomas display diversity with respect to oncogenic drivers, which may have implications for targeted therapy in metastatic or unresectable cases. PMID:27067779

  2. 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

  3. Oncogene mutation profiling reveals poor prognosis associated with FGFR1/3 mutation in liposarcoma.

    PubMed

    Li, Chengfang; Shen, Yaoyuan; Ren, Yan; Liu, Wei; Li, Man; Liang, Weihua; Liu, Chunxia; Li, Feng

    2016-09-01

    Liposarcoma (LPS) is one of the most prevalent soft tissue sarcomas. LPS shows a poor response to radiation and chemotherapy. The causes of death in patients with LPS include locally recurrent and metastatic disease. We sought to examine novel gene mutations and pathways in primary and matched recurrent LPSs to identify potential therapeutic targets. We conducted a high-throughput analysis of 238 known mutations in 19 oncogenes using Sequenom MassARRAY technology. Nucleic acids were extracted from 19 primary and recurrent LPS samples, encompassing 9 dedifferentiated LPSs (DDLPS), 9 myxoid/round cell LPSs, and 1 pleomorphic LPS. Mutation screening revealed missense mutations in 21.1% (4/19) of the LPS specimens, including 4 different genes (FGFR1, FGFR3, PIK3CA, and KIT). Based on histologic subtypes, 22.2% DDLPS (2/9) and 22.2% myxoid cell LPS (2/9) contained gene mutations. Specifically, 3 (23.1%) of 13 primary tumors harbored mutations. Furthermore, although gene mutations were identified in 1 (11.1%) of 9 recurrent LPS samples, the difference between the primary and the recurrence was not statistically significant. Analysis of patient survival data indicated that patients harboring FGFR1/3 mutations experienced reduced overall survival (P<.05). Despite the limited number of samples, our findings provide the first evidence of FGFR1/3 mutations in DDLPS, which were associated with poor clinical outcomes. The FGFR pathway may play an important role in the development and progression of DDLPS and warrants further investigation; moreover, PIK3CA mutation is a common event (11.1%) in myxoid cell LPS. PMID:27237367

  4. 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

  5. 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.

  6. 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

  7. Estimating Mutation Load in Human Genomes

    PubMed Central

    Henn, Brenna M.; Botigué, Laura R.; Bustamante, Carlos D.; Clark, Andrew G.; Gravel, Simon

    2016-01-01

    Next-generation sequencing technology has facilitated the discovery of millions of variants in human genomes. A sizeable fraction of these alleles are thought to be deleterious. We review the pattern of deleterious alleles as ascertained in genomic data and ask whether human populations differ in their predicted burden of deleterious alleles, a phenomenon known as “mutation load.” We discuss three demographic models that are predicted to affect mutation load and relate these models to the evidence (or the lack thereof) for variation in the efficacy of purifying selection in diverse human genomes. We also discuss why accurate estimation of mutation load depends on assumptions regarding the distribution of dominance and selection coefficients, quantities that are poorly characterized for current genomic datasets. PMID:25963372

  8. 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

  9. Expanding the phenotype of GMPPB mutations.

    PubMed

    Cabrera-Serrano, Macarena; Ghaoui, Roula; Ravenscroft, Gianina; Johnsen, Russell D; Davis, Mark R; Corbett, Alastair; Reddel, Stephen; Sue, Carolyn M; Liang, Christina; Waddell, Leigh B; Kaur, Simranpreet; Lek, Monkol; North, Kathryn N; MacArthur, Daniel G; Lamont, Phillipa J; Clarke, Nigel F; Laing, Nigel G

    2015-04-01

    Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis. PMID:25681410

  10. Association of mutations in FLNA with craniosynostosis.

    PubMed

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

    2015-12-01

    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 (four of six cases overall); five patients had multiple suture synostosis with the sagittal suture being the most frequently involved (also five 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