Molecular mechanisms of serpin deficiencies

The study of serpin deficiency is currently one of the most active areas in basic medical research. Recently, three hypotheses concerning serpin deficiency have been proposed, which are referred to as the conformational disturbance hypothesis (CDH) , loop-sheet polymerisation hypothesis (LSPH) and multiple binding site hypothesis (MB-SH) . CDH was put forward to explicit serpin deficiency due to conformational change of reactive loop of serpins as a result of mutations occurring away from the reactive site residues and LSPH was to explain deficient serpins due to the formation of polymers. MBSH was proposed to explain the mechanism of the formation of stable enzyme-serpin complex via more than one binding site and blockage or mutation in any of the sites resulting in serpin deficiency. A combination of these mechanisms may be critical in understanding the roles of the many documented mutations and autoimmunities which result in qualitative and quantitative serpin deficiency.     

Molecular mechanisms and clinical applications of angiogenesis

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.     

Molecular mechanisms that confer antibacterial drug resistance

Antibiotics--compounds that are literally 'against life'--are typically antibacterial drugs, interfering with some structure or process that is essential to bacterial growth or survival without harm to the eukaryotic host harbouring the infecting bacteria. We live in an era when antibiotic resistance has spread at an alarming rate and when dire predictions concerning the lack of effective antibacterial drugs occur with increasing frequency. In this context it is apposite to ask a few simple questions about these life-saving molecules. What are antibiotics? Where do they come from? How do they work? Why do they stop being effective? How do we find new antibiotics? And can we slow down the development of antibiotic-resistant superbugs?     

Molecular mechanisms of kinetochore capture by spindle microtubules

For high-fidelity chromosome segregation, kinetochores must be properly captured by spindle microtubules, but the mechanisms underlying initial kinetochore capture have remained elusive. Here we visualized individual kinetochore-microtubule interactions in Saccharomyces cerevisiae by regulating the activity of a centromere. Kinetochores are captured by the side of microtubules extending from spindle poles, and are subsequently transported poleward along them. The microtubule extension from spindle poles requires microtubule plus-end-tracking proteins and the Ran GDP/GTP exchange factor. Distinct kinetochore components are used for kinetochore capture by microtubules and for ensuring subsequent sister kinetochore bi-orientation on the spindle. Kar3, a kinesin-14 family member, is one of the regulators that promote transport of captured kinetochores along microtubules. During such transport, kinetochores ensure that they do not slide off their associated microtubules by facilitating the conversion of microtubule dynamics from shrinkage to growth at the plus ends. This conversion is promoted by the transport of Stu2 from the captured kinetochores to the plus ends of microtubules.     

运动细胞初始极化阶段胞内信号分子双向积聚的分子机制及动态数值模拟

真核细胞（Eukaryotes）,如盘基网柄菌细胞（Dictyo stelium）和白细胞（Leukocyte）等,受到前方传来的外信号刺激后,胞内物质发生两种方向相反的运动：胞质中与质膜结合的磷酸激酶PI3K及其在质膜上的生成物磷脂酰肌醇-3,4,5-三磷酸PI（3,4,5）P3以向前扩散的方式积聚到前沿;而胞质中与质膜结合的磷酸酶PTEN及其在质膜上的生成物磷脂酰肌醇-4,5-双磷酸PI（4,5）P2以向后扩散的方式积聚到质膜的后边.通过这种＂双向积聚＂,细胞形成头部和尾部,并在前沿生出伪足,完成初始极化.本文根据已知的实验,分析了＂双向积聚＂的分子机制,建立了相应的数学模型,通过数值模拟加以分析.以胞内被激活的小G蛋白（Rac）为触发信号,其梯度与外信号场的梯度一致;PI3K和PTEN作为调控因子,PI（3,4,5）P3和PI（4,5）P2作为标识细胞极化的信号分子,它们的浓度变化由一组耦合的非稳态二维反应-扩散方程描述.该反应-扩散体系源项中包含：PI（3,4,5）P3对PI3K,PI（4,5）P2对PTEN的识别和结合过程,是由蒙特-卡诺（Monte-Carlo）法处理;质膜结合态PI3K和PTEN对PI（3,4,5）P3和PI（4,5）P2施加的酶催化作用,由Michaelis-Menten动力学过程描述.反应-扩散方程组采用格子Boltzmann方法进行数值求解.数值试验显示,产生＂双向积聚＂的关键是受外信号梯度刺激后的胞内信号分子相互激发或抑制所形成的正反馈或负反馈回路：给细胞质膜头部一个较高的Rac激活率,Rac→PI3K？PI（3,4,5）P3将形成短程正反馈回路（亦即＂局部激励＂）,引起PI3K和PI（3,4,5）P3快速在细胞头部积聚;头部PI（3,4,5）P3增多,限制了PTEN与PI（4,5）P2结合,使得PI（3,4,5）P3？PTEN→PI（4,5）P2形成长程负反馈回路（亦即＂全局抑制＂）;引起PTEN和PI（4,5）P2慢慢在细胞尾部积聚.同时发现,PI3K和PTEN含量对细胞极化有明显的影响,并存在使细胞正确极化的最佳值.     

The role of Drosophila Piezo in mechanical nociception

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.     

Molecular mechanisms of receptor desensitization using the beta-adrenergic receptor-coupled adenylate cyclase system as a model

Desensitization, the tendency of biological responses to wane over time despite the continuous presence of a stimulus of constant intensity, is observed in organisms as diverse as bacteria and mammals. Recently, new insights into the molecular mechanisms underlying these phenomena have emerged from the study of the receptors coupled to the ubiquitous second messenger-generating system adenylate cyclase. These mechanisms involve sequestration or down-regulation of the receptors from the cell surface as well as functionally significant covalent modifications of the receptors and/or guanine nucleotide regulatory proteins.     

镁合金裂纹顶端塑性变形和失效机理的分子动力学模拟

实验表明镁合金在制造过程中不可避免的会出现缩孔和微裂纹两种微观缺陷,这两种微观缺陷对镁合金的力学性能有着重要影响.通过分子动力学方法在原子尺度下分别对带有缩孔和微裂纹镁合金的塑性变形过程进行了研究,原子间的相互作用由改进嵌入原子势来描述,观察到了 hcp 结构金属裂纹扩展及失效过程.计算结果表明:镁合金的裂纹扩展是一个...     

分子电子学与分子电子器件

介绍了分子电子学与分子器件研究领域的最新进展，展望了分子电子学的发展前景，提出了一些新的想法和建议。     

用分子对称性求取分子轨道

应用分子对称性求得分子轨道,是根据分子反映面对称性质,建立了三个规则。依据对称面性质,将高阶本征行列式约化为低阶本征行列式,因此容易计算。根据这三个规则,对于具有垂直对称面的链型、环型、稠环型和混合型共轭分子,我们都得到了满意的结果。     

Pulsar radiation mechanisms

Gamma rays produced by electrons accelerated in the strong magnetic fields of neutron stars annihilate to electron-positron pairs. This leads to a two-stream situation, which results in bunching and coherent radio emission.     

柔顺机构的机械效益

用能量法详细推导了单输入单输出柔顺机构的机械效益的计算公式 ,并根据不同的边界条件 ,对该公式的使用提出了明确的意见 ;同时还提出了单输入双输出和双输入单输出柔顺机构的机械效益的概念 ;最后还建立了以柔顺机构的机械效益为目标函数的约束最优化设计的数学模型 图 3,参 5     

Neural mechanisms of perceptual learning

The traditional view of cortical visual processing is that primary visual cortex (V1) analyzes simple visual attributes, and that object recognition involves a progressive “complexification” of receptive field (RF) properties along the visual pathway extending into the temporal lobe. Based on our studies with a combination of electrophysiological, imaging, psychophysical and computational approaches, we find to the contrary that V1 is capable of encoding much more complex stimulus features than originally believed, and that it can integrate information over large parts of the visual field. Moreover, V1 is continually involved in encoding information about learned stimulus configurations under top-down influences specific to the trained perceptual task.