Search results for "expression"
showing 10 items of 5168 documents
Identifying Prognostic SNPs in Clinical Cohorts: Complementing Univariate Analyses by Resampling and Multivariable Modeling
2016
Clinical cohorts with time-to-event endpoints are increasingly characterized by measurements of a number of single nucleotide polymorphisms that is by a magnitude larger than the number of measurements typically considered at the gene level. At the same time, the size of clinical cohorts often is still limited, calling for novel analysis strategies for identifying potentially prognostic SNPs that can help to better characterize disease processes. We propose such a strategy, drawing on univariate testing ideas from epidemiological case-controls studies on the one hand, and multivariable regression techniques as developed for gene expression data on the other hand. In particular, we focus on …
The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages
2016
The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 del…
Influence of middle-distance running on muscular micro RNAs
2018
A specific subset of micro RNAs (miRs), including miR-133 and miR-206, is specifically expressed in muscle tissue, so that they are currently defined as muscular miRs (myomiRs). To further elucidate the role of myomiRs in muscle biology, we measured miR-133a and miR-206 in plasma of 28 middle-age recreational athletes. The study population consisted of 28 middle aged, recreation athletes (11 women and 17 men; mean age, 46 years) who completed a 21.1 km, half-marathon. The plasma concentration of miR-133a and miR-206, the serum concentration of creatine kinase (CK) and high-sensitivity (HS) cardiac troponin T (cTnT), as well as capillary lactate, were measured before and immediately after th…
Molecular docking-based design and development of a highly selective probe substrate for UDP-glucuronosyltransferase 1A10
2018
Intestinal and hepatic glucuronidation by the UDP-glucuronosyltransferases (UGTs) greatly affect the bioavailability of phenolic compounds. UGT1A10 catalyzes glucuronidation reactions in the intestine, but not in the liver. Here, our aim was to develop selective, fluorescent substrates to easily elucidate UGT1A10 function. To this end, homology models were constructed and used to design new substrates, and subsequently, six novel C3-substituted (4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 4-methylphenyl, or triazole) 7-hydroxycoumarin derivatives were synthesized from inexpensive starting materials. All tested compounds could be glucuronidated to nonfluorescen…
The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
2020
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptid…
Human norovirus hyper-mutation revealed by ultra-deep sequencing
2016
Human noroviruses (NoVs) are a major cause of gastroenteritis worldwide. It is thought that, similar to other RNA viruses, high mutation rates allow NoVs to evolve fast and to undergo rapid immune escape at the population level. However, the rate and spectrum of spontaneous mutations of human NoVs have not been quantified previously. Here, we analyzed the intra-patient diversity of the NoV capsid by carrying out RT-PCR and ultra-deep sequencing with 100,000-fold coverage of 16 stool samples from symptomatic patients. This revealed the presence of low-frequency sequences carrying large numbers of U-to-C or A-to-G base transitions, suggesting a role for hyper-mutation in NoV diversity. To mor…
Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity
2016
SummaryThe extracellular matrix (ECM) contributes to the biological and clinical heterogeneity of breast cancer, and different prognostic groups can be identified according to specific ECM signatures. In high-grade, but not low-grade, tumors, an ECM signature characterized by high SPARC expression (ECM3) identifies tumors with increased epithelial-to-mesenchymal transition (EMT), reduced treatment response, and poor prognosis. To better understand how this ECM3 signature is contributing to tumorigenesis, we expressed SPARC in isogenic cell lines and found that SPARC overexpression in tumor cells reduces their growth rate and induces EMT. SPARC expression also results in the formation of a h…
Arsenic promotes NF-Κb-mediated fibroblast dysfunction and matrix remodeling to impair muscle stem cell function
2016
Abstract Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration …
Approaching Sex Differences in Cardiovascular Non-Coding RNA Research
2020
International audience; Cardiovascular disease (CVD) is the biggest cause of sickness and mortality worldwide in both males and females. Clinical statistics demonstrate clear sex differences in risk, prevalence, mortality rates, and response to treatment for different entities of CVD. The reason for this remains poorly understood. Non-coding RNAs (ncRNAs) are emerging as key mediators and biomarkers of CVD. Similarly, current knowledge on differential regulation, expression, and pathology-associated function of ncRNAs between sexes is minimal. Here, we provide a state-of-the-art overview of what is known on sex differences in ncRNA research in CVD as well as discussing the contributing biol…
Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells
2018
Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlip(IEC-tg) mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vF…