Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation

Recent experiments on the kinetics of deposition and fibril elongation of the Alzheimer's beta-amyloid peptide on preexisting fibrils are analyzed. A mechanism is developed based on the dock-and-lock scheme recently proposed by Maggio and coworkers to organize their experimental observations of the kinetics of deposition of beta-peptide on preexisting amyloid fibrils and deposits. Our mechanism includes channels for (1) a one-step prion-like direct deposition on fibrils of activated monomeric peptide in solution, and (2) a two-step deposition of unactivated peptide on fibrils and subsequent reorganization of the peptide-fibril complex. In this way, the mechanism and implied "energy landscape" unify a number of schemes proposed to describe the process of fibril elongation. This beta-amyloid landscape mechanism (beta ALM) is found to be in good agreement with existing experimental data. A number of experimental tests of the mechanism are proposed. The mechanism leads to a clear definition of overall equilibrium or rate constants in terms of the energetics of the elementary underlying processes. Analysis of existing experimental data suggests that fibril elongation occurs through a two-step mechanism of nonspecific peptide absorption and reorganization. The mechanism predicts a turnover in the rate of fibril elongation as a function of temperature and denaturant concentration. Proteins 2001;42:217-229.     

克隆植物中国沙棘生长对外源植物激素的响应

关于植物克隆生长调节问题,目前集中于外在机制的研究。为了探讨中国沙棘克隆生长调节的内在机制,采用3×3回归设计进行田间试验,期望了解不同生长性状对IAA和CTK用量及其配比的响应规律。结果表明:(1)生长性状对激素用量的响应规律呈典型的钟形曲面模式,即各生长指标均存在一个产量峰值,峰值以前生长指标随IAA、CTK用量的增大而提高,峰值以后生长指标随IAA、CTK用量的增大而下降。(2)不同生长指标对激素用量及其配比的响应规律具有一定差异,较高的IAA比例有利于促进树高生长,较高的CTK比例有利于促进地径和冠幅生长,而几乎相等的IAA和CTK用量有利于种群生物量积累。(3)在激素用量适宜的情况下,中国沙棘生长潜力得到充分发挥,形成高大的个体,较多的子株,有利于提高种群对生境资源的占据和利用,并提高排斥其他植物种类入侵的能力;当激素用量过高或过低时,中国沙棘以降低生长量为代价,形成矮小的个体,减少子株数量,有利于削弱个体之间的竞争。这一结果为了解中国沙棘克隆生长内在调节机制提供了线索。(4)根据不同生长指标的激素效应方程,求出了相应的IAA和CTK的最佳用量和最佳配比,以及合理施激素区域和最低成本线。(5)克隆子株数量增幅与地径和冠幅生长量增幅呈极显著正相关、与种群生物量增幅呈显著正相关,即适宜的IAA和CTK用量既可加速个体生长、也能促进克隆子株的产生。     

Switching mechanism for branched biochemical fluxes: graph-theoretical analysis

A graph-theoretical method is applied to characterize the structure of a simplest switching mechanism of common biochemical importance. This mechanism is based on competition of two coupled substrate-binding pathways for a single substrate. No other regulatory interactions are shown to be needed for the switching phenomenon to be observed. It is shown that switch in branch effluxes is observed as bistability or reciprocal oscillations, depending on the value of steady influx. Frequency of reciprocal efflux oscillations in branches is regulated by steady influx. Therefore, the switching mechanism can function as the coding mechanism in the manner of "influx steady level-efflux frequency". The calculated kinetic equations for the switching mechanism demonstrate very steep transitions in the branch fluxes without using high non-linearity of these equations.     

Ordered binding model as a general mechanistic mechanism for secondary active transport systems.

The mechanistic mechanism of secondary active transport processes has not been fully elucidated. Based on substrate binding studies dependent on coupling cation concentrations of the glutamate, melibiose, lactose and proline transport carriers in Escherichia coli, the ordered binding mechanism was proposed as the energy coupling mechanism of the transport systems. This ordered binding mechanism satisfactorily explained the properties of the secondary active transport systems. Thus, this mechanism as the general energy coupling mechanism for the transport systems is discussed.     

CPG Control for Biped Hopping Robot in Unpredictable Environment

A CPG control mechanism is proposed for hopping motion control of biped robot in unpredictable environment.Based on analysis of robot motion and biological observation of animal's control mechanism,the motion control task is divided into two simple parts:motion sequence control and output force control.Inspired by a two-level CPG model,a two-level CPG control mechanism is constructed to coordinate the drivers of robot joint,while various feedback information are introduced into the control mechanism.Interneurons within the control mechanism are modeled to generate motion rhythm and pattern promptly for motion sequence control; motoneurons are modeled to control output forces of joint drivers in real time according to feedbacks.The control system can perceive changes caused by unknown perturbations and environment changes according to feedback information,and adapt to unpredictable environment by adjusting outputs of neurons.The control mechanism is applied to a biped hopping robot in unpredictable environment on simulation platform,and stable adaptive motions are obtained.     

SEXUAL SELECTION BY THE HANDICAP MECHANISM

The handicap mechanism of sexual selection by female choice has been strongly criticized because it does not cause sexual selection to reinforce viability selection and it cannot account for the origin of mating preferences. However, several models indicate that the handicap mechanism can have important effects when operating in conjunction with Fisher's mechanism in polygynous populations. These models have been criticized because they require that fitness remains heritable indefinitely. I develop a simple haploid model of the handicap mechanism based on nonheritable variation in paternal investment, thus eliminating the problem of heritable fitness. This model produces the same evolutonary dynamics as both simple and quantitative genetic models of the handicap mechanism based on heritable fitness. If the parameters are such that Fisherian runaway selection does not occur in the null model (i.e., the polymorphic equilibria, which lie along the “Fisher line,” are stable), then the handicap mechanism turns the Fisher line into an evolutionary trajectory upon which all other trajectories converge. This occurs because Fisher's mechanism generates no net selection on female preference when the population is on the Fisher line, so that any additional source of selection (direct or indirect) on female choice causes the population to evolve deterministically along the Fisher line. This change in the evolutionary dynamics has the important consequence of eliminating the potential for rapid population divergence for mating systems via genetic drift along the Fisher line.     

Analysis of ion concentration effects on the kinetics of protein-nucleic acid interactions: Application to lac repressor-operator interactions

The effects of monovalent and divalent cations on the bimolecular rate constant of the reaction of a positively charged ligand with a nucleic acid polyanion are analyzed for two possible reaction mechanisms. One mechanism postulates that the association reaction occurs without intermediates, and that ion effects on the rate constant result entirely from the screening of the charged reactants by ionic atmospheres of low molecular weight ions (a screening-controlled mechanism). This mechanism is analyzed by analogy with the Bronsted-Bjerrum theory for the kinetics of interaction of low molecular weight ions. The second mechanism to be considered here postulates the existence of a ligand-DNA intermediate which is in rapid equilibrium with the reactants (pre-equilibrium mechanism). Ion concentration effects on the association rate constants for the pre-equBibrium mechanism result mainly from the release of counterions from the DNA upon formation of the intermediate. Both of the above mechanisms predict that the logarithm of the association rate constant,_a, will be a linear function of the logarithm of the monovalent cation concentration, [M+] (in the absence of competition by divalent cations or anions). Knowledge of the salt dependences of K_a and of the observed equilibrium constant k_obs of the ligand-nucleic acid interaction should usually be sufficient to determine whether a screening-controlled mechanism or a pre-equilibrium mechanism is suitable to describe the process. If the association reaction can be described by a pre-equilibrium mechanism, the number of ionic interactions involved in the ligand-nucleic acid intermediate can be estimated. This analysis, extended to include the effects of divalent cations on screening or on the pre-equilibrium step, is applied to literature data on the salt dependence of the kinetics of the interaction of lac represser with lac operator DNA. When the operator is present on bacteriophage λ DNA, the observed reaction kinetics are consistent with the formation of an intermediate repressor-DNA complex in a pre-equilibrium step. On the other hand, the kinetics of association of toe represser with synthetic foe operator fragments may be an example of a screening-controlled reaction.     

Integrin-mediated adhesion orients the spindle parallel to the substratum in an EB1- and myosin X-dependent manner

The orientation of mitotic spindles is tightly regulated in polarized cells, but it has been unclear whether there is a mechanism regulating spindle orientation in nonpolarized cells. Here we show that integrin-dependent cell adhesion to the substrate orients the mitotic spindle of nonpolarized cultured cells parallel to the substrate plane. The spindle is properly oriented in cells plated on fibronectin or collagen, but misoriented in cells on poly-L-lysine or treated with the RGD peptide or anti-beta1-integrin antibody, indicating requirement of integrin-mediated cell adhesion for this mechanism. Remarkably, this mechanism is independent of gravitation or cell-cell adhesion, but requires actin cytoskeleton and astral microtubules. Furthermore, myosin X and the microtubule plus-end-tracking protein EB1 are shown to play a role in this mechanism through remodeling of actin cytoskeleton and stabilization of astral microtubules, respectively. Our results thus uncover the existence of a mechanism that orients the spindle parallel to the cell-substrate adhesion plane, and identify crucial factors involved in this novel mechanism.     

昆虫中的核输出现象

核质转运是真核细胞生命活动重要的组成部分,细胞核内蛋白的平衡及转录出的RNA出核成熟过程都依赖于核输出,核输出与真核生物的生命活动密切相关;病原物在侵染昆虫时也会利用宿主的核输出机制干扰宿主的免疫反应或劫持宿主的核输出蛋白以利于病毒的组装及复制.本文主要介绍真核细胞中核输出的基本机制、蚊子和果蝇等模式昆虫中核输出通路;...     

Resistance to Mercuric Chloride in Pseudomonas K-62

Mercuric ion-resistant mechanism in Pseudomonas K-62 was investigated by isolating a mercuric ion-sensitive mutant strain (H-2 strain) from a resistant wild-type strain (P strain) and comparing the physiological properties of these two strains. Growth curves obtained in mercuric ion-containing medium suggested that P strain constitutively has a resistant mechanism. The capacity of P and H-2 strains to decrease the concentration of mercuric ions in the medium was found to be almost equal; thus, the presence of a resistant mechanism was expected other than MMR-enzyme, which is an inducible system. From the characteristic property of the inhibitory effect of mercuric ions on respiration of the two strains, a resistant mechanism, a permeability barrier mechanism, was proposed. The barrier mechanism in P strain traps mercuric ions with high selectivity to prevent the penetration of ions to the intracellular space where the functional units are located. Finally, the resistance mechanism to mercuric ions in the bacterium was discussed including the MMR-enzyme system and the barrier mechanism.     

Pancreatic cytoprotection: a survey

The author gives a brief survey on the concept of cytoprotection, the generation of prostaglandins and the mechanism of their action. The effect of exogenous prostaglandins and the mechanism of their action. The effect of exogenous prostaglandins on pancreatic vasculature, secretion, ductal permeability and their therapeutic effect on experimentally induced acute pancreatitis is discussed. Pancreatic "self-defence" mechanism is also discussed the mechanism of which may be rather different from that of cytoprotection. In such pancreatic "self-defense" mechanism decrease in pancreatic protein synthesis and secretion induced by pancreatic duct ligation or decrease in sensibility of pancreatic acinar cells or their receptors against specific stimulants may participate.     

Contributions to the theory of active transport: III. The effect of drugs on active transport systems

The addition of a drug to a system which contains an active transport mechanism may produce a large number of effects on both the active transport mechanism and the permeability of the system. A general model of such a system is presented, and various possible results of the drug's addition are discussed. Methods of experimentally separating these effects on the active transport mechanism and the permeabilities of the system are then listed and analyzed.     

酵母耐盐机制的研究进展

酵母是一种真核模式生物同时也是一种耐盐微生物,其基因表达和信号传导系统的调节机制及离子运输机制与高等真核生物类似。酵母耐盐机制的研究有助于阐明真核生物的耐盐机制。本文综述了酵母在盐胁迫下的信号传导途径和分子应答机制,以及在酵母耐盐机制研究中主要的研究方法。 Abstract:Yeast is a model eukoryotic organism and salt-tolerant microorganism.The regulative mechanism of gene expression and signal transduction and ion transport of yeast is similar to that of higher eukoryotic organism.The research on salt-tolerant mechanism of yeast will be helpful to the illustrate the salt-tolerant mechanism of higher eukoryotic organism.This review summarized the signal transduction pathway and molercular responses of yeast under salt stress and the major research methods in the research on the salt-tolerant mechenism in yeast.     

The Na(+)-independent Ca2+ efflux mechanism of liver mitochondria is not a passive Ca2+/2H+ exchanger

Whether the Na(2+)-independent Ca2+ efflux mechanism of liver mitochondria is a Ca2+/2H+ exchanger and whether this exchanger is a passive mechanism have been controversial since shortly after the discovery of this mechanism. Here, a new approach to determining if the mechanism is passive is developed based on the energy available to a passive Ca2+/2H+ exchanger. Conditions are identified in which the Na(+)-independent Ca2+ efflux mechanism transports Ca2+ out of mitochondria against a Ca2+ gradient many times greater than that possible for a passive Ca2+/2H+ exchanger, thus ruling this out as a possible mechanism.     

Mechanism of peptide chain initiation in animal cells: A reevaluation

Summary Despite numerous reports from several laboratories, the precise mechanism of peptide chain initiation in animal cells and the roles of different factors involved in this process are not clear. The most widely accepted mechanism for peptide chain initiation is that proposed several years ago by Staehelin, Anderson, Hersey and coworkers. However, results reported from several laboratories differ significantly from the results on which the above mechanism is based. In this article, we have analyzed these different reports and their significance on the proposed mechanism of peptide chain initiation. Also, we have proposed an alternative mechanism based on the results reported from our laboratory.     

The active site composition of porcine pancreatic lipase: possible involvement of lysine

A mechanism is proposed wherein an essential lysine in porcine pancreatic lipase is the acylable residue in the catalytic mechanism of the enzyme. This mechanism involves an initial interfacial activation step were acylation first takes place in a rate-limiting step on a serine residue assisted by histidine and a carboxyl-containing residue, aspartic acid or glutamic acid, and then in a fast subsequent step the acyl group is transferred to the essential lysine residue at the catalytic site. Indirect support for the mechanism is presented. When the essential lysine is made inactive by reductive methylation, the lipase is functionally converted to a proteinase, as predicted by the mechanism.     

城市公立医院内部运行机制改革模式的探索

介绍了齐齐哈尔市第一医院在明确公立医院改革发展思路的基础上,深化内部决策执行机制、人事管理机制、薪酬分配机制、经济运行机制等公立医院内部运行机制改革的做法,加之管理体制、补偿机制、监管机制及服务体系改革,整体推进城市公立医院综合改革试点进程,以实现“维护公益性、调动积极性、保障可持续性”的改革目标。