Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhib...Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.展开更多
We report a low power ASK IF receiver for short-range wireless systems,which includes an AGC loop that compensates the channel attenuation and an ASK detector. A novel current-limited transconductor and feed-forward d...We report a low power ASK IF receiver for short-range wireless systems,which includes an AGC loop that compensates the channel attenuation and an ASK detector. A novel current-limited transconductor and feed-forward differential peak detector have been designed to maintain a high compression ratio and fast response for the AGC with lower power consumption. A storage unit with a zero and a feed-forward structure have been introduced into the peak detector to control the damping characteristic of the AGC loop. A rectifier and low-pass filter included in the ASK detector have been integrated into a more compact structure to further lower the power consumption. The simulation results show the feasibility of the proposed technique.展开更多
This thesis aims at investigating what the discourse patterns are in the asking-for-leave notes written by Chinese students and native English speakers respectively and what excuses are given by Chinese students and n...This thesis aims at investigating what the discourse patterns are in the asking-for-leave notes written by Chinese students and native English speakers respectively and what excuses are given by Chinese students and native English speakers.Role play and retrospective interview were employed as research methords.The results show that the Chinese students all use an inductive pattern,while all native English speakers write the note in a deductive way.Besides,the excuses presented by the two kinds of subjects are different due to their different cultural background.展开更多
文摘Background:Apoptosis signal-regulating kinase 1(ASK1)is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis;therefore,inhibition of ASK1 kinase ac-tivity can protect cells from pathological injury.In this study,we designed and synthe-sized a novel selective ASK1 inhibitor,CS17919,and investigated its pharmacological effects in various animal models of metabolic injury.Methods:First,we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib(GS-4997),a phase III ASK1 inhibitor.We then conducted pharmacokinetic(PK)studies in mice.Finally,we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease(CKD)and non-alcoholic steatohepatitis(NASH).Results:Compared to GS-4997,CS17919 demonstrated comparable inhibition of ASK1 in vitro,exhibited lower toxicity,and provided greater protection in palmitic acid-treated LO2 cells.CS17919 also showed pronounced pharmacokinetic prop-erties such as a high plasma concentration.In the unilateral ureteral obstruction model(UUO),CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis.In the diabetic kidney disease(DKD)model,CS17919 significantly improved serum creatinine and glomerular sclerosis.In the NASH model,the combination of CS17919 and a THRβagonist(CS27109)was found to significantly improve liver inflammation and substantially reduced liver fibrosis.Conclusions:CS17919 showed cell protective,anti-inflammatory,and antifibrotic ef-fects in vitro and in vivo,suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
文摘We report a low power ASK IF receiver for short-range wireless systems,which includes an AGC loop that compensates the channel attenuation and an ASK detector. A novel current-limited transconductor and feed-forward differential peak detector have been designed to maintain a high compression ratio and fast response for the AGC with lower power consumption. A storage unit with a zero and a feed-forward structure have been introduced into the peak detector to control the damping characteristic of the AGC loop. A rectifier and low-pass filter included in the ASK detector have been integrated into a more compact structure to further lower the power consumption. The simulation results show the feasibility of the proposed technique.
文摘This thesis aims at investigating what the discourse patterns are in the asking-for-leave notes written by Chinese students and native English speakers respectively and what excuses are given by Chinese students and native English speakers.Role play and retrospective interview were employed as research methords.The results show that the Chinese students all use an inductive pattern,while all native English speakers write the note in a deductive way.Besides,the excuses presented by the two kinds of subjects are different due to their different cultural background.
