Background Pathological cardiac hypertrophy is a major contributor of heart failure (HF), which seriously threatens human’s health world widely. Deregulation of m6A RNA methylation, and m6A methyltransferases and de-methyltransferases have been demonstrated to act essential roles in cardiac hypertrophy and HF. Here, we studied the potential roles and its underlying mechanisms of m6A Reader YTHDF proteins in HF. In this study, we constructed HF mouse model by transverse aortic constriction surgery. Primary cardiomyocytes were isolated and stimulated with isoproterenol (ISO) or phenylephrine (PHE) to induce myocardial hypertrophy. Results Through single-cell RNA-seq analysis, immunofluorescent staining, HE staining, Western blotting, and real time-PCR detections, we found that YTHDF2 mRNA and protein level, but not YTHDF1 or YTHDF3, was significantly increased during HF development. YTHDF2 overexpression could efficiently alleviate cardiac hypertrophy. Furthermore, through immunoprecipitation accompanied with mass spectrometry analysis, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that ISO stimulation did not evidently affect YTHDF2-interacting proteins. However, ISO or PHE stimulation significantly increased YTHDF2 protein interacting with Myh7 (beta-myosin heavy chain) mRNA, an important cardiac hypertrophy marker, in an m6A-dependent manner. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2 on cardiac hypertrophy. Finally, we found that ISO or PHE stimulation promoted YTHDF2 protein expression through enhancing Ythdf2 mRNA stability in an m6A-dependent manner in cardiomyocytes. Conclusions Overall, our results indicate that the m6A Reader YTHDF2 suppresses cardiac hypertrophy via Myh7 mRNA decoy in an m6A-dependent manner. This study highlights the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and provides a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.

Background Immunoinflammatory and nutritional markers, such as the peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and Onodera’s prognostic nutritional index (OPNI), have gained considerable attention and have been preliminarily revealed as prognostic markers of gastrointestinal stromal tumors (GISTs). Methods In this study, we first investigated the prognostic value of OPNI in GISTs treated with or without TKIs based on the propensity score matching (PSM) method. All of the patients had received surgical resection for primary GIST, and data from 2010 to 2018 were initially and retrospectively identified from our gastrointestinal center. Recurrence-free survival (RFS) was calculated by the Kaplan–Meier method and compared by the log-rank test. Results The patients were divided into groups treated and not treated with TKIs, and we used the propensity score matching method to homogenize their baseline data. Multivariate Cox proportional hazard regression models were applied to identify associations with outcome variables. A total of 563 GISTs were initially chosen, and 280 of them were included for analysis under the inclusion criteria. After PSM, there were 200 patients included. Multivariate analyses identified OPNI as an independent prognostic marker that was associated with primary site, tumor size, mitotic index, tumor rupture, necrosis, and modified NIH risk classification. Low OPNI (< 42.6; HR 0.409; P < 0.001) was associated with worse RFS. Conclusions Preoperative OPNI is a novel and useful prognostic marker for GISTs both treated and not treated with TKIs. Higher NLR and PLR have negative effects on RFS.

Background: Genes associated with arsenite uptake and transport in rice plants (i.e., OsLsi1, OsLsi2, OsLsi3, OsLsi6 and OsABCC1) have been identified to date. However, their expression over time during the whole growth period of rice under arsenite stress conditions is still poorly understood. In this study, the dynamics of gene expression associated with arsenite transport and arsenic concentrations in different organs of rice were investigated to determine the critical period(s) of arsenite uptake and translocation regulated by gene expression during the whole growth period. Results: The relative expression of OsLsi2 and OsLsi1 in the roots was upregulated and reached its highest value (2-ΔΔCt = 4.04 and 1.19, respectively) at the jointing stage (9 weeks after transplantation), in which the arsenic concentration in roots also was the highest at 144 mg/kg. A range from 45.1 to 61.2% of total arsenic accumulated in the roots during seedling to heading stages (3-16 weeks), which was mainly associated with the relatively high expression of OsABCC1 (1.50-7.68), resulting in arsenic located in the vacuoles of roots. Subsequently, the As translocation factor from root to shoot increased over time from heading to milky ripe (16-20 weeks), and 74.3% of the arsenic accumulated in shoots at the milk stage. Such an increase in arsenic accumulation in shoots was likely related to the findings that (i) OsABCC1 expression in roots was suppressed to 0.14-0.75 in 18-20 weeks; (ii) OsLsi3 and OsABCC1 expression in nodes I, II, and III was upregulated to 4.01-25.8 and 1.59-2.36, respectively, in 16-20 weeks; and (iii) OsLsi6 and OsABCC1 expression in leaves and husks was significantly upregulated to 2.03-5.26 at 18 weeks. Conclusions: The jointing stage is the key period for the expression of arsenite-transporting genes in roots, and the heading to milky ripe stages are the key period for the expression of arsenite-transporting genes in shoots, both of which should be considered for regulation during safe rice production in arsenic-contaminated paddy soil.

This meta-analysis suggests that LDV-SOF based therapy is a safe and effective treatment for patients with GT 1 HCV. The addition of RBV to LDV-SOF may increase toxicity without achieving improved efficacy. However, due to the relatively small sample sizes and moderate risk of bias of included studies, large-scale and high-quality clinical research is still needed to confirm the results.