Different switching frequencies are required when SiC metal-oxide-semiconductor field-effect transistors(MOSFETs)are switching in a space environment.In this study,the total ionizing dose(TID)responses of SiC power MO...Different switching frequencies are required when SiC metal-oxide-semiconductor field-effect transistors(MOSFETs)are switching in a space environment.In this study,the total ionizing dose(TID)responses of SiC power MOSFETs are investigated under different switching frequencies from 1 kHz to 10 MHz.A significant shift was observed in the threshold voltage as the frequency increased,which resulted in premature failure of the drain-source breakdown voltage and drain-source leakage current.The degradation is attributed to the high activation and low recovery rates of traps at high frequencies.The results of this study suggest that a targeted TID irradiation test evaluation method can be developed according to the actual switching frequency of SiC power MOSFETs.展开更多
The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long...The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing.As a result of recent technological advances,effcient small nucleic acid delivery for therapeutic and biomedical applications has been achieved,accelerating their clinical translation.Here,we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms.We also discuss the key advances in the design,development and therapeutic application of each delivery platform.Furthermore,this review presents comprehensive profiles of currently approved small nucleic acid drugs,including 11 antisense oligonucleotides(AsOs),2 aptamers and 6 siRNA drugs,summarizing their modifications,disease-specific mechanisms of action and delivery strategies.Other candidates whose clinical trial status has been recorded and updated are also discussed.We also consider strategic issues such as important safety considerations,novel vectors and hurdles for translating academic breakthroughs to the clinic.Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously"undruggable"targets,suggesting that they could be useful for guiding the development of additional clinical candidates.展开更多
In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.A...In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.Although a growing number of therapeutic targets have been identified in preclinical studies,the ones that can ultimately be used in the clinic are limited.Therefore,the research process and clinical application of drugs for treating CNS diseases are still large challenges.Physiological barriers such as the blood‒brain barrier(BBB)act as selective permeable membranes,allowing only certain molecules to enter the brain;this barrier is the major obstacle restricting the arrival of most drugs to brain lesions.Recently,nanoparticles,including lipid-based,cell-derived biomimetic,polymeric and inorganic nanoparticles,have gained increasing attention because of their ability to cross physiological barriers,and could play an important role as delivery carriers and immunomodulators.Additionally,clinical applications of nanoparticles in CNS diseases are underway.This review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases.展开更多
Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic vir...Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.展开更多
基金supported by the National Natural Science Foundation of China under Grant No.11975305the West Light Foundation of The Chinese Academy of Sciences,Grant No.2017-XBQNXZ-B-008。
文摘Different switching frequencies are required when SiC metal-oxide-semiconductor field-effect transistors(MOSFETs)are switching in a space environment.In this study,the total ionizing dose(TID)responses of SiC power MOSFETs are investigated under different switching frequencies from 1 kHz to 10 MHz.A significant shift was observed in the threshold voltage as the frequency increased,which resulted in premature failure of the drain-source breakdown voltage and drain-source leakage current.The degradation is attributed to the high activation and low recovery rates of traps at high frequencies.The results of this study suggest that a targeted TID irradiation test evaluation method can be developed according to the actual switching frequency of SiC power MOSFETs.
基金supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD23008)by the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(No.TFJC202310005)by the Scientific Research and Innovation Team Program of Sichuan University of Science and Technology(No.SUSE652B003).
文摘The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored.Compared with conventional treatments,small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing.As a result of recent technological advances,effcient small nucleic acid delivery for therapeutic and biomedical applications has been achieved,accelerating their clinical translation.Here,we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms.We also discuss the key advances in the design,development and therapeutic application of each delivery platform.Furthermore,this review presents comprehensive profiles of currently approved small nucleic acid drugs,including 11 antisense oligonucleotides(AsOs),2 aptamers and 6 siRNA drugs,summarizing their modifications,disease-specific mechanisms of action and delivery strategies.Other candidates whose clinical trial status has been recorded and updated are also discussed.We also consider strategic issues such as important safety considerations,novel vectors and hurdles for translating academic breakthroughs to the clinic.Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously"undruggable"targets,suggesting that they could be useful for guiding the development of additional clinical candidates.
基金supported by the National Natural Science Foundation of China(Nos.82073366 and 32100748)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18007)the National Natural Science Foundation of Sichuan Province(No.2022NSFSC1642).
文摘In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.Although a growing number of therapeutic targets have been identified in preclinical studies,the ones that can ultimately be used in the clinic are limited.Therefore,the research process and clinical application of drugs for treating CNS diseases are still large challenges.Physiological barriers such as the blood‒brain barrier(BBB)act as selective permeable membranes,allowing only certain molecules to enter the brain;this barrier is the major obstacle restricting the arrival of most drugs to brain lesions.Recently,nanoparticles,including lipid-based,cell-derived biomimetic,polymeric and inorganic nanoparticles,have gained increasing attention because of their ability to cross physiological barriers,and could play an important role as delivery carriers and immunomodulators.Additionally,clinical applications of nanoparticles in CNS diseases are underway.This review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases.
基金funded by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018-013)by Natural Science Foundation Project of Sichuan(No.2022NSFSC0848)+1 种基金as well as supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD18007)The Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC202310005).
文摘Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
