Estimating the Lunar Core Equatorial Ellipticity using Lunar Laser Ranging

No abstract availabl

Hepatitis C virus-induced hepatocellular carcinoma

Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs

Power-Aware Real-Time Scheduling upon Identical Multiprocessor Platforms

In this paper, we address the power-aware scheduling of sporadic constrained-deadline hard real-time tasks using dynamic voltage scaling upon multiprocessor platforms. We propose two distinct algorithms. Our first algorithm is an off-line speed determination mechanism which provides an identical speed for each processor. That speed guarantees that all deadlines are met if the jobs are scheduled using EDF. The second algorithm is an on-line and adaptive speed adjustment mechanism which reduces the energy consumption while the system is running.Comment: The manuscript corresponds to the final version of SUTC 2008 conferenc

Power-Aware Real-Time Scheduling on Identical Multiprocessor Platforms

In the following, we consider the problem of minimizing the energy consumption needed for executing a set of real-time tasks scheduled on a fixed number of identical processors. The scheduling is preemptive and follows the global EDF policy. ``Global'' scheduling algorithms, on the contrary to partitioned algorithms, allows different instances of the same task (also called jobs or processes) to be executed upon different processors. Each process can start its execution on any processor and may migrate at run-time from one processor to another if it gets preempted by smaller-deadline processes. We first tackle the problem of choosing the smallest admissible processor frequency for the set of CPUs such that all deadlines will be met considering the worst-case workload. The procedure is performed off-line and provides a static result in the sense that the computed speed does not change over time. Such a static solution is necessary, however, due to the discrepancy between worst-Case Execution Times (WCET) and Actual-Case Execution Times (ACET), it usually leads to very conservative results. In a second step, we thus propose an on-line ``slack reclaiming'' scheme that monitors task executions and take advantage of unused CPU time to further reduce frequency

ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition

Background: Epithelial mesenchymal transition (EMT) is tightly regulated by a network of transcription factors (EMT-TFs). Among them is the nuclear factor ZEB2, a member of the zinc-finger E-box binding homeobox family. ZEB2 nuclear localization has been identified in several cancer types, and its overexpression is correlated with the malignant progression. ZEB2 transcriptionally represses epithelial genes, such as E-cadherin (CDH1), by directly binding to the promoter of the genes it regulates and activating mesenchymal genes by a mechanism in which there is no full agreement. Recent studies showed that EMT-TFs interact with epigenetic regulatory enzymes that alter the epigenome, thereby providing another level of control. The role of epigenetic regulation on ZEB2 function is not well understood. In this study, we aimed to characterize the epigenetic effect of ZEB2 repressive function on the regulation of a small Rab GTPase RAB25. Results: Using cellular models with conditional ZEB2 expression, we show a clear transcriptional repression of RAB25 and CDH1. RAB25 contributes to the partial suppression of ZEB2-mediated cell migration. Furthermore, a highly significant reverse correlation between RAB25 and ZEB2 expression in several human cancer types could be identified. Mechanistically, ZEB2 binds specifically to E-box sequences on the RAB25 promoter. ZEB2 binding is associated with the local increase in DNA methylation requiring DNA methyltransferases as well as histone deacetylation (H3K9Ac) depending on the activity of SIRT1. Surprisingly, SIRT1 and DNMTs did not interact directly with ZEB2, and while SIRT1 inhibition decreased the stability of long-term repression, it did not prevent down-regulation of RAB25 and CDH1 by ZEB2. Conclusions: ZEB2 expression is resulting in drastic changes at the chromatin level with both clear DNA hypermethylation and histone modifications. Here, we revealed that SIRT1-mediated H3K9 deacetylation helps to maintain gene repression but is not required for the direct ZEB2 repressive function. Targeting epigenetic enzymes to prevent EMT is an appealing approach to limit cancer dissemination, but inhibiting SIRT1 activity alone might have limited effect and will require drug combination to efficiently prevent EMT

Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2

Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box-binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c(+) cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c(+) cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2

Genomic insights into the conservation status of the world’s last remaining Sumatran rhinoceros populations

Highly endangered species like the Sumatran rhinoceros are at risk from inbreeding. Five historical and 16 modern genomes from across the species range show mutational load, but little evidence for local adaptation, suggesting that future inbreeding depression could be mitigated by assisted gene flow among populations. Small populations are often exposed to high inbreeding and mutational load that can increase the risk of extinction. The Sumatran rhinoceros was widespread in Southeast Asia, but is now restricted to small and isolated populations on Sumatra and Borneo, and most likely extinct on the Malay Peninsula. Here, we analyse 5 historical and 16 modern genomes from these populations to investigate the genomic consequences of the recent decline, such as increased inbreeding and mutational load. We find that the Malay Peninsula population experienced increased inbreeding shortly before extirpation, which possibly was accompanied by purging. The populations on Sumatra and Borneo instead show low inbreeding, but high mutational load. The currently small population sizes may thus in the near future lead to inbreeding depression. Moreover, we find little evidence for differences in local adaptation among populations, suggesting that future inbreeding depression could potentially be mitigated by assisted gene flow among populations

A Non-Cytosolic Protein of Trypanosoma evansi Induces CD45-Dependent Lymphocyte Death

In a recent study dealing with a mouse model of Trypanosoma evansi-associated disease, a remarkable synchrony between the parasitaemia peak and the white-blood-cell count nadir was noticed. The present study was designed to establish whether there is a direct causal link between the parasite load during its exponential phase of growth and the disappearance of peripheral blood leukocytes. In vitro experiments performed with trypanosomes and purified peripheral blood mononucleated cells revealed the existence of a lymphotoxin embedded in the T. evansi membrane: a protein sensitive to serine proteases, with a molecular mass of less than 30 kDa. Lymphocytes death induced by this protein was found to depend on the intervention of a lymphocytic protein tyrosine phosphatase. When lymphocytes were exposed to increasing quantities of a monoclonal antibody raised against the extracellular portion of CD45, a transmembrane protein tyrosine phosphatase covering over 10% of the lymphocyte surface, T. evansi membrane extracts showed a dose-dependent decrease in cytotoxicity. As the regulatory functions of CD45 concern not only the fate of lymphocytes but also the activation threshold of the TCR-dependent signal and the amplitude and nature of cytokinic effects, this demonstration of its involvement in T. evansi-dependent lymphotoxicity suggests that T. evansi might manipulate, via CD45, the host's cytokinic and adaptive responses