Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

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.

Statistical Method for Block in Replication Design and Its SAS Program

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.

Replication Strategy with Comprehensive Data Center Selection Method in Cloud Environments

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.

Comparison of the replication and neutralization of different SARS-CoV-2 Omicron subvariants in vitro

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.

Transcriptional regulation of secondary metabolism and autophagy genes in response to DNA replication stress in Setosphaeria turcica

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.

A Broker-Based Task-Scheduling Mechanism Using Replication Approach for Cloud Systems

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.

Graph-Based Replication and Two Factor Authentication in Cloud Computing

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.

Efficient Heuristic Replication Techniques for High Data Availability in Cloud

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.

A Novel Replication-competent Adenovirus CNHK500 in the Treatment of Heptocellular Carcinoma In Vitro

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.

SQL Server CE中RDA与Replication的研究

介绍移动数据库SQL Server CE及其特点,详细分析RDA(远程数据访问)和Replica-tion(合并复制)数据同步技术,探讨两种技术的各自特点和应用环境,描述两种数据同步技术的实现过程,比较这两种技术适合的环境。

一种基于Active Replication的TCP连接容错技术

本文提出一种基于ActiveReplication的TCP连接容错技术(ARTCP),采用两层的Cluster结构,并通过前端的分发器和聚合网关机维持多个同步的TCP连接副本,达到了相互容错的效果。测试结果表明,该技术不仅保证网络服务连接级的高可用性,而且具有恢复时间短、开销小的优势。

Sybase Replication Server12.0的复制服务器技术研究及应用

介绍了分布式数据库数据复制的概念和方法 ,着重探讨了SybaseReplicationServer 12 .0复制服务器机制的基本原理和主要功能 ,给出了一个基于异构数据类型支持 (HDS)的应用实例。

Replication-selective Oncolytic Adenovirus CNHK300 in the Treatment of Breast Cancer Cell Lines in vitro

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.

利用JDBC和MySQL Replication实现数据库集群

数据急剧增长会导致数据库性能下降,当数据库层出现瓶颈时,就得在硬件上花费高额的费用。针对这一情况,提出在现有硬件的基础上利用JDBC规范与MySQL Replication实现数据库集群从而解决数据访问瓶颈。其主要方法是在进行JDBC连接之前实现负载均衡,所有SQL请求由负载均衡器进行统一调度。在数据库端利用MySQL Replication实现数据高并发读写。

Replication Server数据复制技术及实例

介绍Replication Server的复制模型和应用程序体系结构,并举例如何利用Sybase Workspace构建一个完整的Replication Server系统应用,希望能给开发和管理Replication Server系统的管理员一些借鉴。

Replication Server数据复制技术及实例

3实例下面介绍在Sybase Workspace 1.5开发平台上,如何开发一个完整的Replication Server系统应用。实例是大型超市的POS系统数据库到经理办公室的销售数据分析数据库的复制。超市的销售数据在数据库（server_1.source）中,进行数据分析的是数据仓库（server_2.IQ）。各个超市的销售数据在数据库中是相当繁多的,但对于提供决策支持来说,只需要分析部分数据就够了。

基于MySQL Replication的数据库集群解决方案

随着电子商务的快速发展,人们对商务系统数据库的稳定性、可用性、可拓展性等提出了更高的要求,而单一的数据库服务器往往达不到这些要求。数据库集群技术的出现,为我们解决这个问题提供了很好的方法。比较了MySQL簇和MySQL Replication两种MySQL的数据库集群技术,并设计了一种基于MySQL Replication的商务系统数据库集群的解决方案。

Hepatitis B virus and micro RNAs:Complex interactions affecting hepatitis B virus replication and hepatitis B virusassociated diseases

Chronic infection with the hepatitis B virus(HBV) is the leading risk factor for the development of hepatocellular carcinoma(HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause of cancer-related death in the world. Unfortunately, the molecular mechanisms that contribute to the development of HBV-associated HCC remain incompletely understood. Recently, micro RNAs(mi RNAs), a family of small non-coding RNAs that play a role primarily in post-transcriptional gene regulation, have been recognized as important regulators of cellular homeostasis, and altered regulation of mi RNA expression has been suggested to play a significant role in virus-associated diseases and the development of many cancers. With this in mind, many groups have begun to investigate the relationship between mi RNAs and HBV replication and HBV-associated disease. Multiple findings suggest that some mi RNAs, such as mi R-122, and mi R-125 and mi R-199 family members, are playing a role in HBV replication and HBV-associated disease, including the development of HBV-associated HCC. In this review, we discuss the current state of our understanding of the relationship between HBV and mi RNAs, including how HBV affects cellular mi RNAs, how these mi RNAs impact HBV replication, and the relationship between HBV-mediated mi RNA regulation and HCC development. We also address the impact of challenges in studying HBV, such as the lack of an effective model system for infectivity and a reliance on transformed cell lines, on our understanding of the relationship between HBV and mi RNAs, and proposepotential applications of mi RNA-related techniques that could enhance our understanding of the role mi RNAs play in HBV replication and HBV-associated disease, ultimately leading to new therapeutic options and improved patient outcomes.

Effect of oxymatrine on the replication cycle of hepatitis B virus in vitro

AIM:To determine the antiviral mechanism or target of oxymatrine against hepatitis B virus(HBV).METHODS:HepG2.2.15 cells were incubated with culture medium containing 500 μg/mL of oxymatrine for 2 and 5 d.The surface antigen of HBV(HBsAg) and e antigen of HBV(HBeAg) in supernatant were determined by ELISA.HBV DNA in supernatant,and intracellular covalently closed circular DNA(cccDNA),relaxed circular DNA(rcDNA) and pregenomic RNA(pgRNA) were quantif ied by specif ic real-time polymerase chain reaction(PCR) or reverse transcription(RT)-PCR.RESULTS:Treatment with oxymatrine for 2 d and 5 d reduced the production of HBV by the cell line,as indicated by the decline of HBsAg(22.67%,t = 5.439,P = 0.0322 and 22.39%,t = 5.376,P = 0.0329,respectively),HBeAg(55.34%,t = 9.859,P = 0.0101 and 43.97%,t = 14.080,P = 0.0050) and HBV DNA(40.75%,t = 4.570,P = 0.0447 and 75.32%,t = 14.460,P = 0.0047) in the supernatant.Intracellular cccDNA was also markedly reduced by 63.98%(t = 6.152,P = 0.0254) and 80.83%(t = 10.270,P = 0.0093),and intracellular rcDNA by 34.35%(t = 4.776,P = 0.0413) and 39.24%(t = 10.050,P = 0.0097).In contrast,intracellular pgRNA increased by 6.90-fold(t = 8.941,P = 0.0123) and 3.18-fold(t = 7.432,P = 0.0176) after 500 μg/mL of oxymatrine treatment for 2 d and 5 d,respectively.CONCLUSION:Oxymatrine may inhibit the replication of HBV by interfering with the process of packaging pgRNA into the nucleocapsid,or inhibiting the activity of the viral DNA polymerase.

Replication potentials of HIV-1/HSIV in PBMCs from northern pigtailed macaque （Macaca leonina）

The northern pig-tailed macaque （Macaca leonina） has been identified as an independent species of Old World monkey, and we previously found that PBMCs from M. leonina were susceptible to human immunodeficiency virus type 1 （HIV-1）, which may be due to the absence of a TRIM5 protein restricting HIV-1 replication. Here we investigated the infection potentials of six laboratory adapted HIV-1 strains and three primary HIV-1 isolates in PBMCs from M. leonina. The results indicate that these strains are characterized by various but low replication levels, and among which, HIV-INL4-3 shows the highest replication ability. Based on the abundant evidence of species-specific interactions between restriction factors APOBEC3 and HIV/SIV-derived Vif protein, we subsequently examined the replication potentials of v/f-substituted HIV-1 （HSIV） in M. leonina PBMCs. Notably, HSIV-vifmac and stHIV-lsv chimeras, two HIV-1Ni.4-3-derived viruses encoding the viral infectivity factor （Vif） protein from SIVmac239, replicated robustly in cells from M. leonina, which suggests that HSIV could effectively antagonize the antiviral activity of APOBEC3 proteins expressed in cells of M. leonina. Therefore, our data demonstrate that M. leonina has the potential to be developed into a promising animal model for human AIDS.