Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential compone...Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.展开更多
Familial hypercholesterolemia(FH)is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations,presenting with xanthomas,corneal arch,and severe cardiovascular diseases.Early identif...Familial hypercholesterolemia(FH)is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations,presenting with xanthomas,corneal arch,and severe cardiovascular diseases.Early identification,diagnosis,and treatment are crucial to prevent severe complications like acute myocardial infarction.Statins are the primary treatment,supplemented by Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors,though their effectiveness can be limited in severe cases.Over 90%of FH cases remain undiagnosed,and current treatments are often inadequate,underscoring the need for improved diagnostic and management systems.Future strategies include advancements in gene testing,precision medicine,and novel drugs,along with gene therapy approaches like AAV-mediated gene therapy and clustered regularly interspaced short palindromic repeats.Lifestyle modifications,including health education,dietary control,and regular exercise,are essential for managing FH and preventing related diseases.Research into FH-related gene mutations,especially LDLR,is critical for accurate diagnosis and effective treatment.展开更多
The pressure evolution associated with the transient shock-induced infiltration of gas flow through granular media consisting of mobile particles is numerically investigated using a coupled Eulerian–Lagrangian approa...The pressure evolution associated with the transient shock-induced infiltration of gas flow through granular media consisting of mobile particles is numerically investigated using a coupled Eulerian–Lagrangian approach.The coupling between shock compaction and interstitial flow has been revealed.A distinctive two-stage diffusing pressure field with deflection occurring at the tail of the compaction front is found,with corresponding spikes in both gaseous velocity and temperature profiles emerging within the width of the compaction front.The compaction front,together with the deflection pressure,reaches a steady state during the later period.An analytical prediction of the steady deflection pressure that considers the contributions of porosity and the non-isothermal effect is proposed.The isothermal single-phase method we developed,combining the porosity jump condition across the compaction front,shows consistent pressure evolution with the non-isothermal CMP-PIC one under weak shock strength and low column permeability.Lastly,the microscale mechanism governing the formation of not only pressure deflection but also gaseous velocity and temperature spikes within the width of the compaction front has been described.These aforementioned evolutions of the flow field are shown to arise from the nozzling effects associated with the particle-scale variations in the volume fraction.展开更多
Extracellular membrane proteins are crucial for mediating cell attachment,recognition,and signal transduction in the testicular microenvironment,particularly germline stem cells.Cadherin 18(CDH18),a type Ⅱ classical ...Extracellular membrane proteins are crucial for mediating cell attachment,recognition,and signal transduction in the testicular microenvironment,particularly germline stem cells.Cadherin 18(CDH18),a type Ⅱ classical cadherin,is primarily expressed in the nervous and reproductive systems.Here,we investigated the expression of CDH18in neonatal porcine prospermatogonia(ProSGs)and murine spermatogonial stem cells(SSCs).Disruption of CDH18 expression did not adversely affect cell morphology,proliferation,self-renewal,or differentiation in cultured porcine ProSGs,but enhanced cell adhesion and prolonged cell maintenance.Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion.To further elucidate the function of CDH18 in germ cells,Cdh18 knockout mice were generated,which exhibited normal testicular morphology,histology,andspermatogenesis.Transcriptomic analysis showed increased expression of genes associated with adhesion,consistent with the observations in porcine ProSGs.The interaction of CDH18withβ-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency.Collectively,these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs.Understanding this regulatory mechanism provides significant insights into the testicular niche.展开更多
Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated...Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.展开更多
There is considerable potential for integrating transarterial chemoembolization(TACE),programmed death-(ligand)1(PD-[L]1)inhibitors,and molecular targeted treatments(MTT)in hepatocellular carcinoma(HCC).It is necessar...There is considerable potential for integrating transarterial chemoembolization(TACE),programmed death-(ligand)1(PD-[L]1)inhibitors,and molecular targeted treatments(MTT)in hepatocellular carcinoma(HCC).It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations.In this nationwide,retrospective,cohort study,826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT(combination group,n=376)or TACE monotherapy(monotherapy group,n=450)were included from January 2018 to May 2021.The primary endpoint was progression-free survival(PFS)according to modified RECIST.The secondary outcomes included overall survival(OS),objective response rate(ORR),and safety.We performed propensity score matching approaches to reduce bias between two groups.After matching,228 pairs were included with a predominantly advanced disease population.Median PFS in combination group was 9.5 months(95%confidence interval[CI],8.4-11.0)versus 8.0 months(95%CI,6.6-9.5)(adjusted hazard ratio[HR],0.70,P=0.002).OS and ORR were also significantly higher in combination group(median OS,19.2[16.1-27.3]vs.15.7 months[13.0-20.2];adjusted HR,0.63,P=0.001;ORR,60.1%vs.32.0%;P<0.001).Grade 3/4 adverse events were observed at a rate of 15.8%and 7.5%in combination and monotherapy groups,respectively.Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS,OS,and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice,with an acceptable safety profile.展开更多
We concentrate on the skin effects and topological properties in the multilayer non-Hermitian Su−Schrieffer−Heeger (SSH) structure, by taking into account the nonreciprocal couplings between the different sublattices ...We concentrate on the skin effects and topological properties in the multilayer non-Hermitian Su−Schrieffer−Heeger (SSH) structure, by taking into account the nonreciprocal couplings between the different sublattices in the unit cells. Following the detailed demonstration of the theoretical method, we find that in this system, the skin effects and topological phase transitions induced by nonreciprocal couplings display the apparent parity effect, following the increase of the layer number of this SSH structure. On the one hand, the skin effect is determined by the parity of the layer number of this SSH system, as well as the parity of the band index of the bulk states. On the other hand, for the topological edge modes, such an interesting parity effect can also be observed clearly. Next, when the parameter disorders are taken into account, the zero-energy edge modes in the odd-layer structures tend to be more robust, whereas the other edge modes are easy to be destroyed. In view of these results, it can be ascertained that the findings in this work promote to understand the influences of nonreciprocal couplings on the skin effects and topological properties in the multilayer SSH lattices.展开更多
基金supported by grants from the National Natural Science Foundation of China,Nos.92148206,82071330(to ZPT)82201745(to HN)the Natural Science Foundation of Hubei Province,China,Nos.2021BCA109(to ZPT)and 2021CFB067(to HN)。
文摘Ischemic stroke is one of the most common causes of mortality and disability worldwide.However,treatment efficacy and the progress of research remain unsatisfactory.As the critical support system and essential components in neurovascular units,glial cells and blood vessels(including the bloodbrain barrier)together maintain an optimal microenvironment for neuronal function.They provide nutrients,regulate neuronal excitability,and prevent harmful substances from entering brain tissue.The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis,supporting neuronal function,and reacting to injuries.However,most studies have focused on postmortem animals,which inevitably lack critical information about the dynamic changes that occur after ischemic stroke.Therefore,a high-precision technique for research in living animals is urgently needed.Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions.Twophoton fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure,information on multicellular component interactions,and provide images of structure and function in the cranial window.This technique shifts the existing research paradigm from static to dynamic,from flat to stereoscopic,and from single-cell function to multicellular intercommunication,thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain.In this review,we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy,highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems.We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke.
基金Supported by National Key Research and Development Program of China,No.2022YFE0209900.
文摘Familial hypercholesterolemia(FH)is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations,presenting with xanthomas,corneal arch,and severe cardiovascular diseases.Early identification,diagnosis,and treatment are crucial to prevent severe complications like acute myocardial infarction.Statins are the primary treatment,supplemented by Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors,though their effectiveness can be limited in severe cases.Over 90%of FH cases remain undiagnosed,and current treatments are often inadequate,underscoring the need for improved diagnostic and management systems.Future strategies include advancements in gene testing,precision medicine,and novel drugs,along with gene therapy approaches like AAV-mediated gene therapy and clustered regularly interspaced short palindromic repeats.Lifestyle modifications,including health education,dietary control,and regular exercise,are essential for managing FH and preventing related diseases.Research into FH-related gene mutations,especially LDLR,is critical for accurate diagnosis and effective treatment.
基金supported by National Natural Science Foundation of China(Grants No.11972088,No.12122203).
文摘The pressure evolution associated with the transient shock-induced infiltration of gas flow through granular media consisting of mobile particles is numerically investigated using a coupled Eulerian–Lagrangian approach.The coupling between shock compaction and interstitial flow has been revealed.A distinctive two-stage diffusing pressure field with deflection occurring at the tail of the compaction front is found,with corresponding spikes in both gaseous velocity and temperature profiles emerging within the width of the compaction front.The compaction front,together with the deflection pressure,reaches a steady state during the later period.An analytical prediction of the steady deflection pressure that considers the contributions of porosity and the non-isothermal effect is proposed.The isothermal single-phase method we developed,combining the porosity jump condition across the compaction front,shows consistent pressure evolution with the non-isothermal CMP-PIC one under weak shock strength and low column permeability.Lastly,the microscale mechanism governing the formation of not only pressure deflection but also gaseous velocity and temperature spikes within the width of the compaction front has been described.These aforementioned evolutions of the flow field are shown to arise from the nozzling effects associated with the particle-scale variations in the volume fraction.
基金supported by the Jiangsu Seed Industry Revitalization Project(JBGS[2021]024)Fundamental Research Funds for the Central Universities(KYT2023002)+2 种基金Jiangsu Province Capability Improvement Project through Science,TechnologyEducation Jiangsu Provincial Medical Key Discipline(ZDXK202211)Shandong Province Natural Science Foundation(ZR2020MC074)
文摘Extracellular membrane proteins are crucial for mediating cell attachment,recognition,and signal transduction in the testicular microenvironment,particularly germline stem cells.Cadherin 18(CDH18),a type Ⅱ classical cadherin,is primarily expressed in the nervous and reproductive systems.Here,we investigated the expression of CDH18in neonatal porcine prospermatogonia(ProSGs)and murine spermatogonial stem cells(SSCs).Disruption of CDH18 expression did not adversely affect cell morphology,proliferation,self-renewal,or differentiation in cultured porcine ProSGs,but enhanced cell adhesion and prolonged cell maintenance.Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion.To further elucidate the function of CDH18 in germ cells,Cdh18 knockout mice were generated,which exhibited normal testicular morphology,histology,andspermatogenesis.Transcriptomic analysis showed increased expression of genes associated with adhesion,consistent with the observations in porcine ProSGs.The interaction of CDH18withβ-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency.Collectively,these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs.Understanding this regulatory mechanism provides significant insights into the testicular niche.
基金Supported by the National Natural Science Foundation of China,No.82272396and the Youth Medical Talent of Jiangsu Province,No.QNRC2016475.
文摘Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.
基金The study was supported by National Key Research and Development Program(2018YFA0704100,2018YFA0704104)National Natural Science Foundation of China(81827805,82130060)Jiangsu Provincial Special Program of Medical Science(BE2019750).The funding sources had no role in the writing of the report,or decision to submit the paper for publication.
文摘There is considerable potential for integrating transarterial chemoembolization(TACE),programmed death-(ligand)1(PD-[L]1)inhibitors,and molecular targeted treatments(MTT)in hepatocellular carcinoma(HCC).It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations.In this nationwide,retrospective,cohort study,826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT(combination group,n=376)or TACE monotherapy(monotherapy group,n=450)were included from January 2018 to May 2021.The primary endpoint was progression-free survival(PFS)according to modified RECIST.The secondary outcomes included overall survival(OS),objective response rate(ORR),and safety.We performed propensity score matching approaches to reduce bias between two groups.After matching,228 pairs were included with a predominantly advanced disease population.Median PFS in combination group was 9.5 months(95%confidence interval[CI],8.4-11.0)versus 8.0 months(95%CI,6.6-9.5)(adjusted hazard ratio[HR],0.70,P=0.002).OS and ORR were also significantly higher in combination group(median OS,19.2[16.1-27.3]vs.15.7 months[13.0-20.2];adjusted HR,0.63,P=0.001;ORR,60.1%vs.32.0%;P<0.001).Grade 3/4 adverse events were observed at a rate of 15.8%and 7.5%in combination and monotherapy groups,respectively.Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS,OS,and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice,with an acceptable safety profile.
基金the LiaoNing Revitalization Talents Program(Grant No.XLYC1907033)the National Natural Science Foundation of China(Grant No.11905027)+1 种基金the Natural Science Foundation of Liaoning province(Grant No.2023-MS-072)Fundamental Research Funds for the Central Universities of Ministry of Education of China(Grant Nos.N2209005 and N2205015).
文摘We concentrate on the skin effects and topological properties in the multilayer non-Hermitian Su−Schrieffer−Heeger (SSH) structure, by taking into account the nonreciprocal couplings between the different sublattices in the unit cells. Following the detailed demonstration of the theoretical method, we find that in this system, the skin effects and topological phase transitions induced by nonreciprocal couplings display the apparent parity effect, following the increase of the layer number of this SSH structure. On the one hand, the skin effect is determined by the parity of the layer number of this SSH system, as well as the parity of the band index of the bulk states. On the other hand, for the topological edge modes, such an interesting parity effect can also be observed clearly. Next, when the parameter disorders are taken into account, the zero-energy edge modes in the odd-layer structures tend to be more robust, whereas the other edge modes are easy to be destroyed. In view of these results, it can be ascertained that the findings in this work promote to understand the influences of nonreciprocal couplings on the skin effects and topological properties in the multilayer SSH lattices.
