The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant...The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.展开更多
Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitab...Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitable for large population,which is applied to the field experiment of genetic population.The statistical methods of analysis of variance(ANOVA)and heritability estimation in single and multiple environments were derived and implemented using the statistical analysis system(SAS)program for the analysis of BIR.As a work example,a comparison of statistical analysis between BIR design and the completely random block(CRB)design were conducted for the protein content from a panel containing 455 soybean germplasms.The results indicated the different estimates of average heritability in multiple environments.The research results provided technical support for the application of BIR design in genetics and breeding studies.展开更多
As the amount of data continues to grow rapidly,the variety of data produced by applications is becoming more affluent than ever.Cloud computing is the best technology evolving today to provide multi-services for the ...As the amount of data continues to grow rapidly,the variety of data produced by applications is becoming more affluent than ever.Cloud computing is the best technology evolving today to provide multi-services for the mass and variety of data.The cloud computing features are capable of processing,managing,and storing all sorts of data.Although data is stored in many high-end nodes,either in the same data centers or across many data centers in cloud,performance issues are still inevitable.The cloud replication strategy is one of best solutions to address risk of performance degradation in the cloud environment.The real challenge here is developing the right data replication strategy with minimal data movement that guarantees efficient network usage,low fault tolerance,and minimal replication frequency.The key problem discussed in this research is inefficient network usage discovered during selecting a suitable data center to store replica copies induced by inadequate data center selection criteria.Hence,to mitigate the issue,we proposed Replication Strategy with a comprehensive Data Center Selection Method(RS-DCSM),which can determine the appropriate data center to place replicas by considering three key factors:Popularity,space availability,and centrality.The proposed RS-DCSM was simulated using CloudSim and the results proved that data movement between data centers is significantly reduced by 14%reduction in overall replication frequency and 20%decrement in network usage,which outperformed the current replication strategy,known as Dynamic Popularity aware Replication Strategy(DPRS)algorithm.展开更多
Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike pr...Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants,which is likely to cause immune es-cape and the reduction of the protective effect of the vaccine.Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies.Methods:We collected cellular supernatant and cell lysates and measured the viral titers,viral RNA loads,and E subgenomic RNA(E sgRNA)loads in different Omicron subvariants grown in Vero E6 cells,using WH-09 and Delta variants as a reference.Additionally,we evaluated the in vitro neutralizing activity of different Omicron sub-variants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity.Results:As the SARS-CoV-2 evolved into Omicron BA.1,the replication ability in vitro began to decrease.Then with the emergence of new subvariants,the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants.In WH-09-inactivated vaccine sera,geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09.In Delta-inactivated vaccine sera,geometric mean titers of neutrali-zation antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta.Conclusion:According to the findings of this research,the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants,and was lower in BA.1 than in other Omicron subvariants.After two doses of inactivated(WH-09 or Delta)vaccine,cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.展开更多
The fungal pathogen Setosphaeria turcica causes northern corn leaf blight(NCLB),which leads to considerable crop losses.Setosphaeria turcica elaborates a specialized infection structures called appressorium for maize ...The fungal pathogen Setosphaeria turcica causes northern corn leaf blight(NCLB),which leads to considerable crop losses.Setosphaeria turcica elaborates a specialized infection structures called appressorium for maize infection.Previously,we demonstrated that the S.turcica triggers an S-phase checkpoint and ATR(Ataxia Telangiectasia and Rad3 related)-dependent self-protective response to DNA genotoxic insults during maize infection.However,how the regulatory mechanism works was still largely unknown.Here,we report a genome wide transcriptional profile analysis during appressorium formation in the present of DNA replication stress.We performed RNA-Seq analysis to identify S.tuicica genes responsive to DNA replication stress.In the current work,we found that appressorium-mediated maize infection by S.turcica is significantly blocked by S-phase checkpoint.A large serial of secondary metabolite and melanin biosynthesis genes were blocked in appressorium formation of S.turcica during the replication stress.The secondary metabolite biosynthesis genes including alcohol dehydrogenase GroES-like domain,multicopper oxidase,ABCtransporter families,cytochrome P450 and FAD-containing monooxygenase were related to plant pathogen infection.In addition,we demonstrated that autophagy in S.turcica is up-regulated by ATR as a defense response to stress.We identified StATG3,StATG4,StATG5,StATG7 and StATG16 genes for autophagy were induced by ATR-mediated S-phase checkpoint.We therefore propose that in response to genotoxic stress,S.turcica utilizes ATR-dependent pathway to turn off transcription of genes governing appressorium-mediated infection,and meanwhile inducing transcription of autophagy genes likely as a mechanism of self-protection,aside from the more conservative responses in eukaryotes.展开更多
The reliability and availability of cloud systems have become major concerns of service providers,brokers,and end-users.Therefore,studying fault-tolerance mechanisms in cloud computing attracts intense attention in in...The reliability and availability of cloud systems have become major concerns of service providers,brokers,and end-users.Therefore,studying fault-tolerance mechanisms in cloud computing attracts intense attention in industry and academia.The task-scheduling mechanisms can improve the fault-tolerance level of cloud systems.A task-scheduling mechanism distributes tasks to a group of instances to be executed.Much work has been undertaken in this direction to improve the overall outcome of cloud computing,such as improving service qual-ity and reducing power consumption.However,little work on task scheduling has studied the problem of lost tasks from the broker’s perspective.Task loss can hap-pen due to virtual machine failures,server crashes,connection interruption,etc.The broker-based concept means that the backup task can be allocated by the bro-ker on the same cloud service provider(CSP)or a different CSP to reduce costs,for example.This paper proposes a novel fault-tolerant mechanism that employs the primary backup(PB)model of task scheduling to address this issue.The pro-posed mechanism minimizes the impact of failure events by reducing the number of lost tasks.The mechanism is further improved to shorten the makespan time of submitted tasks in cloud systems.The experiments demonstrated that the pro-posed mechanism decreased the number of lost tasks by about 13%–15%com-pared with other mechanisms in the literature.展开更多
Many cutting-edge methods are now possible in real-time commercial settings and are growing in popularity on cloud platforms.By incorporating new,cutting-edge technologies to a larger extent without using more infrast...Many cutting-edge methods are now possible in real-time commercial settings and are growing in popularity on cloud platforms.By incorporating new,cutting-edge technologies to a larger extent without using more infrastructures,the information technology platform is anticipating a completely new level of devel-opment.The following concepts are proposed in this research paper:1)A reliable authentication method Data replication that is optimised;graph-based data encryp-tion and packing colouring in Redundant Array of Independent Disks(RAID)sto-rage.At the data centre,data is encrypted using crypto keys called Key Streams.These keys are produced using the packing colouring method in the web graph’s jump graph.In order to achieve space efficiency,the replication is carried out on optimised many servers employing packing colours.It would be thought that more connections would provide better authentication.This study provides an innovative architecture with robust security,enhanced authentication,and low cost.展开更多
Most social networks allow connections amongst many people based on shared interests.Social networks have to offer shared data like videos,photos with minimum latency to the group,which could be challenging as the sto...Most social networks allow connections amongst many people based on shared interests.Social networks have to offer shared data like videos,photos with minimum latency to the group,which could be challenging as the storage cost has to be minimized and hence entire data replication is not a solution.The replication of data across a network of read-intensive can potentially lead to increased savings in cost and energy and reduce the end-user’s response time.Though simple and adaptive replication strategies exist,the solution is non-deter-ministic;the replicas of the data need to be optimized to the data usability,perfor-mance,and stability of the application systems.To resolve the non-deterministic issue of replication,metaheuristics are applied.In this work,Harmony Search and Tabu Search algorithms are used optimizing the replication process.A novel Har-mony-Tabu search is proposed for effective placement and replication of data.Experiments on large datasets show the effectiveness of the proposed technique.It is seen that the bandwidth saving for proposed harmony-Tabu replication per-forms better in the range of 3.57%to 18.18%for varying number of cloud data-centers when compared to simple replication,Tabu replication and Harmony replication algorithm.展开更多
Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cel...Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains unclear.This study aims to study its role.Methods:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence staining.Glucose-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western blotting.Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown.The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets.Palm reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 cells.Palm also inhibited TRPM5 expression in primary mouse islets.Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis.Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβcells.Conclusion:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.展开更多
Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels inβ-cells,including Na+,K+,and Ca2+channels,aid in t...Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels inβ-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.展开更多
Objective: The aim of this study is to investigate how individuals with type 2 diabetes mellitus’ pancreatic β-cell function index and insulin resistance index are affected by tuberculosis infection. Methods: The st...Objective: The aim of this study is to investigate how individuals with type 2 diabetes mellitus’ pancreatic β-cell function index and insulin resistance index are affected by tuberculosis infection. Methods: The study group consisted of 89 patients with type 2 diabetes mellitus and tuberculosis infection who were admitted to Jingzhou Chest Hospital between March 2019 and March 2021. Gender and duration of diabetes were matching conditions. The control group was made up of 89 patients with type 2 diabetes who were admitted to Jingzhou Central Hospital’s endocrinology department during the same period. The two patient groups provided general information such as gender, age, length of diabetes, and blood biochemical indexes such as glycosylated hemoglobin (HbA1c), fasting glucose (FPG), and fasting C-peptide (FC-P). The HOMA calculator was used to calculate the HOMA-β and the HOMA-IR, and intergroup comparisons and correlation analyses were carried out. Results: Regarding gender, age, disease duration, FC-P, and HbA1c, the differences between the two groups were not statistically significant (P > 0.05). However, BMI, FPG, HOMA-β, and HOMA-IR showed statistically significant differences (P < 0.05). In comparison to the control group, the study group’s HOMA-β was lower and its HOMA-IR was greater. According to Spearman’s correlation analysis, HOMA-β had a negative association (P th FPG, HbA1c, and the length of the disease, and a positive correlation with BMI and FC-P. A positive correlation was found between HOMA-IR and BMI, FPG, and FC-P (P < 0.01), as well as a correlation with the length of the disease (P > 0.05) and HbA1c. Conclusions: In type 2 diabetes mellitus combined with tuberculosis infection, the patients had higher FPG levels and lower FC-P levels, the secretory function of pancreatic β-cells was more severely impaired, and insulin resistance was more obvious.展开更多
Objective: To evaluate the therapeutic efficacy of replicative adenovirus CNHK500 in the treatment of hepatocellular carcinoma. Methods: Virus proliferation assay, cell viability assay and Western blot were performed ...Objective: To evaluate the therapeutic efficacy of replicative adenovirus CNHK500 in the treatment of hepatocellular carcinoma. Methods: Virus proliferation assay, cell viability assay and Western blot were performed to assess the selective replication and cytolysis of CNHK500 in telomerase positive liver cancer cells Hep3B, HepGII, SMMC7721 and in normal cells. Results: The replicative multiples of CNHK500 in HepGII, Hep3B and SMMC7221 after 96 h of virus proliferation were 52 000, 396 984.9 and 632 911.3 fold respectively, similar to those of wtAd5. However, CNHK500 demonstrated more significant attenuated replicative ability in normal cell lines than wtAd5. CNHK500 replicated only 3.1-100 fold at 96 h, while the wtAd5 still reached 3160-17 357 fold. CNHK500 could cause half of HepGII cells death within 7 days at MOI 2, in Hep3B cell lines the IC50 was as low as MOI 0.01, whereas the IC50 in BJ cell was as high as MOI 1000. CNHK500 E1A protein could only be detected in hepatocellular cancer cells but not in normal cells under normoxia. E1B protein could only be detected under hypoxia condition at a MOI of 1. Conclusion: CNHK500 can efficiently replicate in and kill liver cancer cells as well as wtAd5 do while it is severely attenuated in proliferation and cytolysis among normal cells. It would be a prominsing strategy for liver cancer tratment.展开更多
Objective： To evaluate the tumor selectivity and therapeutic efficiency of replication-competent adenovirus CNHK300 on human breast cancer cells. Methods： RT-PCR was used to detect the hTERT mRNA activity in various...Objective： To evaluate the tumor selectivity and therapeutic efficiency of replication-competent adenovirus CNHK300 on human breast cancer cells. Methods： RT-PCR was used to detect the hTERT mRNA activity in various breast cancer and normal fibroblast cell lines. Virus proliferation assay, cell viability assay and Western blot were applied to evaluate the proliferation and cytolysis selectivity of CNHK300. Results： The telomerase activity of MCF-7, BT-549 and SK-BR-3 was positive, while telomerase in MRC-5 and BJ was negative. The progeny virus titers in MCF-7, BT-549 and SK-BR-3 after 48 h of CNHK300 exposure was 40 625, 1 265 and 20 000 fold higher than those of 0 h, even slightly higher than those of wtAd5 （except in SK-BR-3）. ONYX-015 virus proliferation ability was weaker than that of CNHK300 in cancer cells. However, CNHK300 exhibited attenuated replicative ability as compared with wtAd5 in MRC-5 and BJ. The CNHK300 replicatative multiple was 63 and 192 fold at 48 h respectively, while the wtAd5 still multiplied 3 160-4 846 fold. CNHK300 could cause about half of breast cancer cells to die within 7 days at MOI 10 pfu/cell and below, whereas the IC50 in BJ and MRC-5 was as high as MOI 100 pfu/cell. CNHK300 E1A protein could be detected in breast cancer cells and 293 cells but not in normal fibroblast cells. Conclusion： hTERT promoter can successfully modulate the CNHK300 to be selectively replicated in breast cancer cells positive for telomerase, which may be a potential treatment strategy in breast cancer.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.82173601)Yili&Jiangsu Joint Institute of Health(Grant No.yl2021ms02).
文摘The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.
基金Supported by Key Research and Development Project of Heilongjiang Province(GA21B009-6)Heilongjiang Province Natural Science Foundation(C2015009)。
文摘Large-scale genetic population used for genetic breeding researches covers a large area in the field experiment,and the effect of local control would be gradually weakened.The block in replication(BIR)design is suitable for large population,which is applied to the field experiment of genetic population.The statistical methods of analysis of variance(ANOVA)and heritability estimation in single and multiple environments were derived and implemented using the statistical analysis system(SAS)program for the analysis of BIR.As a work example,a comparison of statistical analysis between BIR design and the completely random block(CRB)design were conducted for the protein content from a panel containing 455 soybean germplasms.The results indicated the different estimates of average heritability in multiple environments.The research results provided technical support for the application of BIR design in genetics and breeding studies.
基金supported by Universiti Putra Malaysia and the Ministry of Education(MOE).
文摘As the amount of data continues to grow rapidly,the variety of data produced by applications is becoming more affluent than ever.Cloud computing is the best technology evolving today to provide multi-services for the mass and variety of data.The cloud computing features are capable of processing,managing,and storing all sorts of data.Although data is stored in many high-end nodes,either in the same data centers or across many data centers in cloud,performance issues are still inevitable.The cloud replication strategy is one of best solutions to address risk of performance degradation in the cloud environment.The real challenge here is developing the right data replication strategy with minimal data movement that guarantees efficient network usage,low fault tolerance,and minimal replication frequency.The key problem discussed in this research is inefficient network usage discovered during selecting a suitable data center to store replica copies induced by inadequate data center selection criteria.Hence,to mitigate the issue,we proposed Replication Strategy with a comprehensive Data Center Selection Method(RS-DCSM),which can determine the appropriate data center to place replicas by considering three key factors:Popularity,space availability,and centrality.The proposed RS-DCSM was simulated using CloudSim and the results proved that data movement between data centers is significantly reduced by 14%reduction in overall replication frequency and 20%decrement in network usage,which outperformed the current replication strategy,known as Dynamic Popularity aware Replication Strategy(DPRS)algorithm.
基金National Research and Development Project of China,Grant/Award Number:2022YFC0867600CAMS initiative for Innovative Medicine of China,Grant/Award Number:2021-I2M-1-035。
文摘Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants,which is likely to cause immune es-cape and the reduction of the protective effect of the vaccine.Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies.Methods:We collected cellular supernatant and cell lysates and measured the viral titers,viral RNA loads,and E subgenomic RNA(E sgRNA)loads in different Omicron subvariants grown in Vero E6 cells,using WH-09 and Delta variants as a reference.Additionally,we evaluated the in vitro neutralizing activity of different Omicron sub-variants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity.Results:As the SARS-CoV-2 evolved into Omicron BA.1,the replication ability in vitro began to decrease.Then with the emergence of new subvariants,the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants.In WH-09-inactivated vaccine sera,geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09.In Delta-inactivated vaccine sera,geometric mean titers of neutrali-zation antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta.Conclusion:According to the findings of this research,the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants,and was lower in BA.1 than in other Omicron subvariants.After two doses of inactivated(WH-09 or Delta)vaccine,cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.
基金supported by the grants from the Youth Top Talent Project from Hebei Provincial Department of Education,China(BJ2020003)the China Agriculture Research System of MOF and MARA(CARS-02-25)+3 种基金the State Key Laboratory of North China Crop Improvement and RegulationOpen Project of Key Laboratory of Microbial Diversity Research and Application of Hebei Province(MDRA202101)the Hebei Provincial Department of Bureau of Science and Technology(360-0803-JSN-3YGS)the Natural Science Foundation of Hebei Province(C202204138)。
文摘The fungal pathogen Setosphaeria turcica causes northern corn leaf blight(NCLB),which leads to considerable crop losses.Setosphaeria turcica elaborates a specialized infection structures called appressorium for maize infection.Previously,we demonstrated that the S.turcica triggers an S-phase checkpoint and ATR(Ataxia Telangiectasia and Rad3 related)-dependent self-protective response to DNA genotoxic insults during maize infection.However,how the regulatory mechanism works was still largely unknown.Here,we report a genome wide transcriptional profile analysis during appressorium formation in the present of DNA replication stress.We performed RNA-Seq analysis to identify S.tuicica genes responsive to DNA replication stress.In the current work,we found that appressorium-mediated maize infection by S.turcica is significantly blocked by S-phase checkpoint.A large serial of secondary metabolite and melanin biosynthesis genes were blocked in appressorium formation of S.turcica during the replication stress.The secondary metabolite biosynthesis genes including alcohol dehydrogenase GroES-like domain,multicopper oxidase,ABCtransporter families,cytochrome P450 and FAD-containing monooxygenase were related to plant pathogen infection.In addition,we demonstrated that autophagy in S.turcica is up-regulated by ATR as a defense response to stress.We identified StATG3,StATG4,StATG5,StATG7 and StATG16 genes for autophagy were induced by ATR-mediated S-phase checkpoint.We therefore propose that in response to genotoxic stress,S.turcica utilizes ATR-dependent pathway to turn off transcription of genes governing appressorium-mediated infection,and meanwhile inducing transcription of autophagy genes likely as a mechanism of self-protection,aside from the more conservative responses in eukaryotes.
基金supported by the Deanship of Scientific Research at Prince Sattam Bin Abdulaziz University under research Project No.2018/01/9371.
文摘The reliability and availability of cloud systems have become major concerns of service providers,brokers,and end-users.Therefore,studying fault-tolerance mechanisms in cloud computing attracts intense attention in industry and academia.The task-scheduling mechanisms can improve the fault-tolerance level of cloud systems.A task-scheduling mechanism distributes tasks to a group of instances to be executed.Much work has been undertaken in this direction to improve the overall outcome of cloud computing,such as improving service qual-ity and reducing power consumption.However,little work on task scheduling has studied the problem of lost tasks from the broker’s perspective.Task loss can hap-pen due to virtual machine failures,server crashes,connection interruption,etc.The broker-based concept means that the backup task can be allocated by the bro-ker on the same cloud service provider(CSP)or a different CSP to reduce costs,for example.This paper proposes a novel fault-tolerant mechanism that employs the primary backup(PB)model of task scheduling to address this issue.The pro-posed mechanism minimizes the impact of failure events by reducing the number of lost tasks.The mechanism is further improved to shorten the makespan time of submitted tasks in cloud systems.The experiments demonstrated that the pro-posed mechanism decreased the number of lost tasks by about 13%–15%com-pared with other mechanisms in the literature.
文摘Many cutting-edge methods are now possible in real-time commercial settings and are growing in popularity on cloud platforms.By incorporating new,cutting-edge technologies to a larger extent without using more infrastructures,the information technology platform is anticipating a completely new level of devel-opment.The following concepts are proposed in this research paper:1)A reliable authentication method Data replication that is optimised;graph-based data encryp-tion and packing colouring in Redundant Array of Independent Disks(RAID)sto-rage.At the data centre,data is encrypted using crypto keys called Key Streams.These keys are produced using the packing colouring method in the web graph’s jump graph.In order to achieve space efficiency,the replication is carried out on optimised many servers employing packing colours.It would be thought that more connections would provide better authentication.This study provides an innovative architecture with robust security,enhanced authentication,and low cost.
文摘Most social networks allow connections amongst many people based on shared interests.Social networks have to offer shared data like videos,photos with minimum latency to the group,which could be challenging as the storage cost has to be minimized and hence entire data replication is not a solution.The replication of data across a network of read-intensive can potentially lead to increased savings in cost and energy and reduce the end-user’s response time.Though simple and adaptive replication strategies exist,the solution is non-deter-ministic;the replicas of the data need to be optimized to the data usability,perfor-mance,and stability of the application systems.To resolve the non-deterministic issue of replication,metaheuristics are applied.In this work,Harmony Search and Tabu Search algorithms are used optimizing the replication process.A novel Har-mony-Tabu search is proposed for effective placement and replication of data.Experiments on large datasets show the effectiveness of the proposed technique.It is seen that the bandwidth saving for proposed harmony-Tabu replication per-forms better in the range of 3.57%to 18.18%for varying number of cloud data-centers when compared to simple replication,Tabu replication and Harmony replication algorithm.
基金supported by grants from the National Natural Science Foundation of China(No.81830024,No.82270844 and No.82070843).
文摘Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains unclear.This study aims to study its role.Methods:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence staining.Glucose-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western blotting.Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown.The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets.Palm reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 cells.Palm also inhibited TRPM5 expression in primary mouse islets.Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis.Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβcells.Conclusion:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.
基金supported by the National Natural Science Foundation of China(Grant Nos.81870467 and 82270717 to XL,and 81970673 to FC)China Postdoctoral Science Foundation(Grant No.2023M731630 to XZhang)Postgraduate Research and Practice Innovation Program of Jiangsu Province(Grant No.KYCX21_1588 to XZhou).
文摘Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels inβ-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in theβ-cells.In the current study,we found thatα-ENaC was expressed in human pancreatic glandule and pancreatic isletβ-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse isletβ-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.Whenα-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured isletβ-cells and suppressed insulin synthesis and secretion,but increasedα-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a−/−)in MIN6 cells attenuatedβ-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 inβ-cells.α-ENaC also modulatedβ-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest thatα-ENaC may play a novel role in insulin synthesis and secretion in theβ-cells,and the upregulation ofα-ENaC promotes isletβ-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in isletβ-cell damage and a potential therapeutic target for type 2 diabetes mellitus.
文摘Objective: The aim of this study is to investigate how individuals with type 2 diabetes mellitus’ pancreatic β-cell function index and insulin resistance index are affected by tuberculosis infection. Methods: The study group consisted of 89 patients with type 2 diabetes mellitus and tuberculosis infection who were admitted to Jingzhou Chest Hospital between March 2019 and March 2021. Gender and duration of diabetes were matching conditions. The control group was made up of 89 patients with type 2 diabetes who were admitted to Jingzhou Central Hospital’s endocrinology department during the same period. The two patient groups provided general information such as gender, age, length of diabetes, and blood biochemical indexes such as glycosylated hemoglobin (HbA1c), fasting glucose (FPG), and fasting C-peptide (FC-P). The HOMA calculator was used to calculate the HOMA-β and the HOMA-IR, and intergroup comparisons and correlation analyses were carried out. Results: Regarding gender, age, disease duration, FC-P, and HbA1c, the differences between the two groups were not statistically significant (P > 0.05). However, BMI, FPG, HOMA-β, and HOMA-IR showed statistically significant differences (P < 0.05). In comparison to the control group, the study group’s HOMA-β was lower and its HOMA-IR was greater. According to Spearman’s correlation analysis, HOMA-β had a negative association (P th FPG, HbA1c, and the length of the disease, and a positive correlation with BMI and FC-P. A positive correlation was found between HOMA-IR and BMI, FPG, and FC-P (P < 0.01), as well as a correlation with the length of the disease (P > 0.05) and HbA1c. Conclusions: In type 2 diabetes mellitus combined with tuberculosis infection, the patients had higher FPG levels and lower FC-P levels, the secretory function of pancreatic β-cells was more severely impaired, and insulin resistance was more obvious.
基金This work is supported by International Cooperation Important Project of National Natural Science Foundation of China(No.30120160824)the State 863 High Technology R&D Project of China(No.2001AA217031).
文摘Objective: To evaluate the therapeutic efficacy of replicative adenovirus CNHK500 in the treatment of hepatocellular carcinoma. Methods: Virus proliferation assay, cell viability assay and Western blot were performed to assess the selective replication and cytolysis of CNHK500 in telomerase positive liver cancer cells Hep3B, HepGII, SMMC7721 and in normal cells. Results: The replicative multiples of CNHK500 in HepGII, Hep3B and SMMC7221 after 96 h of virus proliferation were 52 000, 396 984.9 and 632 911.3 fold respectively, similar to those of wtAd5. However, CNHK500 demonstrated more significant attenuated replicative ability in normal cell lines than wtAd5. CNHK500 replicated only 3.1-100 fold at 96 h, while the wtAd5 still reached 3160-17 357 fold. CNHK500 could cause half of HepGII cells death within 7 days at MOI 2, in Hep3B cell lines the IC50 was as low as MOI 0.01, whereas the IC50 in BJ cell was as high as MOI 1000. CNHK500 E1A protein could only be detected in hepatocellular cancer cells but not in normal cells under normoxia. E1B protein could only be detected under hypoxia condition at a MOI of 1. Conclusion: CNHK500 can efficiently replicate in and kill liver cancer cells as well as wtAd5 do while it is severely attenuated in proliferation and cytolysis among normal cells. It would be a prominsing strategy for liver cancer tratment.
基金This work was supported by International Cooperation Important Project of National Natural Sciences Foundation of China(No. 30120160824) and the State 863 High Technology R&D Project of China (No. 2001AA217031)
文摘Objective： To evaluate the tumor selectivity and therapeutic efficiency of replication-competent adenovirus CNHK300 on human breast cancer cells. Methods： RT-PCR was used to detect the hTERT mRNA activity in various breast cancer and normal fibroblast cell lines. Virus proliferation assay, cell viability assay and Western blot were applied to evaluate the proliferation and cytolysis selectivity of CNHK300. Results： The telomerase activity of MCF-7, BT-549 and SK-BR-3 was positive, while telomerase in MRC-5 and BJ was negative. The progeny virus titers in MCF-7, BT-549 and SK-BR-3 after 48 h of CNHK300 exposure was 40 625, 1 265 and 20 000 fold higher than those of 0 h, even slightly higher than those of wtAd5 （except in SK-BR-3）. ONYX-015 virus proliferation ability was weaker than that of CNHK300 in cancer cells. However, CNHK300 exhibited attenuated replicative ability as compared with wtAd5 in MRC-5 and BJ. The CNHK300 replicatative multiple was 63 and 192 fold at 48 h respectively, while the wtAd5 still multiplied 3 160-4 846 fold. CNHK300 could cause about half of breast cancer cells to die within 7 days at MOI 10 pfu/cell and below, whereas the IC50 in BJ and MRC-5 was as high as MOI 100 pfu/cell. CNHK300 E1A protein could be detected in breast cancer cells and 293 cells but not in normal fibroblast cells. Conclusion： hTERT promoter can successfully modulate the CNHK300 to be selectively replicated in breast cancer cells positive for telomerase, which may be a potential treatment strategy in breast cancer.
