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Background As a class of natural antioxidants in plants, fruit flavonol metabolites are beneficial to human health. However, the regulatory networks for flavonol biosynthesis in most fruits are largely unknown. Previously, we reported a spontaneous pear bud sport ‘Red Zaosu’ ( Pyrus bretschneideri Rehd.) with a high flavonoid content in its fruit. The identification of the flavonol biosynthetic regulatory network in this mutant pear fruit is crucial for elucidating the flavonol biosynthetic mechanism in fruit. Results Here, we demonstrated the PbMYB12b positively regulated flavonols biosynthesis in ‘Red Zaosu’ fruit. Initially, we investigated the accumulation patterns of four major quercetin glycosides and two major isorhamnetin glycosides in the fruit of ‘Red Zaosu’ and its wild-type ‘Zaosu’. A PRODUCTION OF FLAVONOL GLYCOSIDES (PFG)-type MYB transcription factor PbMYB12b was also screened for because of its correlation with flavonol accumulation in pear fruit. The biofunction of PbMYB12b was verified by transient overexpression and RNAi assays in pear fruit and young leaves. Overexpression of PbMYB12b enhanced the biosynthesis of quercetin glycosides and isorhamnetin glycosides by positively regulating a general flavonoids biosynthesis gene PbCHSb and a flavonol biosynthesis gene PbFLS . This finding was also supported by dual-luciferase transient expression assay and transient β-glucuronidase (GUS) reporter assay. Conclusions Our study indicated that PbMYB12b positively regulated flavonol biosynthesis, including four major quercetin glycosides and two major isorhamnetin glycosides, by promoting the expression of PbCHSb and PbFLS in pear fruit. Electronic supplementary material The online version of this article (10.1186/s12870-019-1687-0) contains supplementary material, which is available to authorized users.

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BackgroundInactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC).MethodWe performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan–Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients.ResultsThe CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2.Conclusion KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0613-z) contains supplementary material, which is available to authorized users.

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Emerging evidence has shown that aberrant alternative splicing (AS) events are involved in the carcinogenesis. The association between genetic variants in AS and bladder cancer susceptibility remains to be fully elucidated. We searched for single nucleotide polymorphisms (SNPs) which are located in splicing quantitative trait loci (sQTLs) in bladder cancer through CancerSplicingQTL database and the 1000 Genomes Project. A case‐control study including 580 cases and 1,101 controls was conducted to assess the association between the functional genetic variants and bladder cancer risk. Next, we used GTEx, TCGA, and GEO databases conducting sQTL analysis and gene expression differences analysis to evaluate the potential biological function of the candidate SNPs and related genes. We found that SNP rs4383 C>G was remarkably related with the reduced risk of bladder cancer (odds ratio = 0.68, 95% confidence interval = 0.59‐0.79, P = 3.91 × 10−7). Similar results were obtained in codominant, dominant and recessive model. Stratified analyses revealed that the effect of SNP rs4383 C>G on bladder cancer was more significant in the older subjects (age > 65), female and nonsmokers. sQTL analysis showed that SNP rs4383 was associated with the AS events of its downstream gene MAFF with a splicing event of alternative 5′ splice site. The messenger RNA expression of MAFF in bladder tumor tissues was lowered compared with normal tissues. Patients with high expression of MAFF had higher survival rates. These findings indicated that SNP rs4383 related with the AS events of MAFF was associated with bladder cancer risk and could represent a possible biomarker for bladder cancer susceptibility.

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BACKGROUND COVID-19 and diabetes both contribute to large global disease burdens. PURPOSE To quantify the prevalence of diabetes in various COVID-19 disease stages and calculate the population attributable fraction (PAF) of diabetes to COVID-19–related severity and mortality. DATA SOURCES Systematic review identified 729 studies with 29,874,938 COVID-19 patients. STUDY SELECTION Studies detailed the prevalence of diabetes in subjects with known COVID-19 diagnosis and severity. DATA EXTRACTION Study information, COVID-19 disease stages, and diabetes prevalence were extracted. DATA SYNTHESIS The pooled prevalence of diabetes in stratified COVID-19 groups was 14.7% (95% CI 12.5–16.9) among confirmed cases, 10.4% (7.6–13.6) among nonhospitalized cases, 21.4% (20.4–22.5) among hospitalized cases, 11.9% (10.2–13.7) among nonsevere cases, 28.9% (27.0–30.8) among severe cases, and 34.6% (32.8–36.5) among deceased individuals, respectively. Multivariate metaregression analysis explained 53–83% heterogeneity of the pooled prevalence. Based on a modified version of the comparative risk assessment model, we estimated that the overall PAF of diabetes was 9.5% (7.3–11.7) for the presence of severe disease in COVID-19–infected individuals and 16.8% (14.8–18.8) for COVID-19–related deaths. Subgroup analyses demonstrated that countries with high income levels, high health care access and quality index, and low diabetes disease burden had lower PAF of diabetes contributing to COVID-19 severity and death. LIMITATIONS Most studies had a high risk of bias. CONCLUSIONS The prevalence of diabetes increases with COVID-19 severity, and diabetes accounts for 9.5% of severe COVID-19 cases and 16.8% of deaths, with disparities according to country income, health care access and quality index, and diabetes disease burden.