AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METH...AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METHODS:Immunofluorescence staining was used to detect the expression of desmin,glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin(α-SMA) after freshly isolated,normal rat HSCs had been activated in culture for different numbers of days(0,1,3,7 and 10 d).The expression of α-SMA,collagen1α2(COL1α2),Notch receptors(Notch1-4),and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction.Luciferase reporter assays and Western blot were used to study the regulation of α-SMA,COL1α1,COL1α2 and Hes1 by NICD1,Hes1,CA-ALK3,and CA-ALK5 in HSC-T6 cells.Moreover,the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated.RESULTS:The expression of Notch1 and Hes1 m RNAs was significantly down-regulated during the culture of freshly isolated HSCs.In HSC-T6 cells,Notch1 inhibited the promoter activities of α-SMA,COL1α1 and COL1α2.On the other hand,Hes1 enhanced the promoter activities of α-SMA and COL1α2,and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy.Furthermore,co-transfection of pc DNA3-CAALK3(BMP signaling activin receptor-like kinase 3) and pc DNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells,while pc DNA3-CA-ALK5(TGF-β signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression.CONCLUSION:Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2,and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.展开更多
China Jinping Underground Laboratory(CJPL)is ideal for studying solar,geo-,and supernova neutrinos.A precise measurement of the cosmic-ray background is essential in proceeding with R&D research for these MeV-scal...China Jinping Underground Laboratory(CJPL)is ideal for studying solar,geo-,and supernova neutrinos.A precise measurement of the cosmic-ray background is essential in proceeding with R&D research for these MeV-scale neutrino experiments.Using a 1-ton prototype detector for the Jinping Neutrino Experiment(JNE),we detected 264 high-energy muon events from a 645.2-day dataset from the first phase of CJPL(CJPL-I),reconstructed their directions,and measured the cosmic-ray muon flux to be (3.53±0.22_stat.±0.07_sys.)×-10^(-10)cm^(-2).The observed angular distributions indicate the leakage of cosmic-ray muon background and agree with simulation data accounting for Jinping mountain's terrain.A survey of muon fluxes at different laboratory locations,considering both those situated under mountains and those down mine shafts,indicates that the flux at the former is generally a factor of (4±2) larger than at the latter,with the same vertical overburden.This study provides a convenient back-of-the-envelope estimation for the muon flux of an underground experiment.展开更多
基金Supported by National Natural Science Foundation of China,No.81170412,No.81070348 and No.81200307Health Department of Hubei Province of China,No.JX6C-26
文摘AIM:To determine the role of Notch1 and Hes1 in regulating the activation of hepatic stellate cells(HSCs) and whether Hes1 is regulated by transforming growth factor(TGF)/bone morphogenetic protein(BMP) signaling.METHODS:Immunofluorescence staining was used to detect the expression of desmin,glial fibrillary acidic protein and the myofibroblastic marker α-smooth muscle actin(α-SMA) after freshly isolated,normal rat HSCs had been activated in culture for different numbers of days(0,1,3,7 and 10 d).The expression of α-SMA,collagen1α2(COL1α2),Notch receptors(Notch1-4),and the Notch target genes Hes1 and Hey1 were analyzed by reverse transcriptase-polymerase chain reaction.Luciferase reporter assays and Western blot were used to study the regulation of α-SMA,COL1α1,COL1α2 and Hes1 by NICD1,Hes1,CA-ALK3,and CA-ALK5 in HSC-T6 cells.Moreover,the effects of inhibiting Hes1 function in HSC-T6 cells using a Hes1 decoy were also investigated.RESULTS:The expression of Notch1 and Hes1 m RNAs was significantly down-regulated during the culture of freshly isolated HSCs.In HSC-T6 cells,Notch1 inhibited the promoter activities of α-SMA,COL1α1 and COL1α2.On the other hand,Hes1 enhanced the promoter activities of α-SMA and COL1α2,and this effect could be blocked by inhibiting Hes1 function with a Hes1 decoy.Furthermore,co-transfection of pc DNA3-CAALK3(BMP signaling activin receptor-like kinase 3) and pc DNA3.1-NICD1 further increased the expression of Hes1 compared with transfection of either vector alone in HSC-T6 cells,while pc DNA3-CA-ALK5(TGF-β signaling activin receptor-like kinase 5) reduced the effect of NICD1 on Hes1 expression.CONCLUSION:Selective interruption of Hes1 or maintenance of Hes1 at a reasonable level decreases the promoter activities of α-SMA and COL1α2,and these conditions may provide an anti-fibrotic strategy against hepatic fibrosis.
基金Supported in part by the National Natural Science Foundation of China(11620101004,11475093)the Key Laboratory of Particle&Radiation Imaging(Tsinghua University,the CAS Center for Excellence in Particle Physics(CCEPP),and Guangdong Basic and Applied Basic Research Foundation(2019A1515012216)Portion of this work performed at Brookhaven National Laboratory is supponted in part by the United States Department of Energy(DE-SC0012704)。
文摘China Jinping Underground Laboratory(CJPL)is ideal for studying solar,geo-,and supernova neutrinos.A precise measurement of the cosmic-ray background is essential in proceeding with R&D research for these MeV-scale neutrino experiments.Using a 1-ton prototype detector for the Jinping Neutrino Experiment(JNE),we detected 264 high-energy muon events from a 645.2-day dataset from the first phase of CJPL(CJPL-I),reconstructed their directions,and measured the cosmic-ray muon flux to be (3.53±0.22_stat.±0.07_sys.)×-10^(-10)cm^(-2).The observed angular distributions indicate the leakage of cosmic-ray muon background and agree with simulation data accounting for Jinping mountain's terrain.A survey of muon fluxes at different laboratory locations,considering both those situated under mountains and those down mine shafts,indicates that the flux at the former is generally a factor of (4±2) larger than at the latter,with the same vertical overburden.This study provides a convenient back-of-the-envelope estimation for the muon flux of an underground experiment.
