Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates sub...Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.Methods:GSDMD-NT^(ki/wt)mice and Alb-cre^(ki/wt)mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.Results:Doxycycline-treated GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice.Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.展开更多
Ultrastable continuous-wave lasers are one of the important elements for space-based gravitational wave detection.Here we present a Pound–Drever–Hall laser frequency-locked system based on a field-programmable gate ...Ultrastable continuous-wave lasers are one of the important elements for space-based gravitational wave detection.Here we present a Pound–Drever–Hall laser frequency-locked system based on a field-programmable gate array,demonstrating its potential to achieve 10-16levels of frequency stability for space applications.The system is employed to lock a spacequalified 1064-nm neodymium-doped yttrium aluminum garnet laser to a laboratory-operated 20-cm ultrastable optical cavity.Major noise contributors are identified as laser intensity fluctuation and residual amplitude modulation.The heterodyne beat measurement shows that the frequency noise spectral density of a single laser is reduced to 2.5 Hz/√Hz at a Fourier frequency of 1 m Hz,and the frequency instability is 2.1×10^(-16)at 1 s and remains below 3.5×10^(-16)up to 6000 s.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:82174292Key Project of Jiangsu Provincial Administration of Traditional Chinese Medicine,Grant/Award Number:ZD202312+2 种基金Natural Science Foundation of Laboratory Medicine School in Chengdu Medical College,Grant/Award Number:JYZK202203Sichuan Province Science and Technology Program,Grant/Award Number:2024NSFSC0577 and 2021YFG0316Technology innovation group project of Foshan 2019,Grant/Award Number:FS0AA-KJ919-4402-0027。
文摘Background:The emerging incidence of pathogenic liver conditions is turning into a major concern for global health.Induction of pyroptosis in hepatocytes instigates cel-lular disintegration,which in turn liberates substantial quantities of pro-inflammatory intracellular substances,thereby accelerating the advancement of liver fibrosis.Consequently,directing therapeutic efforts towards inhibiting pyroptosis could po-tentially serve as an innovative approach in managing inflammation related chronic hepatic disorders.Methods:GSDMD-NT^(ki/wt)mice and Alb-cre^(ki/wt)mice were generated using CRISPR/Cas9 technology.After crossing the two strains together,we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis.We analyzed differ-entially expressed genes by RNA sequencing and explored their biological functions.The efficacy of obeticholic acid(OCA)in the treatment of liver fibrosis was assessed.Results:Doxycycline-treated GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice showed severe liver damage,vacuolation of hepatocytes,increased collagen fibers,and accumulation of lipid droplets.The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver.RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses,cell activation,and metabolic processes.Treatment with OCA alleviated the liver fibrosis,with reduced ALT and AST levels seen in the GSDMD-NT^(ki/wt)×Alb-cre^(ki/wt)mice.Conclusions:We successfully constructed a novel mouse model for liver fibrosis.This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism.Our re-sults demonstrated that we successfully constructed a mouse model of liver fibrosis,and GSDMD-NT induced fibrosis by mediating lipid metabolism.
基金supported by the National Key Research and Development Program of China(Nos.2021YFC2201800 and 2020YFC2200300)the National Natural Science Foundation of China(Nos.11327407,11654004,and 11235004)the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB21010300 and XDB23030202)。
文摘Ultrastable continuous-wave lasers are one of the important elements for space-based gravitational wave detection.Here we present a Pound–Drever–Hall laser frequency-locked system based on a field-programmable gate array,demonstrating its potential to achieve 10-16levels of frequency stability for space applications.The system is employed to lock a spacequalified 1064-nm neodymium-doped yttrium aluminum garnet laser to a laboratory-operated 20-cm ultrastable optical cavity.Major noise contributors are identified as laser intensity fluctuation and residual amplitude modulation.The heterodyne beat measurement shows that the frequency noise spectral density of a single laser is reduced to 2.5 Hz/√Hz at a Fourier frequency of 1 m Hz,and the frequency instability is 2.1×10^(-16)at 1 s and remains below 3.5×10^(-16)up to 6000 s.
