Antigen - presentation by vascular endothelium : its role for CTL - mediated vascular injury

Background: EC express and present MHC class I restricted peptide antigens and due to the exposed position may be targeted by antigen-specific CTL. We wished to explore the type of vascular injury that is mediated by peptidespecific CTL in vivo when EC express the source protein from which the antigenic peptide is derived. Methods: We immunized mice that express E.coli -galactosidase (LacZ) as an antigen specifically under the control of the thrombomodulin promoter, i.e. in vascular endothelial cells, with -gal(500-507) pulsed dendritic cells. The peptide specific CTL-response was assessed in splenocytes by intracellular cytokine staining after peptide incubation and histopathological tissue sections were scrutinized for CTL-mediated EC injury. Results: After subcutaneous immunization, on average 1% of the CD8+ splenocytes were -gal-peptide specific effector cells. Despite of successful immunization we were unable to detect antigen-specific endothelial injury in TM-LacZ mice. A GVHD-like chronic inflammatory, antigen-specific disease characterized clinically by mild wasting was induced in ROSA26-LacZ mice, which ubiquitously express LacZ. Accidentally we observed persistent lung inflammatory infiltrates in mice that received intravenous injections of splenocytes or dendritic cells. These perivascular granuloma-like lesions consisted of highly proliferating CD11c+ recipient cells and were not the result of DC trapping. Conclusions: Endothelial cells escape CTL-mediated apoptosis in vivo. Intravenous injection of splenocytes and dendritic cells or both, leads to a model of pulmonary granuloma formation and this may represent an early stage of vasculitis

A Rare Case of a Primary Cardiac Tumor Presenting as Fatal Ventricular Tachycardia

Primary cardiac tumors are extremely uncommon. Here, we report the case of a patient with a primary left ventricular interstitial tumor presenting with hemodynamically unstable ventricular tachycardia. In response to hemodynamically unstable ventricular tachycardia, an implantable cardioverter-defibrillator was inserted. One month after defibrillator implantation, the patient developed episodes of high ventricular tachycardia that could not be effectively terminated by catheter radiofrequency ablation, thus further confirming that the ventricular tachycardia was induced by the left ventricular interstitial tumor. The patient is doing well on medical therapy to date

Identification of long non-protein coding RNAs in chicken skeletal muscle using next generation sequencing

AbstractVertebrate genomes encode thousands of non-coding RNAs including short non-coding RNAs (such as microRNAs) and long non-coding RNAs (lncRNAs). Chicken (Gallus gallus) is an important model organism for developmental biology, and the recently assembled genome sequences for chicken will facilitate the understanding of the functional roles of non-coding RNA genes during development. The present study concerns the first systematic identification of lncRNAs using RNA-Seq to sample the transcriptome during chicken muscle development. A computational approach was used to identify 281 new intergenic lncRNAs in the chicken genome. Novel lncRNAs in general are less conserved than protein-coding genes and slightly more conserved than random non-coding sequences. The present study has provided an initial chicken lncRNA catalog and greatly increased the number of chicken ncRNAs in the non-protein coding RNA database. Furthermore, the computational pipeline presented in the current work will be useful for characterizing lncRNAs obtained from deep sequencing data

Synthesis and Characterization of Cobalt-Doped WS2 Nanorods for Lithium Battery Applications

Cobalt-doped tungsten disulfide nanorods were synthesized by an approach involving exfoliation, intercalation, and the hydrothermal process, using commercial WS2 powder as the precursor and n-butyllithium as the exfoliating reagent. XRD results indicate that the crystal phase of the sample is 2H-WS2. TEM images show that the sample consists of bamboo-like nanorods with a diameter of around 20 nm and a length of about 200 nm. The Co-doped WS2 nanorods exhibit the reversible capacity of 568 mAh g−1 in a voltage range of 0.01–3.0 V versus Li/Li+. As an electrode material for the lithium battery, the Co-doped WS2 nanorods show enhanced charge capacity and cycling stability compared with the raw WS2 powder

Transcription factors TEAD2 and E2A globally repress acetyl-CoA synthesis to promote tumorigenesis.

Acetyl-coenzyme A (acetyl-CoA) plays an important role in metabolism, gene expression, signaling, and other cellular processes via transfer of its acetyl group to proteins and metabolites. However, the synthesis and usage of acetyl-CoA in disease states such as cancer are poorly characterized. Here, we investigated global acetyl-CoA synthesis and protein acetylation in a mouse model and patient samples of hepatocellular carcinoma (HCC). Unexpectedly, we found that acetyl-CoA levels are decreased in HCC due to transcriptional downregulation of all six acetyl-CoA biosynthesis pathways. This led to hypo-acetylation specifically of non-histone proteins, including many enzymes in metabolic pathways. Importantly, repression of acetyl-CoA synthesis promoted oncogenic dedifferentiation and proliferation. Mechanistically, acetyl-CoA synthesis was repressed by the transcription factors TEAD2 and E2A, previously unknown to control acetyl-CoA synthesis. Knockdown of TEAD2 and E2A restored acetyl-CoA levels and inhibited tumor growth. Our findings causally link transcriptional reprogramming of acetyl-CoA metabolism, dedifferentiation, and cancer

USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients

Proteogenomic characterization of hepatocellular carcinoma

We performed a proteogenomic analysis of hepatocellular carcinomas (HCCs) across clinical stages and etiologies. We identified pathways differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. These pathways are involved in the organization of cellular components, cell cycle control, signaling pathways, transcriptional and translational control and metabolism. Analyses of CNA-mRNA and mRNA-protein correlations identified candidate driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β- catenin pathway, transcriptional control, cholesterol biosynthesis and sphingolipid metabolism. The activity of targetable kinases aurora kinase A and CDKs was upregulated. We found that CTNNB1 mutations are associated with altered phosphorylation of proteins involved in actin filament organization, whereas TP53 mutations are associated with elevated CDK1/2/5 activity and altered phosphorylation of proteins involved in lipid and mRNA metabolism. Integrative clustering identified HCC subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our analysis provides insights into the molecular processes underlying HCCs

Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages.

Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome

Smooth ROC curve estimation via Bernstein polynomials.

The receiver operating characteristic (ROC) curve is commonly used to evaluate the accuracy of a diagnostic test for classifying observations into two groups. We propose two novel tuning parameters for estimating the ROC curve via Bernstein polynomial smoothing of the empirical ROC curve. The new estimator is very easy to implement with the naturally selected tuning parameter, as illustrated by analyzing both real and simulated data sets. Empirical performance is investigated through extensive simulation studies with a variety of scenarios where the two groups are both from a single family of distributions (symmetric or right skewed) or one from a symmetric and the other from a right skewed distribution. The new estimator is uniformly more efficient than the empirical ROC estimator, and very competitive to eleven other existing smooth ROC estimators in terms of mean integrated square errors

Virtual displacement based discontinuity layout optimization

Discontinuity layout optimization (DLO) is a relatively new upper bound limit analysis method. Compared to classic topology optimization methods, aimed at obtaining the optimum design of a structure by considering its self-weight, building cost, or bearing capacity, DLO optimizes the failure pattern of the structure under specific loading conditions and constraints by minimizing the dissipation energy. In this work, we present a modified DLO algorithm that contains all of the advantages of DLO. It is referred to virtual displacement-based discontinuity layout optimization (VDLO). VDLO takes the stress state of a loaded structure as a snapshot and correspondingly provides the optimum failure pattern, which greatly extends the application potential of DLO. Numerical examples indicate the effectiveness and flexibility of VDLO. It is regarded as a highly promising supplemental tool for other numerical methods in element-/node-based frameworks