Hepatitis B virus(HBV)infection is a major risk factor for hepatocellular carcinoma(HCC),but its pathogenic mechanism remains to be explored.The RNA N^(6)-methyladenosine(m^(6)A)reader,YTH(YT521-B homology)domain 2(YT...Hepatitis B virus(HBV)infection is a major risk factor for hepatocellular carcinoma(HCC),but its pathogenic mechanism remains to be explored.The RNA N^(6)-methyladenosine(m^(6)A)reader,YTH(YT521-B homology)domain 2(YTHDF2),plays a critical role in the HCC progression.However,the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive.Here,we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection.O-GlcNAc transferase(OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination.Mechanistically,YTHDF2 stabilized minichromosome maintenance protein 2(MCM2)and MCM5 transcripts in an m^(6)A-dependent manner,thus promoting cell cycle progression and HBV-related HCC tumorigenesis.Moreover,targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression.Taken together,our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m^(6)A methylation and HCC progression.Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.展开更多
Debris flows are rapid mass movements with a mixture of rock,soil and water.High-intensity rainfall events have triggered multiple debris flows around the globe,making it an important concern from the disaster managem...Debris flows are rapid mass movements with a mixture of rock,soil and water.High-intensity rainfall events have triggered multiple debris flows around the globe,making it an important concern from the disaster management perspective.This study presents a numerical model called debris flow simulation 2D(DFS 2D)and applicability of the proposed model is investigated through the values of the model parameters used for the reproduction of an occurred debris flow at Yindongzi gully in China on 13 August 2010.The model can be used to simulate debris flows using three different rheologies and has a userfriendly interface for providing the inputs.Using DFS 2D,flow parameters can be estimated with respect to space and time.The values of the flow resistance parameters of model,dry-Coulomb and turbulent friction,were calibrated through the back analysis and the values obtained are 0.1 and 1000 m/s^(2),respectively.Two new methods of calibration are proposed in this study,considering the crosssectional area of flow and topographical changes induced by the debris flow.The proposed methods of calibration provide an effective solution to the cumulative errors induced by coarse-resolution digital elevation models(DEMs)in numerical modelling of debris flows.The statistical indices such as Willmott's index of agreement,mean-absolute-error,and normalized-root-mean-square-error of the calibrated model are 0.5,1.02 and 1.44,respectively.The comparison between simulated and observed values of topographic changes indicates that DFS 2D provides satisfactory results and can be used for dynamic modelling of debris flows.展开更多
基金This work was supported by the China National Natural Science Foundation(grant no.82272975,U20A20392,82072286,82073251)the 111 Project(No.D20028)+4 种基金the Innovative and Entrepreneurial Team of Chongqing Talents Plan,the Natural Science Foundation Project of Chongqing(cstc2019jscx-dxwtBX0019,cstc2021jcyj-bsh0017)Chongqing Medical Scientific Research Project(Joint project of Chongqing Health Commission and Science and Technology Bureau,2023DBXM007)the Kuanren talents program of the second affiliated hospital of Chongqing Medical University,the Program for Youth Innovation in Future Medicine of Chongqing Medical University(W0036,W0101)the Science and Technology Research Program of Chongqing Municipal Education Commission(HZ2021006,KJZD-M202000401)the Postgraduate research and innovation projects of Chongqing Municipal Education Commission(CYB21174).
文摘Hepatitis B virus(HBV)infection is a major risk factor for hepatocellular carcinoma(HCC),but its pathogenic mechanism remains to be explored.The RNA N^(6)-methyladenosine(m^(6)A)reader,YTH(YT521-B homology)domain 2(YTHDF2),plays a critical role in the HCC progression.However,the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive.Here,we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection.O-GlcNAc transferase(OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination.Mechanistically,YTHDF2 stabilized minichromosome maintenance protein 2(MCM2)and MCM5 transcripts in an m^(6)A-dependent manner,thus promoting cell cycle progression and HBV-related HCC tumorigenesis.Moreover,targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression.Taken together,our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m^(6)A methylation and HCC progression.Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.
基金financially supported by Department of Space,India(Grant No.ISRO/RES/4/663/18-19)。
文摘Debris flows are rapid mass movements with a mixture of rock,soil and water.High-intensity rainfall events have triggered multiple debris flows around the globe,making it an important concern from the disaster management perspective.This study presents a numerical model called debris flow simulation 2D(DFS 2D)and applicability of the proposed model is investigated through the values of the model parameters used for the reproduction of an occurred debris flow at Yindongzi gully in China on 13 August 2010.The model can be used to simulate debris flows using three different rheologies and has a userfriendly interface for providing the inputs.Using DFS 2D,flow parameters can be estimated with respect to space and time.The values of the flow resistance parameters of model,dry-Coulomb and turbulent friction,were calibrated through the back analysis and the values obtained are 0.1 and 1000 m/s^(2),respectively.Two new methods of calibration are proposed in this study,considering the crosssectional area of flow and topographical changes induced by the debris flow.The proposed methods of calibration provide an effective solution to the cumulative errors induced by coarse-resolution digital elevation models(DEMs)in numerical modelling of debris flows.The statistical indices such as Willmott's index of agreement,mean-absolute-error,and normalized-root-mean-square-error of the calibrated model are 0.5,1.02 and 1.44,respectively.The comparison between simulated and observed values of topographic changes indicates that DFS 2D provides satisfactory results and can be used for dynamic modelling of debris flows.
