Signaling oscillations: Molecular mechanisms and functional roles

Mounting evidence shows that oscillatory activity is widespread in cell signaling. Here, we review some of this recent evidence, focusing on both the molecular mechanisms that potentially underlie such dynamical behavior, and the potential advantages that signaling oscillations might have in cell function. The biological processes considered include cellular differentiation and tissue maintenance, intermittent responses in pluripotent stem cells, and collective cell migration during wound healing. With the aid of mathematical modeling, we review recent examples in which delayed negative feedback has been seen to act as a unifying principle that underpins this wide variety of phenomena.     

雌、孕激素在癫痫发病中的作用及其机制研究

临床资料显示 ,某些女性癫痫患者体内雌、孕激素的周期性变化可能影响癫痫发作的易感性。为了探索雌、孕激素在癫痫发病中的作用 ,阐明其作用机制 ,本工作分别以马桑内酯(CL)侧脑室注射致痫、贝美格 (Be)腹腔注射致痫大鼠为实验对象 ,采用神经电生理、流式细胞免疫荧光、高效液相色谱、免疫细胞化学、原位杂交技术 ,从整体、行为、细胞、分子以及基因水平研究了雌、孕激素对大鼠中枢神经系统 (CNS)功能的影响。研究结果表明 ,卵巢甾体激素属于神经甾体激素 ,其作为新的神经调质对CNS具有广泛的影响 ,它们分别通过调节即刻早期基因、氨基酸类神经递质及神经递质受体而多环节影响CNS的兴奋性。     

Microbial quorum sensing signaling molecules and their roles in the biosynthesis of natural products

<正>Microorganisms act as a double-edged sword that can bring benefits and diseases to humans. Their physiological and metabolic processes are under precise control of intricate regulatory networks, in which signaling systems are critical for cells coordinating or competing with each other to overcome unfavorable environmental conditions, including the prompt and acute responses to endogenous or exogenous stimuli. In Streptomyces,     

tRNA-targeting ribonucleases: molecular mechanisms and insights into their physiological roles

Most bacteria produce antibacterial proteins known as bacteriocins, which aid bacterial defence systems to provide a physiological advantage. To date, many kinds of bacteriocins have been characterized. Colicin has long been known as a plasmidborne bacteriocin that kills other Escherichia coli cells lacking the same plasmid. To defeat other cells, colicins exert specific activities such as ion-channel, DNase, and RNase activity. Colicin E5 and colicin D impair protein synthesis in sensitive E. coli cells; however, their physiological targets have not long been identified. This review describes our finding that colicins E5 and D are novel RNases targeting specific E. coli tRNAs and elucidates their enzymatic properties based on biochemical analyses and X-ray crystal structures. Moreover, tRNA cleavage mediates bacteriostasis, which depends on trans-translation. Based on these results and others, cell growth regulation depending on tRNA cleavage is also discussed.     

Molecular mechanisms of bacterial quorum sensing as a new drug target

Bacterial quorum sensing evolved as a means for bacterial communities to rapidly and coordinately change genome expression patterns in response to environmental cues. Each cell in a community produces and responds to a signaling molecule called an autoinducer that serves as an indicator of the population density. A high concentration of autoinducer is associated with a large, often confined population, which requires altered gene expression for survival. Quorum sensing is one mechanism through which a bacterial population receives input from the environment and elicits an appropriate response. Because many pathogens require quorum sensing to produce virulence factors in response to association with a human host, the signaling pathway is a target for design of small-molecule inhibitors.     

Steroid hormone-induced effects on membrane fluidity and their potential roles in non-genomic mechanisms

Steroid hormones are lipophilic suggesting they intercalate into the bilayer of target cell plasma membranes, potentially altering the fluidity and function of the membrane. The present study measured the effects of steroidal exposure on both phospholipid fluidity and integral protein mobility. Studies were performed on the effects of a variety of steroids on phosphatidylcholine liposomes, synaptosomal plasma membranes and sarcoplasmic reticulum membranes. Progesterone decreased the lipid fluidity, whereas testosterone had no effect on lipid movement. The estrogen, 17 beta-estradiol, an aromatised metabolite of testosterone, increased lipid mobility. In each case, the steroid action was concentration-dependent. The steroids all increased the activity of the Ca2+ ATPase of SR membrane, in keeping with their effects on this enzyme's aggregation state. The results suggest that, although lipid fluidity is a factor influencing protein activity, their mobility within the bilayer is the primary determinant of enzyme activity in the membrane for most proteins.     

微生物耐砷机理及其在砷地球化学循环中的作用北大核心CSCD

砷是一种无处不在的有毒类金属,其强致癌性引起了人类的广泛关注。在自然环境中,砷的转化存在物理化学过程和生物过程,其中微生物介导的砷转化是环境砷行为的主要影响因素。微生物的耐砷特性与砷吸收、氧化还原、甲基化、区隔化和外排等过程密切相关。砷在微生物体内的转运转化主要与砷解毒有关,但某些微生物可利用氧化还原过程产生的能量以维持其生长需求。本文综述了微生物介导的砷吸收、转化、区隔化和外排机制,这对阐明砷的地球化学循环过程及指导砷污染土壤和水体修复、阻控农作物砷吸收等方面具有重要意义。     

Metabolic regulatory mechanisms and physiological roles of functional amino acids and their applications in yeast

ABSTRACT

In yeast, amino acid metabolism and its regulatory mechanisms vary under different growth environments by regulating anabolic and catabolic processes, including uptake and export, and the metabolic styles form a complicated but robust network. There is also crosstalk with various metabolic pathways, products and signal molecules. The elucidation of metabolic regulatory mechanisms and physiological roles is important fundamental research for understanding life phenomenon. In terms of industrial application, the control of amino acid composition and content is expected to contribute to an improvement in productivity, and to add to the value of fermented foods, alcoholic beverages, bioethanol, and other valuable compounds (proteins and amino acids, etc.). This review article mainly describes our research in constructing yeast strains with high functionality, focused on the metabolic regulatory mechanisms and physiological roles of “functional amino acids”, such as l-proline, l-arginine, l-leucine, l-valine, l-cysteine, and l-methionine, found in yeast.     

Molecular mechanisms of sleep-wake regulation: roles of prostaglandins D2 and E2

Although sleep-wake cycles are repeated every day and night and almost one-third of our lifetime is spent sleeping, the molecular mechanisms of sleep-wake regulation have remained little understood. Recent experimental evidence indicates that prostaglandins (PG) D2 and E2 are probably two of the major endogenous sleep-regulating substances, one promoting sleep and the other wakefulness, in rats, dogs, rabbits, monkeys, and probably in humans as well. Preliminary evidence indicates that the sites of action of PGD2 and E2 are located in the sleep and wake centers in or near the preoptic area and posterior hypothalamus, respectively.     

Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration

Mitotic inheritance of the DNA methylome is a challenging task for the maintenance of cell identity. Whether DNA methylation pattern in different genomic contexts can all be faithfully maintained is an open question. A replication-coupled DNA methylation maintenance model was proposed decades ago, but some observations suggest that a replication-uncoupled maintenance mechanism exists. However, the capacity and the underlying molecular events of replication-uncoupled maintenance are unclear. By measuring maintenance kinetics at the single-molecule level and assessing mutant cells with perturbation of various mechanisms, we found that the kinetics of replication-coupled maintenance are governed by the UHRF1–Ligase 1 and PCNA–DNMT1 interactions, whereas nucleosome occupancy and the interaction between UHRF1 and methylated H3K9 specifically regulate replication-uncoupled maintenance. Surprisingly, replication-uncoupled maintenance is sufficiently robust to largely restore the methylome when replication-coupled maintenance is severely impaired. However, solo-WCGW sites and other CpG sites displaying aging- and cancer-associated hypomethylation exhibit low maintenance efficiency, suggesting that although quite robust, mitotic inheritance of methylation is imperfect and that this imperfection may contribute to selective hypomethylation during aging and tumorigenesis.Subject terms: Mechanisms of disease, DNA methylation     

基因组拷贝数变异及其突变机理与人类疾病

拷贝数变异(Copy number variation,CNV)是由基因组发生重排而导致的,一般指长度为1 kb以上的基因组大片段的拷贝数增加或者减少,主要表现为亚显微水平的缺失和重复。CNV是基因组结构变异(Structural variation,SV)的重要组成部分。CNV位点的突变率远高于SNP(Single nucleotide polymorphism),是人类疾病的重要致病因素之一。目前,用来进行全基因组范围的CNV研究的方法有:基于芯片的比较基因组杂交技术(array-based comparative genomic hybridization,aCGH)、SNP分型芯片技术和新一代测序技术。CNV的形成机制有多种,并可分为DNA重组和DNA错误复制两大类。CNV可以导致呈孟德尔遗传的单基因病与罕见疾病,同时与复杂疾病也相关。其致病的可能机制有基因剂量效应、基因断裂、基因融合和位置效应等。对CNV的深入研究,可以使我们对人类基因组的构成、个体间的遗传差异、以及遗传致病因素有新的认识。