Oligodendroglia metabolically support axons and contribute to neurodegeneration

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.     

疲劳累积损伤理论的适用性研究

疲劳累积损伤理论是结构疲劳寿命分析的基础。本文首先推导有代表性的疲劳累积损伤理论在二级加载模式下的预测模型;然后通过试验数据析了在二级加载下金属疲劳累积损伤理论的适用性。分析结果表明:各模型在不同加载方式下对结果预测的准确性差别较大。Manson模型和韧性耗散模型等非线性模型比较好地改善了Miner理论预测的精度,并且Manson模型对于旋转弯曲的钢材料具有更好的适用性;而对于受拉压的铝合金材料,韧性耗散模型具有更好的适用性。Miner理论、韧性耗散模型和Manson模型在用于随机谱的预测时,预测的误差有减小的趋势;而Carten-Dolar模型预测的误差有增大的趋势。     

Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans

Necrotic cell death underlies the pathology of numerous human neurodegenerative conditions. In the nematode Caenorhabditis elegans, gain-of-function mutations in specific ion channel genes such as the degenerin genes deg-1 and mec-4, the acetylcholine receptor channel subunit gene deg-3 and the G(s) protein alpha-subunit gene gsa-1 evoke an analogous pattern of degenerative (necrotic-like) cell death in neurons that express the mutant proteins. An increase in concentrations of cytoplasmic calcium in dying cells, elicited either by extracellular calcium influx or by release of endoplasmic reticulum stores, is thought to comprise a major death-signalling event. But the biochemical mechanisms by which calcium triggers cellular demise remain largely unknown. Here we report that neuronal degeneration inflicted by various genetic lesions in C. elegans requires the activity of the calcium-regulated CLP-1 and TRA-3 calpain proteases and aspartyl proteases ASP-3 and ASP-4. Our findings show that two distinct classes of proteases are involved in necrotic cell death and suggest that perturbation of intracellular concentrations of calcium may initiate neuronal degeneration by deregulating proteolysis. Similar proteases may mediate necrotic cell death in humans.     

Unique features of action potential initiation in cortical neurons

Neurons process and encode information by generating sequences of action potentials. For all spiking neurons, the encoding of single-neuron computations into sequences of spikes is biophysically determined by the cell's action-potential-generating mechanism. It has recently been discovered that apparently minor modifications of this mechanism can qualitatively change the nature of neuronal encoding. Here we quantitatively analyse the dynamics of action potential initiation in cortical neurons in vivo, in vitro and in computational models. Unexpectedly, key features of the initiation dynamics of cortical neuron action potentials--their rapid initiation and variable onset potential--are outside the range of behaviours described by the classical Hodgkin-Huxley theory. We propose a new model based on the cooperative activation of sodium channels that reproduces the observed dynamics of action potential initiation. This new model predicts that Hodgkin-Huxley-type dynamics of action potential initiation can be induced by artificially decreasing the effective density of sodium channels. In vitro experiments confirm this prediction, supporting the hypothesis that cooperative sodium channel activation underlies the dynamics of action potential initiation in cortical neurons.     

Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.

Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.     

非等效累积损伤模型

开展了45号钢在变幅加载下的疲劳试验,基于试验结果,对Miner模型、Manson-Halford模型、Corten-Dolan模型和叶笃毅模型的预测精度进行对比分析,并基于非等效累积损伤原则,以Miner模型和Manson-Halford模型为基础分别构建了2种新的非等效累积损伤模型.结果表明:4种模型中,Manson-Halford模型的预测精度好于其余3种模型,而本文构建的新的非等效累积损伤模型的预测结果要优于Manson-Halford模型,并且其计算模式较为简便,适宜工程应用.     

No evidence for preservation of somatostatin-containing neurons after intrastriatal injections of quinolinic acid

Intrastriatal injections of excitotoxic amino acids and their analogues (for example kainate and ibotenate) elicit a pattern of neuronal degeneration that is similar in many respects to that observed in Huntington's disease. In this disease there is a progressive degeneration of most types of intrinsic neuron but somatostatin and neuropeptide Y levels are increased 3-5-fold. This may be attributed to the selective preservation of a sub-class of striatal aspiny neurons, in which these two peptides are co-localized together with the enzyme NADPH-diaphorase. Beal et al. reported recently that following intrastriatal injections of quinolinic acid in rats, medium-sized aspiny neurons were selectively preserved and they suggested that quinolinic acid which is found in human brain might cause the neuronal degeneration seen in Huntington's disease. We have used immunocytochemical and enzyme histochemical techniques to examine this selective toxicity but find no evidence to support this finding. We conclude that there are substantial differences between the immunocytochemical changes detected in postmortem Huntington's disease brain and those following quinolinic-acid-induced degeneration.     

脑缺血损伤的研究进展

缺血性脑血管疾病是一种致死致残的常见病、多发病. 近年来,对脑缺血再灌注损伤的研究越来越深入. 大量的实验研究表明,脑缺血再灌注损伤对脑损害的机制是非常复杂的,在缺血性损伤过程中除缺氧和能量代谢衰竭外,由缺血诱导的一系列瀑布样效应是导致缺血性神经元死亡的重要机制. 同时脑缺血损伤的研究受到很多因素的影响,诸如血糖浓度、脑温、脑血流量、血压、鼠种以及大鼠的性别等. 本文就脑缺血损伤的相关病理生理机制、影响因素及治疗等方面的进展进行综述,以期对缺血后神经元的死亡机制作进一步的探索.     

基于TMAES对GrC神经元放电活动影响的仿真

经颅磁声电刺激（TMAES）是一种新型无创的脑神经调控技术,具有良好的应用前景.该技术利用静磁场和超声波共同作用所产生的磁声电效应,在神经组织中产生感应电流,进而对神经组织实施刺激.作者基于小脑颗粒细胞模型（GrC模型）,建立了突触连接GrC模型,对TMAES刺激下突触连接GrC模型的动作电位进行仿真,分析了动作电位的传播方向.在TMAES神经元的不同突触连接方式下,对比了兴奋性与抑制性对神经元放电的影响.通过改变抑制点的位置分析了抑制作用在TMAES下对神经元放电模式的影响.仿真结果显示,经颅磁声电刺激对GrC模型神经元放电节律具有重要影响.实现了两个神经元突触连接模型在TMAES下的仿真,对进一步发掘和研究神经元的传导及连接模式具有重要意义.     

The DNA damage response: putting checkpoints in perspective

The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development. Organisms respond to chromosomal insults by activating a complex damage response pathway. This pathway regulates known responses such as cell-cycle arrest and apoptosis (programmed cell death), and has recently been shown to control additional processes including direct activation of DNA repair networks.     

Re-mention of an old neurodegenerative disease: Alzheimer’s disease

Alzheimer’s disease(AD),the most common form of neuropsychiatric disorder,is characterized by neuronal degeneration and inexorably progressing dementia,especially in the elderly population.With a rapidly aging population in both developed and developing countries,AD has emerged as one of the largest growing problems worldwide.Current drugs improve the symptoms of AD,but do not have any profound intervention to delay its onset.Thus,understanding the molecular mechanisms underlying the genes tied to AD will be crucial to the development of therapeutic targets.This review will summarize the aetiology,pathology,and the evidence for the genetic components in AD,discuss the proposed amyloid cascade and the following tau hyperphosphorylation hypothesises,oxidative stress mediated neuronal cell death,as well as the function of Retromer complex during the developing of AD.Our laboratory’s current research progress and the challenges that still remained will be also highlighted.     

静态直流电场作用下神经元放电动力学分析

无创式直流电刺激中枢神经系统是现在用来减轻多种神经疾病症状的有效方法.为了探究静态直流电场对神经活动的作用机制,利用二维最小模型研究了其在静态直流电场作用下的动力学行为.通过分岔和相平面分析,发现3类神经元兴奋性对相同刺激的不同响应是由不同的峰放电起始动力过程造成的.从起始动力学的角度得到了静态直流电场对神经活动的影响,研究结果可以为无创式直流脑调制技术的应用和发展提供一定的理论指导.     

框支网格式轻质墙板损伤性能分析

基于不同构造形式框支网格式轻质墙板低周反复荷载试验,通过不同损伤性能评估模型的比较,提出适合该类结构的损伤模型.采用OpenSees准确模拟结构的力学性能,得出相应力学参数,验证损伤模型的合理性.给出与框支网格式轻质墙板结构各累积损伤阶段对应的损伤指数取值范围.基于试验,分阶段对结构累积损伤性能进行描述,并采用ANSYS模拟累积损伤发展阶段,提出框支网格式轻质墙板结构后期修复建议.     

一种更精确的现实性动态神经网络模型

神经元的功能主要由突触后膜、胞体膜和始段膜三种膜结构的不同活动特性决定的．根据这三种膜结构的电生理性质及其形态结构提出了一个比较精确的现实性动态神经网络模型．计算机仿真结果表明这个模型在具有比较简明的形式及较小的计算量的同时，能较全面地反映神经元的活动特性．通过与其他模型的比较，对神经元各部分的结构与其功能的关系有进一步的认识．     

灯盏花注射液抗新生鼠缺氧缺血脑损伤的药效作用

为观察灯盏花注射液治疗新生鼠缺氧缺血脑损伤的药物疗效及其药理作用机制,采用新生7日龄大鼠缺氧缺血性脑损伤模型,设立假手术组、缺氧缺血脑损伤模型组、灯盏花注射液治疗10,20,40 mg/kg剂量组、无菌注射用水对照组.采用硫堇染色、免疫组织化学染色的方法测定各实验组海马CA1区神经元密度、组织学分级、凋亡相关基因bcl-2和bax的表达情况,并计数各时间点Bcl-2和Bax蛋白免疫阳性细胞数目及积分光密度值.假手术组,大鼠海马CA1区无锥体细胞缺失,未见明显阳性细胞.与假手术组比较,缺氧缺血脑损伤模型组、无菌注射用水对照组Bcl-2,Bax蛋白表达均于3 d时达到高峰(与其余各时间点比较差别有显著意义p0.05),神经元密度明显降低,组织学分级显著增高,积分光密度值增加.灯盏花治疗组,与无菌注射用水对照组比较,Bcl-2阳性表达进一步增加,积分光密度值增加;而Bax阳性表达则减少,积分光密度值降低;神经元密度显著高于对照组,组织学分级明显降低.灯盏花注射液可能是通过上调Bcl-2表达,抑制Bax表达,减轻缺氧缺血引起的神经元凋亡及迟发性神经元死亡.     

p53振子的形成机制及microRNA对p53目标基因表达的精细调控

肿瘤抑制因子p53调控着大量的基因,在肿瘤抑制中起着关键作用.实验结果表明,当DNA受损后,p53的表达呈现周期性振荡.已有的一些p53振子的理论模型,其振子产生机制通常依赖于p53和Mdm2之间相互作用的时滞因素.考虑基因表达的转录和翻译过程,运用动力学方程建模的方法,给出一种新模型,并利用Hopf分叉理论,给出p53振子产生的条件.数值模拟结果表明,与已有的时滞模型相比,该模型对参数具有更好的鲁棒性,较好地解释了p53振子的产生机制.最近的许多实验表明,p53调控着miR-34家族中大量microRNA的表达,这些microRNA又在后转录水平上对p53的下游目标基因起着调控作用.在这一模型基础上,研究microRNA加入p53调控网络后所起的调控作用,数值模拟结果初步表明,microRNA对p53下游目标基因表达起到了精细调控作用.     

植物有性生殖过程中的细胞程序性死亡

细胞程序性死亡(pmgrammed cell death,PCD)已成为当前生物学的研究热点之一,PCD是植物发育过程中的一种普遍现象,植物生殖器官中一些细胞的死亡对植物有性生殖具有重要作用,有性生殖过程中的植物细胞程序性死亡具有细胞类型特异性,即在特定时期,只有特定的细胞才会发生程序性死亡,本文介绍了植物有性生殖过程中各种类型的细胞在特定时期所发生的程序性死亡的形态和生化特征,这些PCD类型包括单性花的形成、性别决定、大小孢子的退化、花粉发育及绒毡层的解体、雌雄配子体的发育、花粉管的生长、胚胎发育过程中胚柄、胚乳以及糊粉层的消失等等。     

Prevention of natural motoneurone cell death by dibutyryl cyclic GMP

Natural neuronal cell death is a well-described developmental phenomenon common to many nerve centres in a variety of animal species. Neuronal survival has been shown to depend on the presence and size of the available target tissue and it has been suggested that neuronal survival is dependent on successful competition for either a limited number of synaptic sites or a limited amount of trophic factor(s). In the lateral motor column of the lumbar spinal cord in the chick embryo, the period of axon elongation and innervation of the periphery has been shown to precede that of natural motoneurone cell death. While muscle contractile activity appears to regulate the extent of motoneurone death, to date the intracellular molecular events that initiate and regulate the developmental process of natural neuronal cell death or, more importantly, neuronal survival are unknown. Our earlier studies suggested that either contact or association between spinal cord processes and muscle cells during neuromuscular junction formation in vivo leads to an increase in cyclic GMP in whole spinal cord. We now show that treatment of chick embryos with the membrane-permeable cyclic GMP analogue, dibutyryl cyclic GMP during the period of natural motoneurone cell death prevents greater than 58% of natural motoneurone cell death in the lumbar lateral motor column.     

基于离散过程神经网络页岩油气储层有机碳含量预测

受地层岩性变化影响,传统方法进行有机碳含量(TOC)拟合预测精度偏低。为提高TOC拟合精度,减小普通神经网络对连续信号的时间累积误差,提出一种极限学习离散过程神经网络的TOC拟合预测模型。模型用向量模拟过程式输入,内部通过抛物插值的数值积分完成离散样本的时域聚合。通过对离散过程神经元的结构分析,提出极限学习训练算法,在隐层相关参数随机赋值后,通过Moore-Penrose广义逆求解输出权值,模型学习速度快。最后将该方法应用于TOC拟合预测,利用相关性分析,选取对TOC响应最敏感的测井曲线作为模型的特征输入。与传统方法和其他神经网络对比,该方法的拟合精度较高,预测TOC与实测值有更好的相关性。     

A G1 rate model accounts for cell-cycle kinetics attributed to 'transition probability'

Smith and his colleagues have proposed that the duration of the cell cycle is determined by a random transition, analogous to the random decay of a radioactive nucleus, by which a cell passes from an 'A state' within the G1 phase to a 'B phase' that includes the rest of the cycle. The experimental support for this transition probability hypothesis is the tendency of a cumulative plot of differences of cycle times of sibling cells (the beta curve) to be exponential ad parallel to the exponential tail of a cumulative plot of the cycle times themselves (the alpha curve). However, a close examination of four of the most extensive sets of experimental data now suggests that the two beta curves with the steepest slopes may not, in fact, be exponential. These and all the other characteristics of the experimental curves are best matched by computer simulations using a cell-cycle model that will be termed here a G1 rate model. This model is consistent with differences in cell metabolism, rather than a transition at an inherently unpredictable time, being the physiological basis for differences in cycle times within a cell population.