293 research outputs found

    An epistatic mini-circuitry between the transcription factors Snail and HNF4\uce\ub1 controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

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    Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4\uce\ub1, directly represses the expression of the epithelial microRNAs (miRs)-200c and-34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4\uce\ub1, previously identified as a transcriptional repressor of Snail, induces the miRs-34a and-200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4\uce\ub1 and miRs-200a, b, c and-34a as epistatic elements controlling hepatic stem cell maintenance/differentiation. \uc2\ua9 2012 Macmillan Publishers Limited. All rights reserved

    Different aspects of emotional processes in apathy: Application of the French translated dimensional apathy scale

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    Apathy is a behavioural symptom that occurs in neuropsychiatric, neurological and neurodegenerative disease. It is defined as a lack of motivation and/or a quantitative reduction of goal-directed behaviour. Levy and Dubois Cerebral Cortex, 16(7), 916–928 (2006) proposed a triadic substructure of apathy and similar subtypes can be assessed using the Dimensional Apathy Scale (DAS), via the Executive, Emotional and Initiation subscales. The aim of this study was to translate the DAS in to French (f-DAS), examine its psychometric properties and the substructure of apathy using Confirmatory Factor Analysis (CFA). The results showed an acceptable internal consistency reliability of the f-DAS and a similar relationship to depression as in the original DAS development study. The CFA supported a triadic dimensional substructure of the f-DAS, similar to the original DAS but suggested a more complex substructure, specifically, two further processes of the Emotional apathy dimension relating to “Social Emotional” and “Individual Emotional” aspects of demotivation. To conclude, the f-DAS is a robust and reliable tool for assessing multidimensional apathy. Further research should explore the utility of the f-DAS in patients with neuropsychiatric diseases in view of social emotional aspects in apathy

    Genetic diversity and local connectivity in the mediterranean red gorgonian coral after mass mortality events

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    Estimating the patterns of connectivity in marine taxa with planktonic dispersive stages is a challenging but crucial task because of its conservation implications. The red gorgonian Paramuricea clavata is a habitat forming species, characterized by short larval dispersal and high reproductive output, but low recruitment. In the recent past, the species was impacted by mass mortality events caused by increased water temperatures in summer. In the present study, we used 9 microsatellites to investigate the genetic structure and connectivity in the highly threatened populations from the Ligurian Sea (NW Mediterranean). No evidence for a recent bottleneck neither decreased genetic diversity in sites impacted by mass mortality events were found. Significant IBD pattern and high global F-ST confirmed low larval dispersal capability in the red gorgonian. The maximum dispersal distance was estimated at 20-60 km. Larval exchange between sites separated by hundreds of meters and between different depths was detected at each site, supporting the hypothesis that deeper subpopulations unaffected by surface warming peaks may provide larvae for shallower ones, enabling recovery after climatically induced mortality events

    The Outcome of Phagocytic Cell Division with Infectious Cargo Depends on Single Phagosome Formation

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    Given that macrophages can proliferate and that certain microbes survive inside phagocytic cells, the question arises as to the post-mitotic distribution of microbial cargo. Using macrophage-like cells we evaluated the post-mitotic distribution of intracellular Cryptococcus yeasts and polystyrene beads by comparing experimental data to a stochastic model. For beads, the post-mitotic distribution was that expected from chance alone. However, for yeast cells the post-mitotic distribution was unequal, implying preferential sorting to one daughter cell. This mechanism for unequal distribution was phagosomal fusion, which effectively reduced the intracellular particle number. Hence, post-mitotic intracellular particle distribution is stochastic, unless microbial and/or host factors promote unequal distribution into daughter cells. In our system unequal cargo distribution appeared to benefit the microbe by promoting host cell exocytosis. Post-mitotic infectious cargo distribution is a new parameter to consider in the study of intracellular pathogens since it could potentially define the outcome of phagocytic-microbial interactions

    Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]

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    BACKGROUND: Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. METHODS: 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. RESULTS: During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. CONCLUSION: In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding

    Growth landscape formed by perception and import of glucose in yeast

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    An important challenge in systems biology is to quantitatively describe microbial growth using a few measurable parameters that capture the essence of this complex phenomenon. Two key events at the cell membrane—extracellular glucose sensing and uptake—initiate the budding yeast’s growth on glucose. However, conventional growth models focus almost exclusively on glucose uptake. Here we present results from growth-rate experiments that cannot be explained by focusing on glucose uptake alone. By imposing a glucose uptake rate independent of the sensed extracellular glucose level, we show that despite increasing both the sensed glucose concentration and uptake rate, the cell’s growth rate can decrease or even approach zero. We resolve this puzzle by showing that the interaction between glucose perception and import, not their individual actions, determines the central features of growth, and characterize this interaction using a quantitative model. Disrupting this interaction by knocking out two key glucose sensors significantly changes the cell’s growth rate, yet uptake rates are unchanged. This is due to a decrease in burden that glucose perception places on the cells. Our work shows that glucose perception and import are separate and pivotal modules of yeast growth, the interaction of which can be precisely tuned and measured.National Institutes of Health (U.S.). Pioneer AwardNatural Sciences and Engineering Research Council of Canada (NSERC). Graduate Fellowshi

    The Tempered Polymerization of Human Neuroserpin

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    Neuroserpin, a member of the serpin protein superfamily, is an inhibitor of proteolytic activity that is involved in pathologies such as ischemia, Alzheimer's disease, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The latter belongs to a class of conformational diseases, known as serpinopathies, which are related to the aberrant polymerization of serpin mutants. Neuroserpin is known to polymerize, even in its wild type form, under thermal stress. Here, we study the mechanism of neuroserpin polymerization over a wide range of temperatures by different techniques. Our experiments show how the onset of polymerization is dependent on the formation of an intermediate monomeric conformer, which then associates with a native monomer to yield a dimeric species. After the formation of small polymers, the aggregation proceeds via monomer addition as well as polymer-polymer association. No further secondary mechanism takes place up to very high temperatures, thus resulting in the formation of neuroserpin linear polymeric chains. Most interesting, the overall aggregation is tuned by the co-occurrence of monomer inactivation (i.e. the formation of latent neuroserpin) and by a mechanism of fragmentation. The polymerization kinetics exhibit a unique modulation of the average mass and size of polymers, which might suggest synchronization among the different processes involved. Thus, fragmentation would control and temper the aggregation process, instead of enhancing it, as typically observed (e.g.) for amyloid fibrillation
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