MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of β-catenin and its target genes CD44 and Lgr5. CONCLUSION Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling.BACKGROUND Wearable activity monitors that track step count can increase the wearer's physical activity and motivation but are infrequently designed for the slower gait speed and compensatory patterns after stroke. New and available technology may allow for the design of stroke-specific wearable monitoring devices, capable of detecting more than just step counts, which may enhance how rehabilitation is delivered. The objective of this study was to identify important considerations in the development of stroke-specific lower extremity wearable monitoring technology for rehabilitation, from the perspective of physical therapists and individuals with stroke. METHODS A qualitative research design with focus groups was used to collect data. Five focus groups were conducted, audio recorded, and transcribed verbatim. Data were analyzed using content analysis to generate overarching categories representing the stakeholder considerations for the development of stroke-specific wearable monitor technology for the lower elopment of stroke-specific lower extremity wearable monitoring technology is viewed positively by physical therapists and individuals with stroke. While a single, specific device or function may not accommodate all the variable needs of therapists and their clients, it was agreed that wearable monitoring technology could enhance how physical therapists assess and treat their clients. Future wearable devices should be developed in consideration of the highlighted design features and potential barriers for uptake.BACKGROUND Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM). METHODS RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3'UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints. RESULTS Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients. CONCLUSION Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively.BACKGROUND Top tier commercial physical activity apps rarely undergo peer-reviewed evaluation. Even fewer are assessed beyond six months, the theoretical threshold for behaviour maintenance. The purpose of this study was to examine whether a multi-component commercial app rewarding users with digital incentives for walking was associated with an increase in physical activity over one year. METHODS This 12-month quasi-experimental study was conducted in two Canadian provinces (n = 39,113 participants). Following a two-week baseline period, participants earned digital incentives ($0.04 CAD/day) every day they reached a personalized daily step goal. Mixed-effects models estimated changes in weekly mean daily step count between the baseline period and the last two recorded weeks. Models were fit for several engagement groups and separately by baseline physical activity status within engagement groups. RESULTS Nearly half of participants (43%) were categorized as physically inactive at baseline (fewer than 5000 daily steps), and 60% engaged with the app for at least six months ['Regular' (24-51 weeks of step data) or 'Committed' sub-groups (52 weeks)]. Weekly mean daily step count increased for physically inactive users regardless of engagement status (P  less then  .0001). The increase was largest for 'Regular' and 'Committed' participants-1215 and 1821 steps/day, respectively. For physically active participants, step count increases were only observed in the 'Committed' sub-group (P  less then  .0001).  https://www.selleckchem.com/products/bismuth-subnitrate.html  Effect sizes were modest-to-medium depending on the sub-group analyzed. CONCLUSIONS A commercial app providing small but immediate digital incentives for individualized goals was associated with an increased weekly mean daily step count on a population-scale over one year. This effect was more evident for physically inactive and more engaged participants.BACKGROUND The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). METHODS We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach.