Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin

In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy.     

Proteasomes in apoptosis: villains or guardians?

The proteasome (multicatalytic proteinase complex, prosome) is a major cytoplasmic proteolytic enzyme, responsible for degradation of the vast majority of intracellular proteins. Proteins degraded by the proteasome are usually tagged with multiple ubiquitin moieties, conjugated to the substrates by a complicated cascade of enzymes. Over the last years, evidence has accumulated that changes in the expression and activity of the different components of the ubiquitin-proteasome system occur during apoptosis. Proteasome inhibitors have been used to induce apoptosis in various cell types, whereas in others, these compounds were able to prevent apoptosis induced by different stimuli. The proteasome mediated step(s) in apoptosis is located upstream of mitochondrial changes and caspase activation, and can involve in different systems Bcl-2, Jun N-terminal kinase, heat shock proteins, Myc, p53, polyamines and other factors.     

Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives

Despite the considerable progress in modern tumor therapy, the prognosis for patients with glioblastoma, the most frequent malignant brain tumor, has not been substantially improved. Although cytoreductive surgery and radiotherapy are the mainstays of treatment for malignant glioma at present, novel cytotoxic drugs and immunotherapeutic approaches hold great promise as effective weapons against these malignancies. Thus, great efforts are being made to enhance antitumoral efficacy by combining various cytotoxic agents, by novel routes of drug administration, or by combining anticancer drugs and immune modulators. Immunotherapeutic approaches include cytotoxic cytokines, targeted antibodies, and vaccination strategies. However, the success of most of these experimental therapies is prevented by the marked molecular resistance of glioma cells to diverse cytotoxic agents or by glioma-associated immunosuppression. One promising experimental strategy to target glioma is the employment of death ligands such as CD95 (Fas/Apo1) ligand or Apo2 ligand (TRAIL). Specific proapoptotic approaches may overcome many of the obvious obstacles to a satisfactory management of malignant brain tumors. Received 8 March 1999; received after revision 27 May 1999; accepted 14 June 1999     

Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease

The AAA domain, a conserved Walker-type ATPase module, is a feature of members of the AAA family of proteins, which are involved in many cellular processes, including vesicular transport, organelle biogenesis, microtubule rearrangement and protein degradation. The function of the AAA domain, however, has not been explained. Membrane-anchored AAA proteases of prokaryotic and eukaryotic cells comprise a subfamily of AAA proteins that have metal-dependent peptidase activity and mediate the degradation of non-assembled membrane proteins. Inactivation of an orthologue of this protease family in humans causes neurodegeneration in hereditary spastic paraplegia. Here we investigate the AAA domain of the yeast protein Yme1, a subunit of the iota-AAA protease located in the inner membrane of mitochondria. We show that Yme1 senses the folding state of solvent-exposed domains and specifically degrades unfolded membrane proteins. Substrate recognition and binding are mediated by the amino-terminal region of the AAA domain. The purified AAA domain of Yme1 binds unfolded polypeptides and suppresses their aggregation. Our results indicate that the AAA domain of Ymel has a chaperone-like activity and suggest that the AAA domains of other AAA proteins may have a similar function.     

下一代传输网络：传输、管理和控制位面

本书全面论述了传输、管理和控制位面的技术，介绍了一些有用的、现行的和下一代电讯网络技术的参考信息。四位作者均在电信学研究、产品开发等方面具有20年以上的经验。     

一种新型微机械热导压力敏感器及其数值模拟

本文研究了一种新型微机械ＣＭＯＳ热导压力敏感器。其压力测量范围是０．００１－１００ Ｔｏｒｒ。整个量程范围内，多晶硅热敏电阻相对变化（即灵敏度）优於３０％。为使敏感器结构性能优化，我们首次开发了一软件包对器件热电性能进行数值模拟。三维模拟问题被简化为两个２－Ｄ模拟，并将由稳态能量平衡得到的方程组离散化用非线性Ｇａｕｓｓ－Ｓｅｉｄｅｌ算法迭代求解。器件敏度的模拟结果和实验值相吻合。文中还对温度分布进     

关于高空防空导弹制导设计的综合考虑

本文介绍一种高空雷达导引防空导弹的实用设计考虑。讨论了影响脱靶距离的三种主要因素——雷达信号反射、雷达导引头组合不完善和导弹响应限制。在高空,闪烁是雷达信号中的主要干扰。此外,导引头组合不完善,如框架稳定不理想、天线罩折射率和导引头陀螺对加速度的敏感度都引起稳定性和脱靶距离问题。制导系统设计人员必须解决这些问题。 最后,由于加速度能力下降、响应时间延长以及控制舵面速率饱和,导弹对制导指令的响应也受到限制。文中讨论了脱靶距离对每一种因素的敏感度,另外,也论述了与组合不完善引起的多余反馈通道有关的稳定性问题。介绍了几个数字实例,它们说明:在构成系统时,如果要在高空满足性能目标,那么在初步设计中考虑实际硬件的不完善是很重要的。本文提供了对实际问题的一个透视,在理论研究中常常把这些问题看成是第二位的,但是实际上它们可能是决定制导和控制设计参数的主导因素。     

数学的不合情理的有效性

数学的不合情理的有效性,是西方数学基础研究中,受人注目的问题之一。作者首先概要地介绍了该问题的讨论的沿革,然后深入分析了数学的实质,并且在此基础上,提出了自己对该问题的看法:对数学的不合情理的有效性的探讨是有意义的,但很困难,目前离该问题的解决,为期尚远。     

美国的区域性仪器设备中心

目前,我国一些科研单位和高等院校的现代化大型仪器,如加速器、大型电子计算机、电子显微镜……等使用率不高,有的则在同一省、市打算搞两个电子计算机计算中心,这就没有必要。特别像我们这样一个发展中的社会主义国家,办任何事情都要从实际出发,以发挥现有各类仪器的效用。美国近年来发展起来的区域性仪器设备中心,这一做法很值得我们借鉴。希望我国的科学技术管理部门、教育部门的同志都来研究一下,以较少的投资,取得更大的效益。这篇文章所提供的经验值得参考。