44 research outputs found

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

    Reactivity and Dynamics at Liquid Interfaces

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    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

    Autisme infantile : participation et retour d'expérience d'un secteur de pédopsychiatrie à une recherche clinique multicentrique

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    Médecine. PsychiatrieRésumé : Le terme d’autisme a été utilisé pour la première fois en 1943 par Leo Kanner pour caractériser des enfants sans retard mental ni symptômes schizophréniques, mais présentant néanmoins une symptomatologie marquée par « l’isolement et l’immuabilité ». Avant et après lui, l’abord de ces enfants a beaucoup évolué, comme en témoigne l’évolution de la nosographie relative à ce que l’on nomme aujourd’hui autisme infantile. Les dernières décennies en particulier ont vu l’essor de nouveaux programmes de prises en charge. Leur évaluation scientifique est attendue par l’État, les professionnels et certaines associations de famille. Nous retraçons la participation du secteur de pédopsychiatrie 67I02 à une étude multicentrique d’évaluation des prises en charge intégratives pour des enfants autistes. (Etude PREPS coordonnée par Dr Nicole Garret-Gloanec sous la responsabilité du CHU de Nantes).Sumary : the term autism was coined in 1943 by Leo Kanner to characterize children without mental retardation or schizophrenic symptoms, but nevertheless presenting "isolation and immutability". Before and after him, the approach of caring for these children has evolved a lot, as evidenced by the evolution of the nosography about what is now called infantile autism. The last decades in particular have seen the rise of new care programs. Their scientific assessment is expected by Policy makers, professionals and some family support associations. In this work, we retrace the participation of the child psychiatry sector 67I02 in a multicentric study evaluating integrative care for children with autism. (PREPS study coordinated by Dr. Nicole Garret-Gloanec under the responsibility of Nantes University Hospital)

    Approches statistiques pour la détection de changements en IRM de diffusion (application au suivi longitudinal de pathologies neuro-dégénératives)

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    L'IRM de diffusion (IRMd) est une modalité d'imagerie médicale qui suscite un intérêt croissant dans la recherche en neuro-imagerie. Elle permet d'apporter in vivo des informations nouvelles sur les micro-structures locales des tissus. En chaque point d'une acquisition d'IRMd, la distribution des directions de diffusion des molécules d'eau est modélisée par un tenseur de diffusion. La nature multivariée de ces images requiert la conception de nouvelles méthodes de traitement adaptées. Le contexte de cette thèse est l'analyse automatique de changements longitudinaux intra-patient avec pour application le suivi de pathologies neuro-dégénératives. Notre recherche a ainsi porté sur le développement de nouveaux modèles et tests statistiques permettant la détection automatique de changements sur des séquences temporelles d'images de diffusion. Cette thèse a ainsi permis une meilleure prise en compte de la nature tensorielle des modèles d'ordre 2 (tests statistiques sur des matrices définies positives), une extension vers des modèles d'ordre supérieur et une gestion plus fine des voisinages sur lesquels les tests sont menés, avec en particulier la conception de tests statistiques sur des faisceaux de fibres.Diffusion MRI is a new medical imaging modality of great interest in neuroimaging research. This modality enables the characterization in vivo of local micro-structures. Tensors have commonly been used to model the diffusivity profile at each voxel. This multivariate data set requires the design of new dedicated image processing techniques. The context of this thesis is the automatic analysis of intra-patient longitudinal changes with application to the follow-up of neuro-degenerative pathologies. Our research focused on the development of new models and statistical tests for the automatic detection of changes in temporal sequences of diffusion images. Thereby, this thesis led to a better modeling of second order tensors (statistical tests on positive definite matrices), to an extension to higher-order models, and to the definition of refined neighborhoods on which tests are conducted, in particular the design of statistical tests on fiber bundles.STRASBOURG-Bib.electronique 063 (674829902) / SudocSudocFranceF

    Use of Cleavable Coordinating Rings as Protective Groups in the Synthesis of a Rotaxane with an Axis that Incorporates More Chelating Groups Than Threaded Macrocycles

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    International audienceA new methodology allowing preparation of a linear “unsaturated” [3]rotaxane consisting of an axis incorporating more coordination sites than threaded rings was developed. It was based on the preliminary synthesis of a “saturated” [5]rotaxane consisting of a four‐chelating site axis threaded through four macrocyclic components, two of them being cleavable rings incorporating a lactone function and the two others being “secure” non‐cleavable rings. The stoppering reaction was based on click chemistry. Subsequently, cleavage and removal of the two lactone‐containing macrocycles from the [5]rotaxane in basic medium afforded the desired “unsaturated” [3]rotaxane in quantitative yield

    Copper(I)-Assembled [3]Rotaxane Whose Two Rings Act as Flapping Wings

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    International audienceA new copper-complexed [3]rotaxane consisting of two coordinating 30-membered rings threaded by a two-binding-site axis has been prepared in good yield from relatively simple organic fragments. The main specificity of the system originates from the stoppering reaction, based on “click” chemistry, and thus from the presence of two triazole groups at positions next to the bidentate chelates of the axis central part. The geometry of the coordinating atoms belonging to the axis is such that the triazole groups can either be part of the coordinating fragments when the metal center is 5-coordinate or be not at all involved in coordination to the metal when the latter is 4-coordinate. To be more specific, when the two complexed metal centers are monovalent copper(I) centers, the triazoles are not included in the metal coordination sphere, whereas when the metal centers are Cu(II) or Zn2+, the triazole groups are bound to the metals. This is easily explained by the fact that Cu(I) is preferably 4-coordinate and Cu(II) and Zn2+ are 5-coordinate. The interconversion between both situations (4- or 5-coordinate) can be quantitatively induced by metal exchange (Cu(I)/Zn2+) or by a redox process (Cu(II)/Cu(I)). It leads to important geometrical changes and in particular to a strong modification of the angle between the two rings. As a consequence, the two threaded rings undergo a motion which is reminiscent of a wing-flapping movement similar to that of birds. This flapping motion is fast and quantitative. It should lead to new functional molecular machines in the future

    Formation of copper(I)-templated [2]rotaxanes using “click” methodology: influence of the base, the thread and the catalyst

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    International audienceThree new copper(I)-assembled [2]rotaxanes incorporating the same macrocycle and different axes containing a bipy, a phen or a terpy have been synthesized thanks to CuAAC reaction for attaching the stoppers. The influence of the nature of the base used for the stoppering reaction was investigated on the formation of the bipy-containing rotaxane. The yield of the [2]rotaxane synthesis was increased when using a phen as a coordinating unit in the thread with [Cu(CH3CN)4](PF6) as catalyst. The strong influence of the nature of the catalyst was clearly evidenced for the formation of the terpy rotaxane, increasing the yield of the stoppering reaction from 0 to 95% by just substituting the Cu(I) catalyst. Finally, the best conditions found for our systems are the use of Na2CO3 as a base and Cu(tren′)Br as a catalyst
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