Bioinformatics analysis of two-component regulatory systems in Staphylococcus epidermidis

Sixteen pairs of two-component regulatory systems are identified in the genome of Staphylococcus epidermidis ATCC12228 strain, which is newly sequenced by our laboratory for Medical Molecular Virology and Chinese National Human Genome Center at Shanghai, by using bio- informatics analysis. Comparative analysis of the two- component regulatory systems in S. epidermidis and that of S. aureus and Bacillus subtilis shows that these systems may regulate some important biological functions, e.g. growth, biofilm formation, and expression of virulence factors in S. epidermidis. Two conserved domains, i.e. HATPase_c and REC domains, are found in all 16 pairs of two-component proteins. Homologous modelling analysis indicates that there are 4 similar HATPase_c domain structures of histidine kinases and 13 similar REC domain structures of response regulators, and there is one AMP-PNP binding pocket in the HATPase_c domain and three active aspartate residues in the REC domain. Preliminary experiment reveals that the bioinfor- matics analysis of the conserved domain structures in the two-component regulatory systems in S. epidermidis may provide useful information for discovery of potential drug target.

Review of the Regulatory Requirements for the Maintenance of Aerobic Treatment Units and Greywater Treatment Systems in Western Australia

Aerobic Treatment Units (ATU) and Greywater Treatment Systems (GTS) are onsite wastewater treatment systems (OWTS) designed to treat wastewater to secondary effluent quality standards. Consequently, the electrical, mechanical and chemical components of these OWTS need to be regularly maintained to ensure their consistent and reliable operation to the required standards. In Western Australia (WA), the Department of Health set out the regulatory requirements for the maintenance of OWTS as well as when and how it is to occur. This paper reviews the maintenance requirements for ATU and GTS in WA and provides recommendations for the proposed changes in guidelines and regulations. State and national guidelines were reviewed and information from industry and regulators was obtained through surveys. The review found that although the guidelines are generally satisfactory there are a number of areas which could be improved and specific recommendations are discussed.

Regulatory T Cells and Their Molecular Markers in Peripheral Blood of the Patients with Systemic Lupus Erythematosus

CD4＋CD25＋ regulatory T cells （Tregs） and the expression of their molecular markers （GITR, Foxp3） in peripheral blood of the patients with systemic lupus erythematosus （SLE） were investigated in order to reveal the pathogenesis of SLE on the cellular and molecular levels. The level of Tregs in peripheral blood was detected by flow cytometry. The expression levels of GITR and Foxp3 mRNA in peripheral blood mononuclear cells （PBMCs） were assayed by reverse transcriptase-polymerase chain reaction （RT-PCR）. The level of IL-6 in the plasma was measured by ELISA. Comparisons were made among 3 groups： the active SLE group, the inactive SLE group, and normal control group. The level of Tregs in the active SLE group and the inactive SLE group was significantly lower than in the normal control group （P〈0.01）. The level of Tregs in the active group was lower than in the inactive group with the difference being not significant （P〉0.05）. The level of Tregs in SLE patients was significantly negatively correlated with the disease active index in SLE （SLEDAI） （r=-0.81, P〈0.01）. The expression levels of GITR mRNA in PBMCs of the active SLE group and the inactive SLE group were significantly higher than in the normal control group （P〈0.05）, and those of Foxp3 mRNA in SLE patients of both active and inactive SLE groups were significantly lower than in the normal control group （P〈0.05）. There was no significant difference in the expression of GITR and Foxp3 mRNA between the active SLE group and inactive SLE group （P〉0.05）. The plasma levels of IL-6 in both the inactive SLE group and active SLE group were significantly higher than in the normal control group （P〈0.01）. The plasma level of IL-6 in the active SLE group was sig- nificantly increased as compared with that in the inactive SLE group （P〈0.05）, and the plasma level of IL-6 in SLE was significantly positively correlated with SLEDAI scores （r=0.58, P〈0.01） and significantly negatively correlated with the ratio of CD4＋CD25＋ cells/CD4＋ cells （r=-0.389, P〈0.05）. It was concluded that the levels of Tregs and Foxp3 mRNA in peripheral blood of SLE patients were decreased and the levels of GITR mRNA and plasma IL-6 were increased. The Tregs and their molecular markers GITR, Foxp3 as well as the plasma IL-6 might play an important role in the pathogenesis of SLE.

Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism

Irisin is a polypeptide hormone derived from the proteolytic cleavage of fibronectin-type III domain- containing 5 （FNDC5） protein. Once released to circulation upon exercise or cold exposure, irisin stimulates browning of white adipose tissue （WAT） and uncoupling protein I （UCP1） expression, leading to an increase in total body energy expenditure by augmented UCPl-mediated thermogenesis. It is currently unknown whether irisin is secreted by bone upon exercise or whether it regulates bone metabolism in vivo. In this study, we found that 2 weeks of voluntary wheel-running exercise induced high levels of FNDC5 messenger RNA as well as FNDC5/irisin protein expression in murine bone tissues. Increased immunoreactivity due to exercise-induced FNDC5/irisin expression was detected in different regions of exercised femoral bones, including growth plate, trabecular bone, cortical bone, articular cartilage, and bone-tendon interface. Exercise also increased expression of osteogenic markers in bone and that of UCP1 in WAT, and led to bodyweight loss. Irisin intraperitoneal （IP） administration resulted in increased trabecular and cortical bone thickness and osteoblasts numbers, and concurrently induced UCP1 expression in subcutaneous WAT. Lentiviral FNDC5 IP administration increased cortical bone thickness. In vitro studies in bone cells revealed irisin increases osteoblastogenesis and mineralization, and inhibits receptor activator of nuclear factor-kB ligand （RANKL）- induced osteoclastogenesis. Taken together, our findings show that voluntary exercise increases irisin production in bone, and that an increase in circulating irisin levels enhances osteogenesis in mice.

Association of rs10954213 Polymorphisms and Haplotype Diversity in Interferon Regulatory Factor 5 with Systemic Lupus Erythematosus: A Meta-analysis

The rs10954213 polymorphism and the haplotype diversity in interferon regulatory factor 5 （1RF5） play a special role in systemic lupus erythematosus （SLE） but with inconclusive results. We conducted a meta-analysis integrating case-control and haplotype variant studies in multiple ethnic populations to clearly discern the effect of these two variants on SLE. Eleven studies on the relation between rs10954213 polymorpisms in IRF5 and SLE were included and we selected a random effect model to calculate the pooled odds ratios （ORs） and the corresponding 95% confidence interval （95% CI）. A total of 6982 cases and 8077 controls were involved in the meta-analysis. The pooled results in- dicated that A allele was significantly associated with increased risk of SLE as compared with the IRF5 rS10954213 G allele （A vs. G, P〈0.00001） in all subjects. The same pattern of the results was also ob- tained in the European, African American, and Latin American. Asian population had a much lower prevalence of the A allele （49.1%） than any other population studied, and Europeans had the highest frequency of the IRF5 rs10954213 A allele （62.1%）. The significant association of increased SLE risk and TCA haplotype was indicated in the contrast of TCA vs. TTA as the pooled OR was 2.14 （P=0.002）. The same result was also found in the contrast of TCA vs. TTG as the pooled OR was 1.45 （P=-0.004）. This meta-analysis suggests that the A allele of rs10954213 and TCA haplotype （rs2004640-rs2070197-rs10954213） in IRF5 is associated with the increased risk of SLE in different ethnic groups, and its prevalence is ethnicity dependent.

Risk identification and regulatory system design for the carbon market

Currently,the global carbon trading systems are fragmented and belong to different governments or are under the jurisdiction of different regions,resulting in a series of new problems,such as how to link dispersed trading systems,how to compare the emission reduction of various markets and other issues.Since the development of the international carbon market is relatively immature with uncertain life expectancy and volatility during its short history,and there is a lack of quantitative data on the long-term record,the market could provide few risk management tools.Meanwhile,with the launches of China's regional carbon trading pilots in seven provinces since 2013 and combined with the national voluntary emission trading system,carbon trading will become an important mechanism for China in achieving its emission reduction target.In the first stage,the carbon finance market is at least faced with mechanism design risks,market supply risks and compliance risks.Therefore,to secure the development of the carbon market and for public interest,relevant government departments of China should identify the risks facing the market and should make the basic principles and goals,such as ensuring effective trading and pricing mechanisms to avoid fraud and price manipulation,and balancing transparency and confidentiality of information.Consequently,the governments should develop a comprehensive carbon finance regulatory system covering regulatory legislation,regulatory institutions and their authorities,regulatory scope as well as regulatory objects.

The Regulatory B Cell in Active Systemic Lupus Erythematosus Patients:A Systemic Review and Meta-analysis

Background:The study of regulatory B cells(Bregs)in systemic lupus erythematosus(SLE)has been in full swing in recent years,but the number and function of Bregs in SLE patients have also present quite contradictory results.Therefore,we conducted a meta-analysis to verify the changes in Bregs in active SLE.Methods:We identified studies reporting the proportions of Bregs in SLE patients by searching Pubmed,Embase,Web of Science,Cochrane and CNKI.Due to the degree of heterogeneity is very high,we used a random effects model to assess the mean differences in percentages of Bregs between active SLE and controls.Then,sensitivity analysis and subgroup analysis were performed to verify potential sources of heterogeneity.Results:Seven eligible articles involving 301 active SLE patients and 218 controls were included in the meta-analysis.The pooled percentages of Bregs were found no significant difference between active SLE patients and healthy controls[0.259,(−1.150,1.668),p=0.719],with great heterogeneity(I2=97.5%).The result of sensitivity analysis showed that exclusion of any single study or single article did not materially resolve the heterogeneity,but after excluding the article conducted by Cai X and his colleagues,the percentages of Bregs were significantly higher in active SLE than those in controls[1.394,(0.114,2.675),p=0.033].The results of subgroup analysis revealed that when the disease activity was judged by SLEDAI score≥5,the percentages of Bregs were significantly lower in the SLE groups than in the control groups[-1.99,(-3.241,-0.739),p=0.002],but when the threshold of SLEDAI score≥6 chosen for active SLE,the percentages of Bregs were significantly increased in the SLE groups[2.546,(1.333,3.759),p<0.001].Meanwhile,other subgroup analysis based on the different phenotypes of Bregs,diagnostic criteria,enrolled research countries,treatment status,and organ involvement did not differ in proportion of Bregs between SLE patients and controls.Conclusions:The study implies that Bregs may play a role in the pathogenesis of active SLE,and the thresholds of SLEDAI score to distinguish between active and inactive SLE patients are important factors affecting the percentages of Bregs.

Stochastic resonance induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises

This paper investigates the stochastic resonance （SR） induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises. The expression of the signal-to-noise ratio （SNR） is derived. The results indicate that the existence of a maximum in SNR vs. the additive noise intensity α the multiplicative noise intensity D and the cross-correlated noise intensity λ is the identifying characteristic of the SR phenomenon and there is a critical phenomenon in the SNR as a function of λ, i.e., for the case of smaller values of noise intensity （α or D）, the SNR decreases as λ increases; however, for the case of larger values of noise intensity （α or D）, the SNR increases as λ increases.

Stochastic resonance in the gene transcriptional regulatory system subjected to noises

We have investigated in the adiabatic limit the phenomenon of stochastic resonance in the gene transcriptional regulatory system subjected to an additive noise, a multiplicative noise, and a weakly periodic signal. Using the general two-state approach for the asymmetry system, the analytic expression of signal-to-noise ratio is obtained. The effects of the additive noise intensity a, the multiplicative noise intensity D and the amplitude of input periodic signal A on the signal-to-noise ratio are analysed by numerical calculation. It is found that the existence of a maximum in the RSNR a and RSNR D plots is the identifying characteristic of the stochastic resonance phenomenon in the weakened noise intensity region. The stochastic resonance phenomena are restrained with increasing a and D, and enhanced with increasing A.

Stability Analysis for the Cellular Signaling Systems Composed of Two Phosphorylation-Dephosphorylation Cyclic Reactions

The regulatory mechanisms in cellular signaling systems have been studied intensively from the viewpoint that the malfunction of the regulation is thought to be one of the substantial causes of cancer formation. On the other hand, it is rather difficult to develop the theoretical framework for investigation of the regulatory mechanisms due to their complexity and nonlinearity. In this study, more general approach is proposed for elucidation of characteristics of the stability in cellular signaling systems by construction of mathematical models for a class of cellular signaling systems and stability analysis of the models over variation of the network architectures and the parameter values. The model system is formulated as regulatory network in which every node represents a phosphorylation-dephosphorylation cyclic reaction for respective constituent enzyme. The analysis is performed for all variations of the regulatory networks comprised of two nodes with multiple feedback regulation loops. It is revealed from the analysis that the regulatory networks become mono-stable, bi-stable, tri-stable, or oscillatory and that the negative mutual feedback or positive mutual feedback is favorable for multi-stability, which is augmented by a negatively regulated node with a positive auto-regulation. Furthermore, the multi-stability or the oscillation is more likely to emerge in the case of low value of the Michaelis constant than in the case of high value, implying that the condition of higher saturation levels induces stronger nonlinearity in the networks. The analysis for the parameter regions yielding the multi-stability and the oscillation clarified that the stronger regulation shifts the systems toward multi-stability.

Efficient Numerical Optimization Algorithm Based on New Real-Coded Genetic Algorithm, AREX + JGG, and Application to the Inverse Problem in Systems Biology

In Systems Biology, system identification, which infers regulatory network in genetic system and metabolic pathways using experimentally observed time-course data, is one of the hottest issues. The efficient numerical optimization algorithm to estimate more than 100 real-coded parameters should be developed for this purpose. New real-coded genetic algorithm (RCGA), the combination of AREX (adaptive real-coded ensemble crossover) with JGG (just generation gap), have applied to the inference of genetic interactions involving more than 100 parameters related to the interactions with using experimentally observed time-course data. Compared with conventional RCGA, the combination of UNDX (unimodal normal distribution crossover) with MGG (minimal generation gap), new algorithm has shown the superiority with improving early convergence in the first stage of search and suppressing evolutionary stagnation in the last stage of search.

国内外婴幼儿食品接触材料法规管理体系研究

以国际社会在婴幼儿食品接触材料监管方面的先进国家和地区为研究对象,该文对其婴幼儿食品接触材料法规体系框架进行梳理,总结其在婴幼儿食品接触材料方面的监管重点和典型做法,并通过开展深入分析与比较研究,对我国婴幼儿食品接触材料的监管提出建议。

用于国家监管体系评估的WHO全球基准工具介绍及其应用进展

目的:对世界卫生组织(World Health Organization,WHO)用于国家监管体系(National Regulatory Authorities,NRA)评估的全球基准工具(Global Benchmarking Tool,GBT)及基准流程进行介绍和深入研究,旨在帮助相关人员进一步了解WHO关于NRA评估的新的具体要求,进一步推动医疗产品检验检测和疫苗批签发管理水平提高。方法:介绍GBT框架,对GBT 9大板块进行分析汇总,研究WHO采用GBT进行NRA评估的流程和应用进展以及对我国的启示。结果与结论:GBT针对国家监管体系9大职能板块分别设置一系列指标和268个亚指标进行评估,并引入4级成熟度级别(Maturity Level,ML)的概念;正式基准过程包括提交意向书、对意向书评估、就评估范围和路线图达成协议、正式评估、宣布决定和列名等5个步骤;截至2022年10月,WHO宣布共有12个国家通过了以GBT为基准的NRA评估。我国疫苗NRA评估已达到ML3水平,但仍需深入改进,向ML4水平继续努力。

建设世界一流企业视角下系统重要性实体企业监管治理与服务研究

关于系统重要性金融机构治理与监管的理论和实践取得了丰富成果,但对系统重要性实体企业的研究还很欠缺。基于反垄断理论、外部性理论和风险传染理论分析了系统重要性实体企业的监管治理与服务的理论逻辑,发现其外部监管存在业务盲目扩张、银行信贷漏洞较大、金融理财产品缺乏监管、资本运营缺乏协同监管的问题,在内部治理上存在资本无序扩张、股权架构与境外上市、过度负债、不当分红、薪酬过高、实际控制人逃避责任和转移资产等问题。基于此,提出了建立评价识别体系、高效监管体系、现代治理体系和优质服务体系的对策建议。

社会主义核心价值观融入行业规章体系的法治路径分析

社会主义核心价值观融入行业规章体系,不仅是党和政府提出的将前者融入社会治理规范的具体落实,也是提升行业规章体系的法治化水平的助益手段。核心价值观融入到行业规章体系的法治路径,就是前者融入后者的制度建设、执行机制与遵守机制并提升优化的进程。从实践来看,当前核心价值观融入行业规章体系的制度建设上存在显现度不足与价值宣示色彩过浓的问题,而在行业规章的执行机制与遵守机制方面融入性较低。对此,在制定环节,要规划好融入进程与融入步骤,选择融入的立法表达技术,发挥核心价值观在目的条款中的引领作用以及在行为规范中的指导功能,并注意制度协调问题。在执行环节,需要从主体道德培育、行业价值共识生成、多元督导机制建构等具体维度入手,由党组织、政府主管部门、行业自律组织以及组织成员、社会大众等多元主体共同推动,通过价值内核与规则执行的深度融合,建构以核心价值观为底色的行业规章执行机制。在遵守环节,核心价值观应通过“直接+间接”方式融入行业规章的遵守模式,选择融入遵守机制的原则性条款,保障核心价值观在行业规章遵守机制中落地生根。

“双支柱”调控框架与影子银行风险溢出:抑制缓释还是累积加剧

如何搭建货币政策和宏观审慎政策“双支柱”调控框架,有效防范化解重大风险,是我国现阶段的重要任务。基于我国上市银行数据,本文采用CoVaR方法衡量影子银行导致的银行系统性风险,系统考察“双支柱”调控框架对影子银行风险溢出的影响。结果显示,针对借款人和银行信贷的宏观审慎政策工具与货币政策配合,对影子银行风险溢出起到显著的“抑制缓释”作用;影子银行规模是“累积加剧”和“抑制缓释”效应的渠道,流动性分层则是“累积加剧”效应的渠道。结合银行性质、房地产周期与经济周期的异质性分析结果显示,在不同情景下,“双支柱”调控框架对影子银行风险溢出的有效性存在较大差异。本文结论对于“防风险”目标下“双支柱”调控框架的完善具有一定的指导意义。

我国金融科技“监管沙盒”测试企业退出预备制度研究

测试企业进入金融科技“监管沙盒”正式参与测试后,基于其主观或客观原因而存在主动或被动退出沙盒测试的可能。从沙盒测试退出的实践需求来看,测试企业退出沙盒测试的预备行为亟需统一的制度规范。在充分借鉴澳大利亚相关制度设计经验的基础上,我国应从不同等级风险预防与预警规则设置、解除合作与交易协议及终止线上线下服务规则设计、建立测试企业相关技术与数据的有效处理制度以及制定测试企业退出前的牌照申请计划和准备规则等方面,为我国测试企业退出沙盒测试的预备行为提供合理有效的制度供给。

生成式人工智能教育应用政策比较:共识、差异与实施进路

生成式人工智能教育应用近年来备受瞩目,其强大的生成能力为教育领域注入新的活力。然而,我国关于生成式人工智能教育应用方面的法律法规仍处于空白状态,这无疑对生成式人工智能广泛应用带来了不小挑战。为弥补这一政策空白,运用内容分析法,对国际上已发布的具有代表性的三项政策,从教师教学、学生学习、教学评价、教学研究、学习辅导和教育管理六个核心维度进行分析。在此基础上,挖掘三项政策的共识、差异,以期为我国生成式人工智能教育应用的政策制定提供借鉴,推动其在教育领域的纵深发展和广度辐射,并提出五条实施进路:一是重塑教育蓝图,法规保障消除潜在隐患;二是强化监管体系,法律监管防范潜在风险;三是聚焦育人目标,不断提高教师数字胜任力;四是提升学生数字素养,落实人本主义理念;五是适配场景与对象,创新应用模式和方法。