A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Évangélisation et société coloniale : le cas du De Procuranda indorum salute du père José d’Acosta

Traité missiologique connu, le De Procuranda indorum salute, permet également de prendre connaissance des mécanismes qui régissaient la société coloniale dans le Pérou du XVIe siècle. On étudie ici plus particulièrement la façon dont questionnements missiologiques et problématiques sociales s’articulent, selon Acosta. L’analyse s’ordonne autour de la question de la justice.<br>El tratado misológico De Procuranda indorum salute constituye una base interesante para quien quiera conocer los mecanismos que regían la sociedad colonial en el Perú del siglo XVI. En este artículo, se estudia los lazos que, según Acosta, vinculaban las preoccupaciones misológicas y las problemáticas sociales. El análisis se centra en el tema de la justicia

Des ambiguïtés du droit des gens, de Francisco de Vitoria au Père Acosta

La critique et les spécialistes de l’histoire du droit s’accordent à considérer Vitoria comme l’un des fondateurs du droit international ; ils s’accordent à considérer que le dominicain a formulé une des premières définitions de la communauté internationale, en s’appuyant pour ce faire sur une définition du droit des gens enfin clarifiée, et en reconnaissant dans le droit des gens un droit naturel. Mais, commentant les Leçons sur les Indiens du dominicain de Salamanque, ces mêmes critiques on..

Evaluation du risque fongique en zones conchylicoles (substances toxiques de souches marines du genre Trichoderma )

Ce travail est consacré à l'étude chimique des peptaïbols sécrétés par des souches de Trichoderma endémiques des zones conchylicoles de Loire-Atlantique. La stratégie adoptée a permis de réaliser : Un échantillonnage, à partir de la mycothèque du SMAB (Substances Marines à Activité Biologique), de souches de Trichoderma productrices de peptaïbols dans l'estuaire de la Loire. Neuf souches représentatives ont été sélectionnées. En fonction de leurs contenus en peptaïbols, elles ont été réparties en 4 ensembles, puis une " souche représentative " de chaque ensemble a été choisie pour la suite du travail. Une optimisation des protocoles nécessaires à la production in vitro des peptaïbols. La mise au point d'un mode de fermentation sur milieu gélosé a permis d'augmenter le rendement de cette biosynthèse. Une optimisation des conditions de purification des peptaïbols. Des protocoles simplifiés de pré-purification, de purification par chromatographie en phase liquide (CLHP) ont permis la préparation d'échantillons analysable par spectrométrie de masse. Une identification structurale des peptaïbols produits, grâce au séquençage par spectrométrie de masse, l'ionisation étant réalisée par électronébulisation ou electrospay (ESI) et l'analyseur étant constitué par une trappe d'ions permettant une analyse SMn. Cette analyse a pu être conduite sur des mélanges de peptaïbols de structure très proche (phénomène de microhétérogénéité). Une analyse par chromatographie en phase gazeuse couplée à la spectrométrie de masse (GC-MS-EI) a permis de préciser la nature des acides aminés (AA) de même masse (Valine ou Isovaline ; Leucine ou Isoleucine). Pour les quatre souches de Trichoderma étudiées, 30 peptaïbols ont été mis en évidence dont 24 sont de nouvelles molécules. Ils appartiennent à 5 familles de peptaïbols déjà décrites : les trichokonines, les trichosporines, les hypomurocines, les trichorovines et les suzukacillines. Vingt et un sont à longue séquence (18 à 20 AA) dont 16 sont nouveaux. Neuf sont à courte séquence (11 AA) dont 8 présentent des structures assez originales pour nous permettre de proposer une nouvelle famille, celle des trichobrachines.This work is devoted to the chemical study of peptaïbols produced by endemic Trichoderma strains in the Loire-Atlantique shellfish farming areas. The adopted strategy made possible to realize: A sampling from the marine fungal collection of SMAB (Substances Marines à Activité Biologique) of Trichoderma strains with peptaibols production in the Loire estuary. Nine representative strains were selected. According to their peptaïbols production, they were divided into 4 sets; a "representative strain" of each set was then selected for next steps. The optimization of the used methods for the peptaïbols in vitro production. The development of a fermentation mode on agar medium increases the biosynthesis output. An optimization of the peptaibol purification conditions. Simplified methods of pre-purification and purification by high performance liquid chromatography (HPLC) allowed the preparation of analysable samples by mass spectrometry. The structural identification of the produced peptaibols by use of mass spectrometry sequencing; electro spray ionisation mode (ESI) and ion trap analyser allowing MSn analysis. The latter make possible the identification of peptaïbols with very similar structures (due to the peptaibols microheterogeneity phenomenon). The use of coupled gas chromatography to mass spectrometry (GC-MS-IE) allows the differentiation of the amino acids (AA) of the same mass (Valine or Isovaline; Leucine or Isoleucine). Thirty peptaibols produced by the four studied Trichoderma strains were identified. 24 of which, are new molecules and belong to 5 already described families: trichokonines, trichosporines, hypomurocines, trichorovines and suzukacillines. 21 are long sequences peptaïbols (18 to 20 AA) including 16 new structures. Among the 9 remaining peptaïbols with short sequence (11 AA), 8 have enough original structures to enabling us to propose a new peptaibol family: the trichobrachine's.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

A small galliform and a small cuculiform from the Eocene of Tunisia

International audienceA distal tarsometatarsus and a fragment of carpometacarpus of a small galliform, the size of a recentquail, have been found in the late Early or early Middle Eocene of Chambi, in Tunisia. Although a large numberof stem group representatives of Galliformes are known from the Eocene of the Northern Hemisphere, and onefrom the middle Eocene of Namibia, the taxon from Chambi differs from them and is described as a new genusand species. A very small zygodactyl form, represented by three distal tarsometatarsi, is also present in the samelocality. This form, described as a new genus and species, is a stem group representative of the recent familyCuculidae. It shows a plesiomorphic morphology compared to the recent members of the Cuculidae, but it is,however, more derived than the younger genus Eocuculus. It is the earliest Cuculidae known so far

Barremian intracontinental rift and Aptian Atlantic transgression in the northern boundary of the Central High Atlas (Morocco)

International audienceThe northern boundary of the Central High Atlas was affected by a transgression during the Aptian that reached the junction zone between the Middle and the High Atlas. In this sector (Naour-Aghbala) which corresponds to the presumed closure zone of this Aptian Atlantic marine trough, the sedimentary record reveals a strong dependence on the regional structural framework. The Barremian continental sedimentation is concentrated in an elongated W-E highly subsiding zone, limited to the south by the polyphase Aghbala-Afourer Fault Zone (AAFZ), which corresponds to the contact between the main Atlasic Belt and its northern boundary (Beni Mellal Atlas). The Aptian deposits preserve similar littoral marine characters from West to East without showing any confined facies, which could evoke the eastern limit of the gulf. On the other hand, towards the North, the Aptian layers rapidly change from marine to lagoonal then to continental facies. The paleogeographic boundary of the Aptian shoreline, oriented E-W, is locally controlled by the North El Ksiba Fault (NKF) in the North. The Aptian Atlantic transgression, closely linked to the narrow Barremian graben, shows a wide northward extension of the marine sedimentary area. The Barremian graben highlighted in the Aghbala-Naour area represents only a segment of a major east-west intracontinental rift that continued eastward with the more recent frontal thrust of the eastern Moroccan High Atlas. This faulted structure was the penetration axis of a double transgression: from the Tethys to the East and from the Atlantic Ocean to the West on the emerged Atlasic domain

Zegdoumyidae (Rodentia, Mammalia), stem anomaluroid rodents from the Early to Middle Eocene of Algeria (Gour Lazib, Western Sahara): new dental evidence

International audienceThe Palaeogene fossil record of rodents in Africa is very poor compared to that of North America or Eurasia. Despite this, Africa has long appeared to be a centre of adaptive radiation for two distinct groups of Rodentia: Hystricognathi and Anomaluroidea. The >45-million-year-old enigmatic Zegdoumyidae is the oldest and only rodent family known of this age from Africa (Algeria and Tunisia). Zegdoumyids have been tentatively regarded as a possible early African stem group for Anomaluridae, a link that has never been clearly established because of the highly fragmentary nature of zegdoumyid fossils, as well as the major temporal and morphological gaps between zegdoumyids and the first true anomaluroids from the Late Eocene. About 200 rodent teeth have been sorted after acid treatment of indurated sediments from several new localities in the Gour Lazib of western Algeria dating from the late Early or early Middle Eocene. These new fossils allow us to better describe the morphology of the Zegdoumyidae (especially Glibia and Zegdoumys) and to identify a new taxon, Lazibemys zegdouensis gen. et sp. nov. With this material, we investigated the phylogenetic position of the Zegdoumyidae in a high-level rodent phylogeny with cladistic assessment of the dental evidence. Our analyses have yielded six equally most-parsimonious trees in which zegdoumyids represent the earliest offshoots (pectinately arranged) of a large clade that embraces Eocene anomaluroids plus stem and crown Anomaluridae. This phylogenetic assumption underscores the great antiquity of the Anomaluroidea clade in Africa, as expected given the high morphological divergence of the Late Eocene African anomaluroids. Zegdoumyids exhibit a variety of dental morphologies and provide some suggestions on evolutionary trends within the Anomaluroidea (early stages of pentalophodonty, incisor enamel microstructure transitional from the pauciserial to the uniserial condition). The source of Zegdoumyidae is still unclear inasmuch as there is no well-identified sister group among early Palaeogene rodents. Zegdoumyids seem to share a common ancestry with both stem Myodonta and North American Sciuravidae. Given the high degree of dental specialization of zegdoumyids, we cannot exclude the possibility that zegdoumyids are rooted in a more primitive, as yet unknown, African rodent lineage older than the Early-Middle Eocene

Indicateurs morphosédimentaires des variations de niveau lacustre dans les terrasses du lac de Van (Turquie)

International audienceLe lac de Van, dans les montagnes d’Anatolie orientale, ne possède pas d’exutoire naturel. Malgré son volume (604 km3), les amplitudes des variations de son niveau témoignent, depuis 1944, d’une sensibilité élevée aux fluctuations hydro-climatiques. Dans cette perspective, les dépôts hérités d’anciens hauts niveaux, conservés sous forme de terrasses côtières dans les parties aval anciennement immergées des affluents du lac, permettent d’identifier, de caractériser et de dater les changements de volume d’eau lacustre qu’ont enregistrés les sédiments qui sous-tendent ces terrasses. Plusieurs travaux récents sur les sédiments du fond du lac de Van ont mis en évidence leur intérêt exceptionnel pour la reconstitution des paléoclimats et permis de détailler l’évolution paléoenvironnementale du Tardiglaciaire et de l’Holocène. Cependant, les études des dépôts lacustres émergés restent rares. Ces dépôts font l’objet ici d’une étude géomorphologique de terrain couplée à des caractérisations sédimentologiques de faciès, des mesures altimétriques DGPS, des reconstitutions spatialisées et la mise en place des premiers jalons d’une chronostratigraphie basée sur des datations14C de dépôts organiques et coquilles, 39Ar/40Ar de tephras, et U-Th de travertins. Dans l’attente de datations OSL, nos résultats préliminaires permettent d’identifier au moins deux cycles de transgression, datés respectivement du début du dernier Glaciaire et d’une période couvrant le Dernier Maximum Glaciaire (DMG). Chaque cycle correspond à une phase de transgression rapide, suivie de variations intermédiaires d’amplitude plus ou moins forte, et se terminant par une longue phase de régression par paliers. La cause de ces variations et, notamment, la part qu’y a prise le climat est évidente pour le cycle datant du DMG, mais l’est moins pour celui marquant le début du Glaciaire dont les liens avec le volcanisme et la tectonique sont étroits. La forte instabilité de la paléogéographie est liée au volcanisme qui est à l’origine de barrages ayant entraîné la fermeture du bassin versant du lac

Protective role of LGP2 in influenza virus pathogenesis.

International audienceInfluenza A virus triggers a contagious respiratory disease that can cause considerable morbidity and mortality. Using an in vitro approach, we previously demonstrated that the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) plays a key role in influenza A virus-mediated immune response. However, the importance of RIG-I signaling in vivo has not been thoroughly examined, because of the lack of an appropriate mouse models. To circumvent this issue, we generated a new transgenic mouse overexpressing LGP2 (hereafter, "LGP2 TG mice"), a major regulator of the RIG-I signaling pathway. The time course of several parameters was compared in infected wild-type and LGP2 TG mice. We found that LGP2 TG mice displayed significantly reduced inflammatory mediators and a lower leukocyte infiltration into the bronchoalveolar airspace. More importantly, LGP2 TG mice had a significant survival advantage. Hence, our in vivo study reveals that LGP2 is a major downregulator of the influenza A virus-triggered detrimental inflammatory response