RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RN...RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RNA-derived modified adenosines,N6-methyladenosine(m6A),N6,N6-dimethyladenosine(m6,6A),and N6-isopentenyladenosine(i6A),are sequentially metabolized into inosine monophosphate(IMP)to mitigate their intrinsic cytotoxicity.展开更多
Ménétrier disease(MD)is a rare gastric disorder characterized by hypertrophy of the gastric mucosa,resulting in giant gastric folds,excessive mucus secretion,and significant protein loss.It is most common in...Ménétrier disease(MD)is a rare gastric disorder characterized by hypertrophy of the gastric mucosa,resulting in giant gastric folds,excessive mucus secretion,and significant protein loss.It is most common in middle-aged males,although cases have also been reported in children.This condition,also known as hyperplastic hypersecretory gastropathy,primarily affects the fundus and body of the stomach,leading to protein-losing gastropathy due to increased mucosal permeability.The exact pathogenesis of MD remains unclear;however,it has been linked to excessive transforming growth factor-alpha signaling via the epidermal growth factor receptor(EGFR),which promotes mucosal hyperplasia.Clinical manifestations include epigastric pain,nausea,vomiting,anorexia,weight loss,and peripheral edema due to protein-losing enteropathy.Diagnosis is based on clinical presentation,endoscopic findings,and histopathology revealing foveolar hyperplasia and glandular atrophy.Treatment options vary from symptomatic management with proton pump inhibitors and nutritional support to monoclonal antibodies targeting EGFR(e.g.,cetuximab)in severe cases.In refractory situations,gastrectomy may be required.This review highlights the current understanding,diagnostic approaches,and therapeutic strategies for MD.展开更多
In the era of big data,traditional statistical inference methods are faced with great challenges.Taking the two-sample distribution test scenario of big data as an example,this paper proposes the BB-KS test based on m...In the era of big data,traditional statistical inference methods are faced with great challenges.Taking the two-sample distribution test scenario of big data as an example,this paper proposes the BB-KS test based on m out of n bootstrap for solving a single-machine memory and computing constraints.It is verified to the feasibility and effectiveness of the proposed test method through theoretical analysis and numerical simulation.The results show that the BB-KS test can improve the calculation efficiency of the test to a certain extent in the single machine scenario.展开更多
Objectives:Epigenetic changes,particularly N6-methyladenosine(m6A)modifications,play a pivotal role in cancer development.This study explored the role of ovarian tumor deubiquitinase 7B(OTUD7B)in esophageal squamous c...Objectives:Epigenetic changes,particularly N6-methyladenosine(m6A)modifications,play a pivotal role in cancer development.This study explored the role of ovarian tumor deubiquitinase 7B(OTUD7B)in esophageal squamous cell carcinoma(ESCC)in the context of m6A methylation and the hypoxia-inducible factor-1α(HIF-1α)pathway.Methods:The GSE179267 dataset was used to conduct differential gene expression analysis to identify key m6A-enriched genes.The Cancer Genome Atlas(TCGA),Cancer Cell Line Encyclopedia(CCLE),and Sequence-based RNA Adenosine Methylation Site Predictor(SRAMP)databases were used to evaluate the expression of OTUD7B in ESCC and its correlation with methyltransferase-like 14(METTL14)and HIF-1α.The m6A content in total RNA extracted from ESCC cells was assessed using a dot blot assay.Gene-specific m6A-PCR was used to quantify m6A modifications in OTUD7B mRNA.The functional role of OTUD7B was explored using clonogenic and Transwell assays.The effect of OTUD7B on HIF-1αubiquitination was detected using a co-immunoprecipitation assay.Results:OTUD7B was identified as a pivotal m6A-driven oncogene correlated with METTL14 and HIF-1α.METTL14 enhanced the mRNA stability and expression of OTUD7B through m6A methylation.OTUD7B overexpression counteracted the inhibitory effects of METTL14 knockdown on cell proliferation and invasion and stabilized HIF-1αby promoting deubiquitination.Conclusion:METTL14 plays a crucial role in the stabilization of OTUD7B through m6A methylation,thereby inhibiting the ubiquitin-proteasomal degradation of HIF-1αin ESCC.These findings highlight the potential of targeting the METTL14-OTUD7B axis as a therapeutic strategy for ESCC.展开更多
Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of ...Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.展开更多
现有研究集中于企业国际化节奏的作用及其影响因素,缺乏对CM N Es海外资源获取过程中国际化节奏不规律的后果及其应对机制的关注。本文采用事件路径分析方法,抽取两家典型CM N Es的海外技术与市场资源获取相关事件,基于悖论视角,分析国...现有研究集中于企业国际化节奏的作用及其影响因素,缺乏对CM N Es海外资源获取过程中国际化节奏不规律的后果及其应对机制的关注。本文采用事件路径分析方法,抽取两家典型CM N Es的海外技术与市场资源获取相关事件,基于悖论视角,分析国际化节奏不规律下技术与市场资源获取对立关系的演化趋势。根据资源获取对象和获取方式,本文提出一个海外资源获取矩阵结构,揭示了资源获取跨领域互动过程中的缓冲机制。研究结果表明,CM N Es能够分别通过桥接和支撑协调冲突,形成惯例与能动双缓冲机制,二者共同促进技术和市场领域从二元对立向相互依赖对立演化,以应对连续的国际化节奏不规律。展开更多
文摘RNA contains diverse post-transcriptional modifications,and its catabolic breakdown yields numerous modified nucleosides requiring correct processing,but the mechanisms remain unknown.Here,we demonstrate that three RNA-derived modified adenosines,N6-methyladenosine(m6A),N6,N6-dimethyladenosine(m6,6A),and N6-isopentenyladenosine(i6A),are sequentially metabolized into inosine monophosphate(IMP)to mitigate their intrinsic cytotoxicity.
文摘Ménétrier disease(MD)is a rare gastric disorder characterized by hypertrophy of the gastric mucosa,resulting in giant gastric folds,excessive mucus secretion,and significant protein loss.It is most common in middle-aged males,although cases have also been reported in children.This condition,also known as hyperplastic hypersecretory gastropathy,primarily affects the fundus and body of the stomach,leading to protein-losing gastropathy due to increased mucosal permeability.The exact pathogenesis of MD remains unclear;however,it has been linked to excessive transforming growth factor-alpha signaling via the epidermal growth factor receptor(EGFR),which promotes mucosal hyperplasia.Clinical manifestations include epigastric pain,nausea,vomiting,anorexia,weight loss,and peripheral edema due to protein-losing enteropathy.Diagnosis is based on clinical presentation,endoscopic findings,and histopathology revealing foveolar hyperplasia and glandular atrophy.Treatment options vary from symptomatic management with proton pump inhibitors and nutritional support to monoclonal antibodies targeting EGFR(e.g.,cetuximab)in severe cases.In refractory situations,gastrectomy may be required.This review highlights the current understanding,diagnostic approaches,and therapeutic strategies for MD.
文摘In the era of big data,traditional statistical inference methods are faced with great challenges.Taking the two-sample distribution test scenario of big data as an example,this paper proposes the BB-KS test based on m out of n bootstrap for solving a single-machine memory and computing constraints.It is verified to the feasibility and effectiveness of the proposed test method through theoretical analysis and numerical simulation.The results show that the BB-KS test can improve the calculation efficiency of the test to a certain extent in the single machine scenario.
基金funded by the Doctoral Research Start-up Fund Project at Changzhi Medical College(grant number BS202118)Sichuan Science and Technology Program(grant number 2022YFS0631)Scientific and Technological Innovation Programs ofHigher Education Institutions in Shanxi(grant number 2021L348).
文摘Objectives:Epigenetic changes,particularly N6-methyladenosine(m6A)modifications,play a pivotal role in cancer development.This study explored the role of ovarian tumor deubiquitinase 7B(OTUD7B)in esophageal squamous cell carcinoma(ESCC)in the context of m6A methylation and the hypoxia-inducible factor-1α(HIF-1α)pathway.Methods:The GSE179267 dataset was used to conduct differential gene expression analysis to identify key m6A-enriched genes.The Cancer Genome Atlas(TCGA),Cancer Cell Line Encyclopedia(CCLE),and Sequence-based RNA Adenosine Methylation Site Predictor(SRAMP)databases were used to evaluate the expression of OTUD7B in ESCC and its correlation with methyltransferase-like 14(METTL14)and HIF-1α.The m6A content in total RNA extracted from ESCC cells was assessed using a dot blot assay.Gene-specific m6A-PCR was used to quantify m6A modifications in OTUD7B mRNA.The functional role of OTUD7B was explored using clonogenic and Transwell assays.The effect of OTUD7B on HIF-1αubiquitination was detected using a co-immunoprecipitation assay.Results:OTUD7B was identified as a pivotal m6A-driven oncogene correlated with METTL14 and HIF-1α.METTL14 enhanced the mRNA stability and expression of OTUD7B through m6A methylation.OTUD7B overexpression counteracted the inhibitory effects of METTL14 knockdown on cell proliferation and invasion and stabilized HIF-1αby promoting deubiquitination.Conclusion:METTL14 plays a crucial role in the stabilization of OTUD7B through m6A methylation,thereby inhibiting the ubiquitin-proteasomal degradation of HIF-1αin ESCC.These findings highlight the potential of targeting the METTL14-OTUD7B axis as a therapeutic strategy for ESCC.
基金supported by Natural Science Foundation of Hunan Province of China(project No.2022JJ40413)Outstanding Youth Project of Hunan Provincial Department of Education(project No.22B0814)+1 种基金Regional Consolidated Foundation ofHunan Province of China(project No.2023JJ50065)Natural Science Foundation of Hunan Province of China(project No.2023JJ50412).
文摘Background:Expression of mRNA is widely regulated by N6-methyladenosine(m6A).An increasing number of studies have shown that m6A methylation,facilitated by methyltransferase 3(METTL3),is crucial in the progression of tumors.Previous reports have indicated the involvement of both METTL3 and c-Src kinase in the evolution of liver cancer.However,the potential connection between c-Src and the METTL3-mediated mechanism in liver cancer progression remains elusive.Methods:The correlation expression between c-Src and METTL3 between liver cancer patients and the control group was analyzed using the TCGA database,and was further demonstrated by Western blot and RT-qPCR.The functional roles of c-Src in METTL3-regulated liver cancer progression were investigated by cell proliferation assays and colony formation assays.The regulatory mechanism of METTL3 in c-Src expression was accessed by RNA-immunoprecipitation(RIP)-qPCR.Results:We demonstrated that c-Src kinase promoted liver cancer development,and the expression of SRC(encodes c-Src kinase)was positively correlated with METTL3 in liver cancer cases.We showed that SRC mRNA could be m6A-modified,and METTL3 regulated the transcription of SRC mRNA through interferon regulatory factor 1(IRF1).We revealed that IRF1,the expression of which was positively regulated byMETTL3,was a novel transcription factor of c-Src.Lastly,The pro-proliferative effect of METTL3 on hepatocellular carcinoma was mechanistically linked to IRF1/c-Src axis activation,as evidenced by our experimental data.Conclusion:Results suggested that the METTL3/IRF1/c-Src axis played potential oncogenic roles in liver cancer development and the axis may be a promising therapeutic target in the disease.
文摘现有研究集中于企业国际化节奏的作用及其影响因素,缺乏对CM N Es海外资源获取过程中国际化节奏不规律的后果及其应对机制的关注。本文采用事件路径分析方法,抽取两家典型CM N Es的海外技术与市场资源获取相关事件,基于悖论视角,分析国际化节奏不规律下技术与市场资源获取对立关系的演化趋势。根据资源获取对象和获取方式,本文提出一个海外资源获取矩阵结构,揭示了资源获取跨领域互动过程中的缓冲机制。研究结果表明,CM N Es能够分别通过桥接和支撑协调冲突,形成惯例与能动双缓冲机制,二者共同促进技术和市场领域从二元对立向相互依赖对立演化,以应对连续的国际化节奏不规律。
