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Summary Although the N6‐methyladenosine (m6A) modification is the most prevalent RNA modification in eukaryotes, the global m6A modification landscape and its molecular regulatory mechanism in response to drought stress remain unclear. Transcriptome‐wide m6A methylome profiling revealed that m6A is mainly enriched in the coding sequence and 3′ untranslated region in response to drought stress in apple, by recognizing the plant‐specific sequence motif UGUAH (H=A, U or C). We identified a catalytically active component of the m6A methyltransferase complex, MdMTA. An in vitro methyl transfer assay, dot blot, LC‐MS/MS and m6A‐sequencing (m6A‐seq) suggested that MdMTA is an m6A writer and essential for m6A mRNA modification. Further studies revealed that MdMTA is required for apple drought tolerance. m6A‐seq and RNA‐seq analyses under drought conditions showed that MdMTA mediates m6A modification and transcripts of mRNAs involved in oxidative stress and lignin deposition. Moreover, m6A modification promotes mRNA stability and the translation efficiency of these genes in response to drought stress. Consistently, MdMTA enhances lignin deposition and scavenging of reactive oxygen species under drought conditions. Our results reveal the global involvement of m6A modification in the drought response of perennial apple trees and illustrate its molecular mechanisms, thereby providing candidate genes for the breeding of stress‐tolerant apple cultivars.

Background Multiple studies have compared the efficacy of entecavir with lamivudine in preventing hepatitis B virus (HBV) reactivation among HBV-carrying lymphoma patients with chemotherapy treatment. However, the results were slightly varied. Aim of the review to combine the findings of independent studies assessing the clinical efficacy of the two drugs using a systematic review and meta-analysis. Methods PubMed, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Chongqing VIP and WanFang Data were retrieved. Two independent reviewers evaluated the study eligibility and extracted eight studies, with 770 patients in total. The meta-analysis was conducted using RevMan 5.3 and STATA software. Results HBV-carrying lymphoma patients receiving lamivudine during chemotherapy had a statistically significantly higher odds of HBV reactivation compared to those receiving entecavir (OR 5.0, 95 % CI 2.85-8.78, P < 0.001). The odds of hepatitis, HBV-Reactivation caused hepatitis and chemotherapy disruption was statistically significantly elevated in the patient group receiving lamivudine compared to the entecavir group (OR 4.12, 95 % CI 1.70-9.98, P = 0.002; OR 11.44, 95 % CI 2.70-48.52, P < 0.001; OR 6.71, 95 % CI 2.34-19.26, P < 0.001, respectively). Furthermore, the HBV reactivation rate in Ann Arbor stages I - II patient group was statistically significantly lower than the one in Ann Arbor stages III-IV group, with an overall pooled value of 0.37 (95 % CI 0.17-0.82, P = 0.01). Conclusion The metaanalysis result suggested that among HBV-carrying lymphoma patients undergoing chemotherapy, entecavir is more effective than lamivudine in preventing HBV reactivation.

Hypertrophic scar (HS) is a common type of dermatosis. Botulinum toxin type A (BTXA) can exert an anti-HS effect; however, the regulatory mechanisms underlying this effect remain unclear. Thus, the aim of this study was to examine the effects of BTXA on phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and the fibroblast phenotypic transformation induced by transforming growth factor (TGF)-β1, which is an important regulatory factor involved in the process of HS. For this purpose, fibroblasts were treated with various concentrations of BTXA and then treated with 10 ng/ml of TGF-β1 with gradient concentrations of BTXA. The proliferation and apoptosis of fibroblasts were measured by cell counting kit-8 assay (CCK-8) and flow cytometry, respectively. PTEN methylation was analyzed by methylation-specific PCR (MSP) and DNA methyltransferase (DNMT) activity was determined using a corresponding kit. RT-qPCR and western blot analysis were performed to detect the transcription and translation levels. The results revealed that BTXA suppressed the proliferation and increased the apoptosis of fibroblasts treated with TGF-β1 in a dose-dependent manner. BTXA in combination with TGF-β1 suppressed the expression of molecules related to the extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and apoptosis. BTXA reduced the PTEN methylation level and downregulated the expression levels of methylation-associated genes. BTXA also inhibited the phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt. On the whole, the findings of this study indicate that BTXA may inhibit fibroblast phenotypic transformation by regulating PTEN methylation and the phosphorylation of related pathways. The findings of this study can provide a theoretical basis for HS treatment.

Background and Purpose Aberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS‐based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism‐modulating agents would synergize with proteasome inhibitors. Experimental Approach Lipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP‐seq, western blotting and RT‐qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition. Key Results Accumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid‐lowering drugs and MG‐132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4. Conclusions and Implications Our results provide a proof of principle and support for the further clinical evaluation of the combination of lipid‐modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.