The proximal cis-acting elements Sp1, Sp3 and E2F regulate mouse mer gene transcription in sertoli cells

Mer belongs to the Tyro 3 family of receptor tyrosine kinases (RTKs). Together with Axl and Rse, the three RTKs are believed to play important functional roles in the male gonads because gene knockout male mice lacking all of these receptors are infertile. In the present study, postnatal expression of Axl and Rse in mouse testes decreased during maturation while expression of Mer increased age-dependently during testicular development. To investigate the transcriptional regulation of gene expression in the testis, a ≈ 1.5 kb fragment of the 5′ flanking sequence of Mer was isolated. The sequence lacks a typical TATA or CAAT box. 5′ RACE revealed that the putative major transcriptional start site of Mer is located at +102 bp upstream of the translation initiation site. Using transient transfections of luciferase reporter constructs driven by various lengths of the 5′ flanking sequence, the gene segment -321/+126 showed the highest transcriptional activity in a mouse Sertoli cell line (TM4). DNAase I footprinting experiments revealed four footprints within the region from -321 to -26, including three binding sites for the transcriptional factor Specificity protein 1 (Sp1) and one for an unknown transcriptional factor. Electrophoretic mobility shift assay (EMSA), supershift assay, mutation studies and cotransfection demonstrated that those Sp1 cis-acting motifs interacted either with Sp1 or Sp1/Sp3, depending on location and the nearby nucleotide sequences. An E2F binding site which down-regulates Mer transcription, as revealed by EMSA, deletion and mutation studies, was identified downstream in the proximity of the promoter. Taking all of these data together, the study has demonstrated that Sp1, Sp3, E2F and probably another unknown transcriptional factor play a critical role in regulating the proximal promoter activities of Mer.postprin

Abstract Model Counting: A Novel Approach for Quantification of Information Leaks

acmid: 2590328 keywords: model checking, quantitative information flow, satisfiability modulo theories, symbolic execution location: Kyoto, Japan numpages: 10acmid: 2590328 keywords: model checking, quantitative information flow, satisfiability modulo theories, symbolic execution location: Kyoto, Japan numpages: 10acmid: 2590328 keywords: model checking, quantitative information flow, satisfiability modulo theories, symbolic execution location: Kyoto, Japan numpages: 10We present a novel method for Quantitative Information Flow analysis. We show how the problem of computing information leakage can be viewed as an extension of the Satisfiability Modulo Theories (SMT) problem. This view enables us to develop a framework for QIF analysis based on the framework DPLL(T) used in SMT solvers. We then show that the methodology of Symbolic Execution (SE) also fits our framework. Based on these ideas, we build two QIF analysis tools: the first one employs CBMC, a bounded model checker for ANSI C, and the second one is built on top of Symbolic PathFinder, a Symbolic Executor for Java. We use these tools to quantify leaks in industrial code such as C programs from the Linux kernel, a Java tax program from the European project HATS, and anonymity protocol

Metagenomic evidence for a polymicrobial signature of sepsis

Our understanding of the host component of sepsis has made significant progress. However, detailed study of the microorganisms causing sepsis, either as single pathogens or microbial assemblages, has received far less attention. Metagenomic data offer opportunities to characterize the microbial communities found in septic and healthy individuals. In this study we apply gradient-boosted tree classifiers and a novel computational decontamination technique built upon SHapley Additive exPlanations (SHAP) to identify microbial hallmarks which discriminate blood metagenomic samples of septic patients from that of healthy individuals. Classifiers had high performance when using the read assignments to microbial genera [area under the receiver operating characteristic (AUROC=0.995)], including after removal of species ‘culture-confirmed’ as the cause of sepsis through clinical testing (AUROC=0.915). Models trained on single genera were inferior to those employing a polymicrobial model and we identified multiple co-occurring bacterial genera absent from healthy controls. While prevailing diagnostic paradigms seek to identify single pathogens, our results point to the involvement of a polymicrobial community in sepsis. We demonstrate the importance of the microbial component in characterising sepsis, which may offer new biological insights into the aetiology of sepsis, and ultimately support the development of clinical diagnostic or even prognostic tools

Effect of mixed convection on laminar vortex breakdown in a cylindrical enclosure with a rotating bottom plate

© 2020 Elsevier Masson SAS Vortex breakdown plays a central role in the performance of countless rotating machinery applications, many of which contain thermal gradients either inadvertently or by design. The effect of thermal gradients on vortex breakdown and further flow development in a cylindrical domain with a rotating bottom plate is examined using the Generalized Integral Transformation Technique (GITT) with a streamfunction-only formulation. A thermal gradient is imposed in the axial direction, such that the buoyancy forces oppose the base flow driven by the rotation of the lower plate, i.e. the temperature difference acts to stabilize the flow. The hybrid numerical-analytical approach is shown to accurately capture vortex breakdown phenomena for a variety of conditions involving single, double and triple recirculation bubbles. The buoyancy forces – expressed in terms of the Richardson number (Ri) – act to suppress vortex breakdown in all cases examined and led to a series of flow transitions with increasing Ri, characterized by the appearance of a stratified structure with multiple fluid layers. These flow transitions have a significant impact on the overall performance of the system. The torque coefficient decreases with Ri, compared to the base (isothermal) case following an empirical power law relationship, which is independent of Reynolds number, aspect ratio or number of fluid layers present. Flow stratification suppresses the transport of angular momentum; azimuthal velocity is shown to decline exponentially in the regions where layering occurs, accompanied by a sharp reduction in the Nusselt number, as fluid layers act to insulate the upper plate

A multidisciplinary programme to care people with suicide and attempted suicide in the Eastern District

Congress Theme: New Discoveries and Technologies in Suicide PreventionSession - OP20-7N: Understanding and Helping Suicide Attempters 2BACKGROUND: Suicide is a highly taboo and stigmatized issue in Chinese societies. This greatly affects people’s help-seeking behaviour when encountering such problems. The community -based suicide prevention progamme aims at targeting all individuals with or without risky suicidal behavior to help promote its prevention to minimize its stigmatisation and to enhance help-seeking behavior. Collaboration platform among various disciplines had been ..

Pre-existing T cell-mediated cross-reactivity to SARS-CoV-2 cannot solely be explained by prior exposure to endemic human coronaviruses

T-cell-mediated immunity to SARS-CoV-2-derived peptides in individuals unexposed to SARS-CoV-2 has been previously reported. This pre-existing immunity was suggested to largely derive from prior exposure to ‘common cold’ endemic human coronaviruses (HCoVs). To test this, we characterised the sequence homology of SARS-CoV-2-derived T-cell epitopes reported in the literature across the full proteome of the Coronaviridae family. 54.8% of these epitopes had no homology to any of the HCoVs. Further, the proportion of SARS-CoV-2-derived epitopes with any level of sequence homology to the proteins encoded by any of the coronaviruses tested is well-predicted by their alignment-free phylogenetic distance to SARS-CoV-2 (Pearson's r = −0.958). No coronavirus in our dataset showed a significant excess of T-cell epitope homology relative to the proportion of expected random matches, given their genetic similarity to SARS-CoV-2. Our findings suggest that prior exposure to human or animal-associated coronaviruses cannot completely explain the T-cell repertoire in unexposed individuals that recognise SARS-CoV-2 cross-reactive epitopes

Interpopulation hybridization results in widespread viability selection across the genome in Tigriopus californicus

Background: Genetic interactions within hybrids influence their overall fitness. Understanding the details of these interactions can improve our understanding of speciation. One experimental approach is to investigate deviations from Mendelian expectations (segregation distortion) in the inheritance of mapped genetic markers. In this study, we used the copepod Tigriopus californicus, a species which exhibits high genetic divergence between populations and a general pattern of reduced fitness in F2 interpopulation hybrids. Previous studies have implicated both nuclear-cytoplasmic and nuclear-nuclear interactions in causing this fitness reduction. We identified and mapped population-diagnostic single nucleotide polymorphisms (SNPs) and used these to examine segregation distortion across the genome within F2 hybrids.Results: We generated a linkage map which included 45 newly elucidated SNPs and 8 population-diagnostic microsatellites used in previous studies. The map, the first available for the Copepoda, was estimated to cover 75% of the genome and included markers on all 12 T. californicus chromosomes. We observed little segregation distortion in newly hatched F2 hybrid larvae (fewer than 10% of markers at p < 0.05), but strikingly higher distortion in F2 hybrid adult males (45% of markers at p < 0.05). Hence, segregation distortion was primarily caused by selection against particular genetic combinations which acted between hatching and maturity. Distorted markers were not distributed randomly across the genome but clustered on particular chromosomes. In contrast to other studies in this species we found little evidence for cytonuclear coadaptation. Instead, different linkage groups exhibited markedly different patterns of distortion, which appear to have been influenced by nuclear-nuclear epistatic interactions and may also reflect genetic load carried within the parental lines.Conclusion: Adult male F2 hybrids between two populations of T. californius exhibit dramatic segregation distortion across the genome. Distorted loci are clustered within specific linkage groups, and the direction of distortion differs between chromosomes. This segregation distortion is due to selection acting between hatching and adulthood