FREE ORAL COMMUNICATIONS 2: ALCOHOL AND LIVER—CLINICAL RESEARCHO2.1RAPID DECLINE OF LIVER STIFFNESS WITH ALCOHOL WITHDRAWAL IN HEAVY DRINKERS

Background and aims. Measurement of liver stiffness using real-time elastography appears as a promising tool to evaluate the severity of chronic liver diseases. Previous studies in patients with alcoholic liver disease have suggested that fibrosis was the only histological parameter to influence liver stiffness. To challenge this hypothesis, we have prospectively tested the short-term impact of alcohol withdrawal on liver stiffness value. Methods. All patients hospitalized for alcohol withdrawal in our Liver Unit between September 2008 and December 2010 had a liver stiffness determination (using a FibroScan® device) at entry (D0) and 7 days after alcohol withdrawal (D7). Stiffness values were compared using non-parametric test for paired-values. We compared (i) the 10 measures performed at D0 and at D7 for each patient; (ii) the variation of the median result of all patients (using Wilcoxon test in both cases). Results. A total of 138 patients were included in the study [median alcohol consumption: 150g/day (range: 40-400); hepatitis C: n=22 (15.9%); cirrhosis: n=29 (21.0%)]. From D0 to D7, the liver stiffness decreased significantly in 61 patients (44.2%) and increased significantly in 18 (13.0%). Considering all patients, median liver stiffness value decreased from 7.25 to kPa (P<0.001). The stage of fibrosis indicated by liver stiffness changed in 47 patients between D0 and D7 (decrease in 33 and increase in 14). Conclusion. Liver stiffness decreases significantly in nearly half of alcoholic patients after only 7 days of abstinence. This result strongly suggests that non-fibrotic lesions (such as inflammatory ones) may influence liver stiffness. From a practical point of view, it also shows that variation in alcohol consumption must be taken into account for the interpretation of liver stiffness valu

TOPAZ1, a Novel Germ Cell-Specific Expressed Gene Conserved during Evolution across Vertebrates

BACKGROUND: We had previously reported that the Suppression Subtractive Hybridization (SSH) approach was relevant for the isolation of new mammalian genes involved in oogenesis and early follicle development. Some of these transcripts might be potential new oocyte and granulosa cell markers. We have now characterized one of them, named TOPAZ1 for the Testis and Ovary-specific PAZ domain gene. PRINCIPAL FINDINGS: Sheep and mouse TOPAZ1 mRNA have 4,803 bp and 4,962 bp open reading frames (20 exons), respectively, and encode putative TOPAZ1 proteins containing 1,600 and 1653 amino acids. They possess PAZ and CCCH domains. In sheep, TOPAZ1 mRNA is preferentially expressed in females during fetal life with a peak during prophase I of meiosis, and in males during adulthood. In the mouse, Topaz1 is a germ cell-specific gene. TOPAZ1 protein is highly conserved in vertebrates and specifically expressed in mouse and sheep gonads. It is localized in the cytoplasm of germ cells from the sheep fetal ovary and mouse adult testis. CONCLUSIONS: We have identified a novel PAZ-domain protein that is abundantly expressed in the gonads during germ cell meiosis. The expression pattern of TOPAZ1, and its high degree of conservation, suggests that it may play an important role in germ cell development. Further characterization of TOPAZ1 may elucidate the mechanisms involved in gametogenesis, and particularly in the RNA silencing process in the germ lin

Impacts du changement climatique sur la ressource en eau et la gestion des lacs-réservoirs du bassin de la Seine (France)

National audienceThe Seine River basin is characterized by high stakes on water resources due to a variety of uses and increasing pressure. Satisfying these water needs is a huge challenge on this basin hosting the most urbanized and densely populated area in France: more than 6.5 million inhabitants in the Paris region are supplied with drinkable water coming from rivers while one nuclear power plant and two coal fired plants ensure power generation in the region. Furthermore several large wastewater treatment plants (incl. the largest one in Europe) release their waters into the Seine, with possible consequences on the quality of water during low flows. The Seine Grands Lacs basin authority owns and manages four large artificial reservoirs on the river Seine and its tributaries (totaling a capacity of 800 hm3) with two main goals: flood alleviation and low-flow augmentation. The CLIMAWARE research project (2010-2014) characterized the impacts of climate change on flows of the Seine River basin and on reservoir management by mid-21st century. Performance indicators representative of the tension on water resources were calculated to assess the impact of climate change. Various adaptation measures were tested including the modification of the objective seasonal filling curves, as well as modifications of the real-time management techniques. Adaptation measures can bring some improvements, but even with this adaptive management, the indicators show that the impacts of climate change on low flows will be major on the basin.Impacts du changement climatique sur la ressource en eau et la gestion des lacs-réservoirs du bassin de la Seine (France) Le bassin-versant de la Seine à Paris est caractérisé par de forts enjeux sur la ressource en eau. Les prélèvements y sont considérables : plus de 6,5 millions d'habitants en Ile-de-France sont alimentés en eau potable à partir des eaux de surface, tandis qu'une centrale nucléaire et deux centrales thermiques assurent la production électrique sur le bassin. Par ailleurs, la Seine est le milieu récepteur de plusieurs stations d'épuration (incluant la plus grande d'Europe), impliquant des enjeux pour la qualité de l'eau en période d'étiage. L'EPTB Seine Grands Lacs soutient ces enjeux avec quatre lacs-réservoirs d'une capacité de 800 millions de m3, chargés de soutenir les étiages et écrêter les crues. Le projet CLIMAWARE (2010-2014) a étudié les impacts du changement climatique sur l'hydrologie du bassin et la gestion des lacs-réservoirs à l'horizon du milieu du 21ème siècle, en proposant et évaluant des stratégies d'adaptation de la gestion des lacs-réservoirs. Des indicateurs de performance représentatifs de la tension sur les usages (limitation des autorisations des débits prélevés, risque sur la qualité des eaux...) ont été calculés afin d'évaluer l'impact du changement climatique pour différents scénarios de gestion des réservoirs. Les mesures envisagées d'adaptation des règles de gestion des lacs-réservoirs permettent une légère amélioration des performances, mais même avec cette gestion adaptée, les indicateurs montrent un impact significatif sur les étiages

Cyclin A1 protein shows haplo-insufficiency for normal fertility in male mice

In higher eukaryotes, the cyclins constitute a family of proteins involved in progression through the cell cycle. The cyclin A1 gene (Ccna1) is expressed during meiosis and is required for spermatogenesis. Targeted disruption of the Ccna1 gene with a LacZ reporter gene has allowed us to study the expression pattern of this gene in more detail. We have confirmed expression in mouse pre-meiotic spermatocytes and also detected expression in the accessory olfactory bulb, hippocampus and amygdala of the adult brain. We have also found that the amount of cyclin A1 protein influences the fertility of male mice and its action is modulated by genetic background. On an outbred genetic background (129S6/SvEv × MF1), Ccna1tm1Col -/- animals are sterile due to spermatogenic arrest prior to the first meiotic division while Ccna1tm1Col +/- mice show reduced sperm production and fertility. This is even more pronounced on an inbred genetic background (129S6/SvEv) where Ccna1tm1Col +/- male mice are sterile due to a severe reduction in the total number of sperm

Impacts du changement climatique sur la gestion multi-objectif de réservoirs : cas d'étude sur le bassin versant de la Seine, France

International audienceAdaptation strategies will be needed to cope with the hydrological consequences of projected climate change. In this perspective, the management of many artificial reservoirs will have to be adapted to continue to fulfil downstream objectives (e.g. flow regulation). This study evaluates the sustainability of the management rules of the artificial reservoirs on the Seine River basin, France, under climate change scenarios. The Seine River basin at Paris (43,800 km2) has major socio-economic stakes for France, and the consequences of droughts and floods may be dramatic. In this context, four large multi-purpose reservoirs were built on the basin during the twentieth century for low-flow augmentation and flood alleviation. A hydrological modelling chain was designed to explicitly account for reservoir management rules. It was calibrated in current conditions and then fed by the outputs of seven climate models in present and future conditions, forced by the A1B IPCC scenario, downscaled using a weather-type method and statistically bias-corrected. The results show that the hydrological model performs quite well in current conditions. The simulations made in present and future conditions indicate a decrease in water availability and summer low flows, but no significant trends in high flows. Simulations also indicate that there is room for progress in the current multi-purpose management of reservoirs and that it would be useful to define proper adaptation strategies

Linear TMC-95-based proteasome inhibitors.

International audienc

A Nuclear Export Signal and Phosphorylation Regulate Dok1 Subcellular Localization and Functions

Dok1 is believed to be a mainly cytoplasmic adaptor protein which down-regulates mitogen-activated protein kinase activation, inhibits cell proliferation and transformation, and promotes cell spreading and cell migration. Here we show that Dok1 shuttles between the nucleus and cytoplasm. Treatment of cells with leptomycin B (LMB), a specific inhibitor of the nuclear export signal (NES)-dependent receptor CRM1, causes nuclear accumulation of Dok1. We have identified a functional NES ((348)LLKAKLTDPKED(359)) that plays a major role in the cytoplasmic localization of Dok1. Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1. Dok1 cytoplasmic localization is also dependent on IKKβ. Serum starvation or maintaining cells in suspension favor Dok1 nuclear localization, while serum stimulation, exposure to growth factor, or cell adhesion to a substrate induce cytoplasmic localization. Functionally, nuclear NES-mutant Dok1 had impaired ability to inhibit cell proliferation and to promote cell spreading and cell motility. Taken together, our results provide the first evidence that Dok1 transits through the nucleus and is actively exported into the cytoplasm by the CRM1 nuclear export system. Nuclear export modulated by external stimuli and phosphorylation may be a mechanism by which Dok1 is maintained in the cytoplasm and membrane, thus regulating its signaling functions