Biology subjects

Yin, X.

Publications and source records attributed to Yin, X..

4 recordsLinked to original sources

bioRxiv2018

Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Fibrosis and inflammation promote atrial fibrillation (AF) and worsen its clinical outcome. The underlying molecular mechanisms, that are relevant for effective antifibrotic drug development, are still under debate. This study deciphers a novel mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-inflammatory cytokine osteopontin (OPN) in the pathogenesis of atrial fibrosis. Compared to sinus rhythm (SR) controls, right atrial appendages and isolated right atrial fibroblasts from AF patients showed downregulation of PLK2 mRNA and protein levels, which were accompanied by remarkable hypoxia-sensitive DNA-methylation of the PLK2 promotor. In an experimental setting, both, genetic deletion and pharmacological inhibition of PLK2 induced myofibroblast differentiation and reduced fibroblast proliferation. Notably, proteomics from PLK2-deleted fibroblasts revealed de novo secretion of OPN. Accordingly, we observed higher OPN plasma levels in AF patients with atrial fibrosis compared to non-fibrosis AF patients. Hence, we provide evidence for PLK2 reactivation and/or OPN inhibition as potential novel targets to prevent fibrosis progression in AF.

pharmacology and toxicology↗

bioRxiv2018

NOVEL INSIGHTS INTO SELECTION FOR ANTIBIOTIC RESISTANCE IN COMPLEX MICROBIAL COMMUNITIES

Recent research has demonstrated selection for antibiotic resistance occurs at very low antibiotic concentrations in single species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low sub-inhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a two order magnitude concentration range. This is likely to be due to cross-protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses on sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment for blaCTX-M genes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.

microbiology↗

bioRxiv2018

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

genetics↗

bioRxiv2017

Research on Mitochondrial DNA Mutations in Patients with SCA3/MJD

Spinocerebellar ataxia type 3 (SCA3) is a degenerative neurological disorders caused by trinucleotide repeat expansion within the ataxin-3 gene. It is characterized by multi-system involvement and diverse clinical phenotypes, which cannot be fully explained the length of the CAG repeats. One possible explanation for the phenotypic heterogeneity could be the presence of mitochondrial DNA mutations that modify disease severity. To explore the role of Mitochondrial DNA(mtDNA) variations in SCA3 pathogenesis, we analyzed polymorphisms of six mitochondrial genes, MT-LT1, MT-ND1, MT-CO2, MT-TK, MT-ATP8 and MT-ATP6, in 102 unrelated SCA3/MJD patients and 100 healthy controls. The results showed that there were 24 variations of those mtDNA genes in the SCA3 patients and only 10 in the unrelated healthy controls. There was no difference of the relative mtDNA copy number variation between the SCA3 patients and healthy controls (93.20 vs. 89.66, P>0.05). In the group of SCA3 patients, the relative mtDNA copy number showed a negative correlation between the number of CAG repeats (r=-0.210, P < 0.05), but did not correlate with the age at diagnosis, the age of onset, disease duration, ICARS scores and SARA scores. Our research demonstrated that the frequency of mutated mtDNA in SCA3 patients was higher than that in the healthy group. The mtDNA relative copy number in SCA3 patients was not significantly different compared to the healthy group. Thus, the copy number might not be treated as a biomedical indicator when measuring the severity of illness in SCA3 patients.

genetics↗