A large brain is one of the most distinguishing features of humans compared to other members of the animal kingdom. During mammalian evolution there has been a disproportionate enlargement of the ...brain relative to body size and this expansion has been particularly prominent during the past 3 million years of human lineage. This must be the consequence of adaptive genetic alterations during mammalian evolution, but the genes and molecular processes altered are essentially unknown. One approach for identifying candidate genes for brain size regulation is through characterisation of Mendelian disorders of brain development. In particular, primary microcephaly has received considerable interest as a model disease for studying brain size regulators because patients present with a profoundly reduced brain size but have no other malformations. Genetic studies have identified mutations in seven genes that can cause primary microcephaly. All the primary microcephaly proteins localise to the centrosome at some stage during the cell cycle and have roles in a diverse range of functions including centrosome maturation, centriole formation and microtubule organisation at the spindle pole. The precise mechanism leading to primary microcephaly is not known but a prevalent hypothesis is that centrosome dysfunction disrupts mitosis of neural progenitor cells. Despite there being strong evidence in support of this hypothesis for most primary microcephaly genes, MCPH1 (the first primary microcephaly gene to be identified) always appeared to be functionally distinct from other primary microcephaly proteins. Most work on MCPH1 has focussed on its role in the DNA damage response and cell cycle timing rather than on its mitotic role. As a result, the aim of this thesis is to perform a detailed analysis of MCPH1 function during mitosis. In this thesis, three isoforms of MCPH1 were characterised and their localisation, expression and stability examined. It was established that MCPH1 is highly regulated during mitosis. MCPH1 transcript and protein levels vary significantly throughout the cell cycle and MCPH1 protein is targeted for degradation late in mitosis. In addition, MCPH1 is hyperphosphorylated during mitosis (in prometaphase-arrested cells) suggesting that phosphorylation could potentially regulate MCPH1 mitotic function. Twelve mitotic phosphorylation sites were identified by phosphopeptide mapping, many of which were CDK1 and PLK1 consensus sites. Both PLK1 and CDK1 also contribute to MCPH1 phosphorylation in vivo. Although MCPH1 non-phosphorylatable mutants localise normally during mitosis, binding to interaction partners may be affected which may have functional consequences. During mitosis MCPH1 localises to the centrosomes and kinetochores. Consistent with this localisation, RNAi-mediated knockdown of MCPH1 leads to metaphase arrest with multipolar spindles, major defects in chromosome alignment and loss of chromatid cohesion. In addition, MCPH1 deficient mouse embryonic fibroblast cells also demonstrate similar chromosome alignment defects, strengthening this finding in an independent system. Live-imaging of MCPH1 depleted cells demonstrate that a normal bipolar spindle and metaphase plate are initially formed, but subsequently chromosomes and chromatids drop off the metaphase plate and eventually the spindle collapses. This suggests that the primary function of MCPH1 is to allow timely progression through metaphase, possibly by mediating kinetochore-microtubule attachments to satisfy the spindle activated checkpoint. Therefore my work describes several roles for MCPH1 in mitosis (centrosome stability, chromosome alignment and metaphase progression) suggesting that its role in mitosis could result in primary microcephaly in a number of different ways.
Dans le prolongement de l'histoire des femmes, les études sur le genre conduisent à étendre les analyses sur l'ensemble des domaines qui participent à la construction de la différence des sexes : ...histoire du féminin et du masculin, histoire de la mixité et des rapports sociaux de sexe, histoire des pratiques et des imaginaires sociaux. Cet ouvrage réunit des travaux d'historiens, de sociologues, de littéraires qui analysent les variations des relations homme/femme sur une période de dix siècles. Ils sont regroupés selon cinq thèmes majeurs : l'ajustement des représentations et l'invention des normes, les savoirs, pouvoirs et révolutions, les guerres, les situations inédites. Ces questions sont traitées dans un cadre comparatiste particulièrement fécond, entre les périodes historiques et à l'intérieur du monde occidental. En posant pour problématique : le genre face aux mutations, la différence entre les sexes se vérifie comme une construction sociale en perpétuel renouvellement, sensible à tout changement économique, politique, culturel. Le colloque international, organisé par l'UMR-CNRS 6040 CRHISCO (Centre de recherche historique sur les sociétés et cultures de l'Ouest européen) s'est tenu à l'université Rennes 2 en septembre 2002 a pu montrer que toute mutation de la société s'accompagne d'un ajustement du genre, c'est-à-dire d'un polissage des stéréotypes du masculin/féminin, d'une variation des identités sexuelles, d'un changement dans les relations hommes/femmes. Au moment où le débat public converge sur l'aspiration à la parité homme/femme, cet ouvrage montre que la différence entre les sexes, leurs relations demeurent une institution instable qui, telle la toile de Pénélope, est tissée le jour et dénouée la nuit.
Directors of public companies often are compensated for their service in the form of equity awards. While the practice with respect to director compensation for board representatives of private ...equity funds varies, private equity firms that permit their board representatives to receive equity awards should be mindful that these awards can raise a variety of issues that are not present in the case of cash director fees. PUBLICATION ABSTRACT
ESA's INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL) was launched on 17 Oct 2002 at 06:41 CEST. Since then, it has been providing long, uninterrupted observations (up to about 47 hr, or ...170 ksec, per satellite orbit of 2.7 days) with a large field-of-view (fully coded: 100 deg^2), msec time resolution, keV energy resolution, polarization measurements, as well as additional coverage in the optical. This is realized by two main instruments in the 15 keV to 10 MeV range, the spectrometer SPI (spectral resolution 3 keV at 1.8 MeV) and the imager IBIS (angular resolution 12 arcmin FWHM), complemented by X-ray (JEM-X; 3-35 keV) and optical (OMC; Johnson V-band) monitors. All instruments are co-aligned to simultaneously observe the target region. A particle radiation monitor (IREM) measures charged particle fluxes near the spacecraft. The Anti-coincidence subsystems of the main instruments are also efficient all-sky gamma-ray detectors, which provide omni-directional monitoring above ~75 keV. INTEGRAL can also rapidly (within a couple of hours) re-point and conduct Target of Opportunity observations. INTEGRAL has build an impressive legacy: e.g. discovery of >600 new high-energy sources; first-ever direct detection of 56Ni and 56Co radio-active decay lines from a Type Ia supernova; new insights on positron annihilation in the Galactic bulge and disk; pioneering gamma-ray polarization studies. INTEGRAL is also a successful in multi-messenger astronomy: INTEGRAL found the first prompt electromagnetic radiation in coincidence with a binary neutron star merger. More than 1750 papers based on INTEGRAL data have been published in refereed journals. Here we give a comprehensive update of the satellite status after more than 18 years of operations in a harsh space environment, and an account of the successful Ground Segment.
Les auteurs Accati, Luisa; Băluţă, Ionela; Bergère, Marc ...
Le Genre Face Aux Mutations: Masculin et Féminin, du Moyen Age à Nos Jours,
07/2015
Journal Article
Luisa Accati Universita degli studi di Trieste Ionela Băluță Faculté des Sciences Politiques, université de Bucarest Marc Bergère Université Rennes 2, umr-cnrs 6040 crhisco et chercheur associé à ...l'ihtp-cnrs Isabelle Brouard-Arends Université Rennes 2, laboratoire du celam Luc Capdevila Université Rennes 2, umr-cnrs 6040 crhisco Anne Carol Université d'Aix-Marseille 1, UMR-CNRS Telemme Sophie Cassagnes-Brouquet Université de Limoges Jean-Christophe Cassard Université de Bretagne occidentale, ...
Nanometric movements of the substrate on which endothelial cells are growing, driven by periodic sinusoidal vibration from 1 Hz to 50 Hz applied by piezo actuators, upregulate endothelin-1 and ...Kruppel-like factor 2 expression, and increase cell adhesion. These movements are in the z (vertical) axis and ranges from 5 to 50 nm and are similar in vertical extent to protrusions from the cells themselves already reported in the literature. White noise vibrations do not to produce these effects. Vibrational sweeps, if suitably confined within a narrow frequency range, produce similar stimulatory effects but not at wider sweeps. These effects suggest that coherent vibration is crucial for driving these cellular responses. In addition to this, the applied stimulations are observed to be close to or below the random seismic noise of the surroundings, which may suggest stochastic resonance is being employed. The stimulations also interact with the effects of nanometric patterning of the substrates on cell adhesion and Kruppel-like factor 2 and endothelin-1 expression thus linking cell reactions to nanotopographically patterned surfaces with those to mechanical stimulation.
We present high resolution H-band polarized intensity (PI; FWHM = 0."1: 14 AU) and L'-band imaging data (FWHM = 0."11: 15 AU) of the circumstellar disk around the weak-lined T Tauri star PDS 70 in ...Centaurus at a radial distance of 28 AU (0."2) up to 210 AU (1."5). In both images, a giant inner gap is clearly resolved for the first time, and the radius of the gap is ~70 AU. Our data show that the geometric center of the disk shifts by ~6 AU toward the minor axis. We confirm that the brown dwarf companion candidate to the north of PDS 70 is a background star based on its proper motion. As a result of SED fitting by Monte Carlo radiative transfer modeling, we infer the existence of an optically thick inner disk at a few AU. Combining our observations and modeling, we classify the disk of PDS 70 as a pre-transitional disk. Furthermore, based on the analysis of L'-band imaging data, we put an upper limit mass of companions at ~30 to ~50MJ within the gap. Taking account of the presence of the large and sharp gap, we suggest that the gap could be formed by dynamical interactions of sub-stellar companions or multiple unseen giant planets in the gap.
There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the ...recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials.
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