An in-memory storage system provides submillisecond latency and improves the concurrency of user applications by caching data into memory from external storage.Fault tolerance of in-memory storage systems is essential...An in-memory storage system provides submillisecond latency and improves the concurrency of user applications by caching data into memory from external storage.Fault tolerance of in-memory storage systems is essential,as the loss of cached data requires access to data from external storage,which evidently increases the response latency.Typically,replication and erasure code(EC)are two fault-tolerant schemes that pose different trade-offs between access performance and storage usage.To help make the best performance and space trade-off,we design ElasticMem,a hybrid fault-tolerant distributed in-memory storage system that supports elastic redundancy transition to dynamically change the fault-tolerant scheme.ElasticMem exploits a novel EC-oriented replication(EOR)that carefully designs the data placement of replication according to the future data layout of EC to enhance the I/O efficiency of redundancy transition.ElasticMem solves the consistency problem caused by concurrent data accesses via a lightweight table-based scheme combined with data bypassing.It detects correlated read and write requests and serves subsequent read requests with local data.We implement a prototype that realizes ElasticMem based on Memcached.Experiments show that ElasticMem remarkably reduces the time of redundancy transition,the overall latency of correlated concurrent data accesses,and the latency of single data access among them.展开更多
Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(...Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.展开更多
Ultraviolet nanoimprint lithography(UV-NIL)is a versatile and cost-effective technique for the fabrication of micro-and nanostructures by copying master patterns in a planar or a roll-to-roll process through curing of...Ultraviolet nanoimprint lithography(UV-NIL)is a versatile and cost-effective technique for the fabrication of micro-and nanostructures by copying master patterns in a planar or a roll-to-roll process through curing of a liquid UV-sensitive precursor.For applications with a high pattern complexity,new UV-NIL process chains must be specified.Master fabrication is a challenging part of the development and often cannot be accomplished using a single master fabrication technique.Therefore,an approach combining different patterning fabrication techniques is developed here for polymer masters using laser direct writing and photolithography.The polymer masters produced in this way are molded into inverse silicone stamps that are used for roll-to-roll replication into an acrylate formulation.To fit the required roller size for large-area UV-NIL,several submasters with micrometer-sized dot and line gratings and prism arrays,which have been patterned by these different techniques,are assembled to final size of ~200×600 mm^(2) with an absolute precision of better than 50μm.The size of the submasters allows the use of standard laboratory equipment for patterning and direct writing,thus enabling the fabrication of micro-and even nanostructures when electron-beam writing is utilized.In this way,the effort,time,and costs for the fabrication of masters for UV-NIL processes are reduced,enabling further development for particular structures and applications.Using this approach,patterns fabricated with different laboratory tools are finally replicated by UV-NIL in an acrylate formulation,demonstrating the high quality of the whole process chain.展开更多
The 3CL protease, a highly conserved enzyme in the coronavirus, plays a crucial role in the viral life cycle by facilitating viral replication through precise cleavage of polyproteins. Beyond its proteolytic function,...The 3CL protease, a highly conserved enzyme in the coronavirus, plays a crucial role in the viral life cycle by facilitating viral replication through precise cleavage of polyproteins. Beyond its proteolytic function, the 3CL protease also engages in intricate interactions with host cell proteins involved in critical cellular processes such as transcription, translation, and nuclear-cytoplasmic transport, effectively hijacking cellular machinery to promote viral replication. Additionally, it disrupts innate immune signaling pathways, suppresses interferon activity and cleaves antiviral proteins. Furthermore, it modulates host cell death pathways including pyroptosis and apoptosis, interferes with autophagy and inhibits stress granule formation to maintain viral infection and exacerbate viral pathogenesis. This review highlights the molecular mechanisms by which the 3CL protease orchestrates virus-host interactions, emphasizing its central role in coronavirus pathogenesis and highlighting potential therapeutic targets for future interventions.展开更多
Personal video recorders (PVRs) have altered the way users consume television (TV) content by allowing users to record programs and watch them at their convenience, overcoming the constraints of live broadcasting. How...Personal video recorders (PVRs) have altered the way users consume television (TV) content by allowing users to record programs and watch them at their convenience, overcoming the constraints of live broadcasting. However, standalone PVRs are limited by their individual storage capacities, restricting the number of programs they can store. While online catch-up TV services such as Hulu and Netflix mitigate this limitation by offering on-demand access to broadcast programs shortly after their initial broadcast, they require substantial storage and network resources, leading to significant infrastructural costs for service providers. To address these challenges, we propose a collaborative TV content recording system that leverages distributed PVRs, combining their storage into a virtual shared pool without additional costs. Our system aims to support all concurrent playback requests without service interruption while ensuring program availability comparable to that of local devices. The main contributions of our proposed system are fourfold. First, by sharing storage and upload bandwidth among PVRs, our system significantly expands the overall recording capacity and enables simultaneous recording of multiple programs without the physical constraints of standalone devices. Second, by utilizing erasure coding efficiently, our system reduces the storage space required for each program, allowing more programs to be recorded compared to traditional replication. Third, we propose an adaptive redundancy scheme to control the degree of redundancy of each program based on its evolving playback demand, ensuring high-quality playback by providing sufficient bandwidth for popular programs. Finally, we introduce a contribution-based incentive policy that encourages PVRs to actively participate by contributing resources, while discouraging excessive consumption of the combined storage pool. Through extensive experiments, we demonstrate the effectiveness of our proposed collaborative TV program recording system in terms of storage efficiency and performance.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain geno...The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.展开更多
BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is ...BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is controversial.AIM To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.METHODS A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled.All patients received nucleoside/nucleotide analogues(NAs)therapy,and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.RESULTS The detection rates of a single mutation of rtS106C,rtH126Y,rtD134E,and rtL269I were 8.21%,3.20%,2.55%and 61.49%in 23718 genotype C patients,and 1.31%,1.76%,0.21%,and 92.33%in 4266 genotype B patients,respectively.The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients,accounting for 0.042%of all patients.These 12 patients had received NA treatments except TDF before testing.Among them,6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations,and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations.Compared with the wild-type(WT)strain,the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%,and TDF susceptibility reduced by less than 2-fold,but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility.Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain.In the clinic,emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.CONCLUSION HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.展开更多
Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple dat...Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple data centers poses a significant challenge,especially when balancing opposing goals such as latency,storage costs,energy consumption,and network efficiency.This study introduces a novel Dynamic Optimization Algorithm called Dynamic Multi-Objective Gannet Optimization(DMGO),designed to enhance data replication efficiency in cloud environments.Unlike traditional static replication systems,DMGO adapts dynamically to variations in network conditions,system demand,and resource availability.The approach utilizes multi-objective optimization approaches to efficiently balance data access latency,storage efficiency,and operational costs.DMGO consistently evaluates data center performance and adjusts replication algorithms in real time to guarantee optimal system efficiency.Experimental evaluations conducted in a simulated cloud environment demonstrate that DMGO significantly outperforms conventional static algorithms,achieving faster data access,lower storage overhead,reduced energy consumption,and improved scalability.The proposed methodology offers a robust and adaptable solution for modern cloud systems,ensuring efficient resource consumption while maintaining high performance.展开更多
Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previo...Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previously identified the interaction between the catalytic subunit NSP12 of SARS-CoV-2 RdRp and the host protein CREB-regulated transcription coactivator 3(CRTC3),a member of the CRTC family that regulates cyclic AMP response element-binding protein(CREB)-mediated transcriptional activation.Currently,the implication of CRTC3 in the pathogenesis of HCoVs is poorly understood.Herein,we demonstrated that CRTC3 attenuates RdRp activity and SARS-CoV-2 genome replication,therefore reducing the production of progeny viruses.The interaction of CRTC3 with NSP12 contributes to its inhibitory effect on RdRp activity.Furthermore,we expanded the suppressive effects of two other CRTC family members(CRTC1 and CRTC2)on the RdRp activities of lethal HCoVs,including SARS-CoV-2 and Middle East respiratory syndrome coronavirus(MERS-CoV),along with the CREB antagonization.Overall,our research suggests that CRTCs restrict the replication of HCoVs and are antagonized by CREB,which not only provides new insights into the replication regulation of HCoVs,but also offers important information for the development of anti-HCoV interventions.展开更多
In this short review we summarize the different strategies for discovery and development of antiviral agents, including targeting virus entry into host, virus replication within cells, infant virus assembly and releas...In this short review we summarize the different strategies for discovery and development of antiviral agents, including targeting virus entry into host, virus replication within cells, infant virus assembly and release from the infected cells. The progress on development of various classes of antivirus agents and their potential in virus therapy, mainly targeting human immunodeficiency virus （HIV）, was also discussed.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(WK2150110022)Anhui Provincial Natural Science Foundation(2208085QF189)National Natural Science Foundation of China(62202440).
文摘An in-memory storage system provides submillisecond latency and improves the concurrency of user applications by caching data into memory from external storage.Fault tolerance of in-memory storage systems is essential,as the loss of cached data requires access to data from external storage,which evidently increases the response latency.Typically,replication and erasure code(EC)are two fault-tolerant schemes that pose different trade-offs between access performance and storage usage.To help make the best performance and space trade-off,we design ElasticMem,a hybrid fault-tolerant distributed in-memory storage system that supports elastic redundancy transition to dynamically change the fault-tolerant scheme.ElasticMem exploits a novel EC-oriented replication(EOR)that carefully designs the data placement of replication according to the future data layout of EC to enhance the I/O efficiency of redundancy transition.ElasticMem solves the consistency problem caused by concurrent data accesses via a lightweight table-based scheme combined with data bypassing.It detects correlated read and write requests and serves subsequent read requests with local data.We implement a prototype that realizes ElasticMem based on Memcached.Experiments show that ElasticMem remarkably reduces the time of redundancy transition,the overall latency of correlated concurrent data accesses,and the latency of single data access among them.
基金supported by grants from the National Natural Science Foundation of China(32170238,32400191)Guangdong Basic and Applied Basic Research Foundation(2023A1515111029)+2 种基金the Science,Technology and Innovation Commission of Shenzhen Municipality(RCYX20200714114538196)the Chinese Academy of Agricultural Sciences Elite Youth Program(grant 110243160001007)the Guangdong Pearl River Talent Program(2021QN02N792)。
文摘Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.
文摘Ultraviolet nanoimprint lithography(UV-NIL)is a versatile and cost-effective technique for the fabrication of micro-and nanostructures by copying master patterns in a planar or a roll-to-roll process through curing of a liquid UV-sensitive precursor.For applications with a high pattern complexity,new UV-NIL process chains must be specified.Master fabrication is a challenging part of the development and often cannot be accomplished using a single master fabrication technique.Therefore,an approach combining different patterning fabrication techniques is developed here for polymer masters using laser direct writing and photolithography.The polymer masters produced in this way are molded into inverse silicone stamps that are used for roll-to-roll replication into an acrylate formulation.To fit the required roller size for large-area UV-NIL,several submasters with micrometer-sized dot and line gratings and prism arrays,which have been patterned by these different techniques,are assembled to final size of ~200×600 mm^(2) with an absolute precision of better than 50μm.The size of the submasters allows the use of standard laboratory equipment for patterning and direct writing,thus enabling the fabrication of micro-and even nanostructures when electron-beam writing is utilized.In this way,the effort,time,and costs for the fabrication of masters for UV-NIL processes are reduced,enabling further development for particular structures and applications.Using this approach,patterns fabricated with different laboratory tools are finally replicated by UV-NIL in an acrylate formulation,demonstrating the high quality of the whole process chain.
基金supported by the National Natural Science Foundation of China(grant no.82370015).
文摘The 3CL protease, a highly conserved enzyme in the coronavirus, plays a crucial role in the viral life cycle by facilitating viral replication through precise cleavage of polyproteins. Beyond its proteolytic function, the 3CL protease also engages in intricate interactions with host cell proteins involved in critical cellular processes such as transcription, translation, and nuclear-cytoplasmic transport, effectively hijacking cellular machinery to promote viral replication. Additionally, it disrupts innate immune signaling pathways, suppresses interferon activity and cleaves antiviral proteins. Furthermore, it modulates host cell death pathways including pyroptosis and apoptosis, interferes with autophagy and inhibits stress granule formation to maintain viral infection and exacerbate viral pathogenesis. This review highlights the molecular mechanisms by which the 3CL protease orchestrates virus-host interactions, emphasizing its central role in coronavirus pathogenesis and highlighting potential therapeutic targets for future interventions.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(Nos.2019R1A2C1002221 and RS-2023-00252186)Institute of Information&Communications Technology Planning&Evaluation(IITP)grant funded by the Korea government(MSIT)(Nos.2021-0-00590,RS-2021-II210590Decentralized High Performance Consensus for Large-Scale Blockchains).
文摘Personal video recorders (PVRs) have altered the way users consume television (TV) content by allowing users to record programs and watch them at their convenience, overcoming the constraints of live broadcasting. However, standalone PVRs are limited by their individual storage capacities, restricting the number of programs they can store. While online catch-up TV services such as Hulu and Netflix mitigate this limitation by offering on-demand access to broadcast programs shortly after their initial broadcast, they require substantial storage and network resources, leading to significant infrastructural costs for service providers. To address these challenges, we propose a collaborative TV content recording system that leverages distributed PVRs, combining their storage into a virtual shared pool without additional costs. Our system aims to support all concurrent playback requests without service interruption while ensuring program availability comparable to that of local devices. The main contributions of our proposed system are fourfold. First, by sharing storage and upload bandwidth among PVRs, our system significantly expands the overall recording capacity and enables simultaneous recording of multiple programs without the physical constraints of standalone devices. Second, by utilizing erasure coding efficiently, our system reduces the storage space required for each program, allowing more programs to be recorded compared to traditional replication. Third, we propose an adaptive redundancy scheme to control the degree of redundancy of each program based on its evolving playback demand, ensuring high-quality playback by providing sufficient bandwidth for popular programs. Finally, we introduce a contribution-based incentive policy that encourages PVRs to actively participate by contributing resources, while discouraging excessive consumption of the combined storage pool. Through extensive experiments, we demonstrate the effectiveness of our proposed collaborative TV program recording system in terms of storage efficiency and performance.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金supported by the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(202401AT070186 to K.Q.L.,202201AS070044 to B.Z.)Yunnan Province(202305AH340006 to B.Z.)Kunming Science and Technology Bureau(2022SCP007 to B.Z.)。
文摘The DNA replication stress(RS)response is crucial for maintaining cellular homeostasis and promoting physiological longevity.However,the mechanisms by which long-lived species,such as bats,regulate RS to maintain genomic stability remain unclear.Also,recent studies have uncovered noncanonical roles of ribosome-associated factors in maintaining genomic stability.In this study,somatic skin fibroblasts from the long-lived big-footed bat(Myotis pilosus)were examined,with results showing that bat cells exhibited enhanced RS tolerance compared to mouse cells.Comparative transcriptome analysis under RS conditions revealed pronounced species-specific transcriptional differences,including robust up-regulation of ribosome biogenesis genes in bat cells and a markedly reduced activation of the P53 signaling pathway.These features emphasize a distinct homeostatic strategy in bat cells.Nuclear fragile X mental retardation-interacting protein 1(Nufip1),a ribosome-associated factor highly expressed in bat fibroblasts,was identified as a potential integrator of ribosomal and P53 signaling via its association with ribosomal protein S27-like(Rps27l).These findings provide direct cellular and molecular evidence for a noncanonical RS response in bats,highlighting a deeper understanding of the biological characteristics and genomic maintenance mechanisms of long-lived species.
基金Supported by The National Natural Science Foundation of China,No.82470632.
文摘BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is controversial.AIM To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.METHODS A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled.All patients received nucleoside/nucleotide analogues(NAs)therapy,and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.RESULTS The detection rates of a single mutation of rtS106C,rtH126Y,rtD134E,and rtL269I were 8.21%,3.20%,2.55%and 61.49%in 23718 genotype C patients,and 1.31%,1.76%,0.21%,and 92.33%in 4266 genotype B patients,respectively.The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients,accounting for 0.042%of all patients.These 12 patients had received NA treatments except TDF before testing.Among them,6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations,and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations.Compared with the wild-type(WT)strain,the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%,and TDF susceptibility reduced by less than 2-fold,but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility.Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain.In the clinic,emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.CONCLUSION HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.
文摘Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple data centers poses a significant challenge,especially when balancing opposing goals such as latency,storage costs,energy consumption,and network efficiency.This study introduces a novel Dynamic Optimization Algorithm called Dynamic Multi-Objective Gannet Optimization(DMGO),designed to enhance data replication efficiency in cloud environments.Unlike traditional static replication systems,DMGO adapts dynamically to variations in network conditions,system demand,and resource availability.The approach utilizes multi-objective optimization approaches to efficiently balance data access latency,storage efficiency,and operational costs.DMGO consistently evaluates data center performance and adjusts replication algorithms in real time to guarantee optimal system efficiency.Experimental evaluations conducted in a simulated cloud environment demonstrate that DMGO significantly outperforms conventional static algorithms,achieving faster data access,lower storage overhead,reduced energy consumption,and improved scalability.The proposed methodology offers a robust and adaptable solution for modern cloud systems,ensuring efficient resource consumption while maintaining high performance.
基金supported by grants from the National Natural Science Foundation of China(32071236)the National Science Fund for Distinguished Young Scholars(32225001)+6 种基金the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYGD23018)Key Science and Technology Research Projects in Key Areas of the Corps(2023AB053)the National Key Research and Development Program of China(2022YFC2303700)the Joint Project of Pengzhou People's Hospital with Southwest Medical University(2024PZXNYD02)Project funded by China Postdoctoral Science Foundation(2020M683304)Sichuan Science and Technology Support Project(2021YJ0502)Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH082).
文摘Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previously identified the interaction between the catalytic subunit NSP12 of SARS-CoV-2 RdRp and the host protein CREB-regulated transcription coactivator 3(CRTC3),a member of the CRTC family that regulates cyclic AMP response element-binding protein(CREB)-mediated transcriptional activation.Currently,the implication of CRTC3 in the pathogenesis of HCoVs is poorly understood.Herein,we demonstrated that CRTC3 attenuates RdRp activity and SARS-CoV-2 genome replication,therefore reducing the production of progeny viruses.The interaction of CRTC3 with NSP12 contributes to its inhibitory effect on RdRp activity.Furthermore,we expanded the suppressive effects of two other CRTC family members(CRTC1 and CRTC2)on the RdRp activities of lethal HCoVs,including SARS-CoV-2 and Middle East respiratory syndrome coronavirus(MERS-CoV),along with the CREB antagonization.Overall,our research suggests that CRTCs restrict the replication of HCoVs and are antagonized by CREB,which not only provides new insights into the replication regulation of HCoVs,but also offers important information for the development of anti-HCoV interventions.
基金National Basic Research Program of China(973 Program,Grant No.2010CB-12300)National Natural Science Foundation of China(Grant No.20932001 and 20852001)"985"Project Foundation(Grant No.985-2-126-121)
文摘In this short review we summarize the different strategies for discovery and development of antiviral agents, including targeting virus entry into host, virus replication within cells, infant virus assembly and release from the infected cells. The progress on development of various classes of antivirus agents and their potential in virus therapy, mainly targeting human immunodeficiency virus （HIV）, was also discussed.
