Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability.

International audienceA single heat shock factor (HSF), mediating the heat shock response, exists from yeast to Drosophila, whereas several related HSFs have been found in mammals. This raises the question of the specific or redundant functions of the different members of the HSF family and in particular of HSF1 and HSF2, which are both ubiquitously expressed. Using immortalized mouse embryonic fibroblasts (iMEFs) derived from wild-type, Hsf1(-/-), Hsf2(-/-) or double-mutant mice, we observed the distinctive behaviors of these mutants with respect to proteasome inhibition. This proteotoxic stress reduces to the same extent the viability of Hsf1(-/-)- and Hsf2(-/-)-deficient cells, but through different underlying mechanisms. Contrary to Hsf2(-/-) cells, Hsf1(-/-) cells are unable to induce pro-survival heat shock protein expression. Conversely, proteasome activity is lower in Hsf2(-/-) cells and the expression of some proteasome subunits, such as Psmb5 and gankyrin, is decreased. As gankyrin is an oncoprotein involved in p53 degradation, we analyzed the status of p53 in HSF-deficient iMEFs and observed that it was strongly stabilized in Hsf2(-/-) cells. This study points a new role for HSF2 in the regulation of protein degradation and suggests that pan-HSF inhibitors could be valuable tools to reduce chemoresistance to proteasome inhibition observed in cancer therapy

Cartographie morpho-karstique du Causse Méjean : nouveaux apports sur la connaissance géologique et hydrogéologique

International audienc

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Death and the Societies of Late Antiquity

Ce volume bilingue, comprenant un ensemble de 28 contributions disponibles en français et en anglais (dans leur version longue ou abrégée), propose d’établir un état des lieux des réflexions, recherches et études conduites sur le fait funéraire à l’époque tardo-antique au sein des provinces de l’Empire romain et sur leurs régions limitrophes, afin d’ouvrir de nouvelles perspectives sur ses évolutions possibles. Au cours des trois dernières décennies, les transformations considérables des méthodologies déployées sur le terrain et en laboratoire ont permis un renouveau des questionnements sur les populations et les pratiques funéraires de l’Antiquité tardive, période marquée par de multiples changements politiques, sociaux, démographiques et culturels. L’apparition de ce qui a été initialement désigné comme une « Anthropologie de terrain », qui fut le début de la démarche archéothanatologique, puis le récent développement d’approches collaboratives entre des domaines scientifiques divers (archéothanatologie, biochimie et géochimie, génétique, histoire, épigraphie par exemple) ont été décisives pour le renouvellement des problématiques d’étude : révision d’anciens concepts comme apparition d’axes d’analyse inédits. Les recherches rassemblées dans cet ouvrage sont articulées autour de quatre grands thèmes : l’évolution des pratiques funéraires dans le temps, l’identité sociale dans la mort, les ensembles funéraires en transformation (organisation et topographie) et les territoires de l’empire (du cœur aux marges). Ces études proposent un réexamen et une révision des données, tant anthropologiques qu’archéologiques ou historiques sur l’Antiquité tardive, et révèlent, à cet égard, une mosaïque de paysages politiques, sociaux et culturels singulièrement riches et complexes. Elles accroissent nos connaissances sur le traitement des défunts, l’emplacement des aires funéraires ou encore la structure des sépultures, en révélant une diversité de pratiques, et permettent au final de relancer la réflexion sur la manière dont les sociétés tardo-antiques envisagent la mort et sur les éléments permettant d’identifier et de définir la diversité des groupes qui les composent. Elles démontrent ce faisant que nous pouvons véritablement appréhender les structures culturelles et sociales des communautés anciennes et leurs potentielles transformations, à partir de l’étude des pratiques funéraires.This bilingual volume proposes to draw up an assessment of the recent research conducted on funerary behavior during Late Antiquity in the provinces of the Roman Empire and on their borders, in order to open new perspectives on its possible developments. The considerable transformations of the methodologies have raised the need for a renewal of the questions on the funerary practices during Late Antiquity, a period marked by multiple political, social, demographic and cultural changes. The emergence field anthropology, which was the beginning of archaeothanatology, and then the recent development of collaborative approaches between various scientific fields (archaeothanatology, biochemistry and geochemistry, genetics, history, epigraphy, for example), have been decisive. The research collected in this book is structured around four main themes: Evolution of funerary practices over time; Social identity through death; Changing burial grounds (organisation and topography); Territories of the Empire (from the heart to the margins). These studies propose a review and a revision of the data, both anthropological and archaeological or historical on Late Antiquity, and reveal a mosaic of political, social, and cultural landscapes singularly rich and complex. In doing so, they demonstrate that we can truly understand the cultural and social structures of ancient communities and their potential transformations, based on the study of funerary practices

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Depuis 1985, les mouvements de main-d'oeuvre s'accélèrent

[eng] Since 1985, Personnel Turnover has increased - Between 1985 and 1990, personnel turnover has increased in establishments employing 50 or more salaried workers. An essential part of these fluctuations comes from contracts of a limited period. However, after 1988, the hiring of permanent employees increased faster than the hiring of employees for a limited period, which dropped in 1990 for the first times. . There is more mobility in average-sized establishments than in big ones. Mobility is also higher in the service sector than in other areas. Lastly, young people, women and persons employed in less-skilled professions hold the least steady jobs. [spa] Desde 1985 se registra una aceleración de los movimientos de mano de obra - Entre 1 985 y 1990, los movimientos de mano de obra se intensificaron en los establecimientos de 50 y más asalariados. Una parte importante de estos flujos proviene de los contratos de duración determinada. No obstante ello, los contrataciones de duración indeterminada aumentaron más rápidemante que aquellos, que en 1990 disminuyeron por primera vez. . . La movilidad es mâs importante en los establecimientos de talla mediana que en los grandes. La misma es también mâs elevada en el sector terciario que en los otros sectores._Por ultimo, los jôvenes, las mujeres y los que desempenan los empleos menos calificados ocupan los puestos menos estables. [fre] Entre 1985 et 1990, les mouvements de main-d'œuvre se sont intensifiés dans les établissements de 50 salariés et plus. Une part essentielle de ces flux provient des contrats à durée déterminée. Toutefois, à partir de 1988, les embauches fermes augmentent plus rapidement que les recrutements à durée déterminée qui, pour la première fois depuis 1983, diminuent en 1990. . La mobilité est plus importante dans les établissements de taille moyenne que dans les grands. Elle est aussi plus élevée dans le tertiaire que dans les autres secteurs. Enfin, les jeunes, les femmes et les professions les moins qualifiées occupent les emplois les moins stables.