Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development

Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling with diverse physiological functions. Because of their great market potential and therapeutic importance, PDE inhibitors became recognized as important therapeutic agents in the treatment of various diseases. Currently, there are seven PDE inhibitors on the market, and the pharmacological and safety evaluations of many drug candidates are in progress. Three-dimensional (3D) structures of catalytic domains of PDE 1, -3, -4, -5 and -9 in the presence of their inhibitors are now available, and can be utilized for rational drug design. Recent advances in molecular pharmacology of PDE isoenzymes resulted in identification of new potential applications of PDE inhibitors in various therapeutic areas, including dementia, depression and schizophrenia. This review will describe the latest advances in PDE research on 3D structural studies, the potential of therapeutic applications and the development of drug candidates.Received 30 November 2004; received after revision 24 January 2005; accepted 5 February 2005     

Moses Maimonides and Judah Halevi on order and law in the world of nature,and beyond

The concept of order, expressed by a number of forms of the Arabic root n.z.m., was of paramount importance in the natural philosophy of medieval Jewish thinkers, far more important than the related concept of law. Moses Maimonides walked a very tight rope between the order that is present in the cosmos, and which testifies to its intelligent Creator, and some minor streaks of apparent disorder, which indicate that the universe is not an eternally self-maintaining entity ruled only by necessity. Judah Halevi was mostly concerned with hierarchical levels of increasing order: a basic orderliness, which describes the cosmos, and a higher level of order, which applies to the Jewish people.     

Aptamer and its applications in neurodegenerative diseases

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, transmissible spongiform encephalopathy, Huntington’s disease and multiple sclerosis.     

信息几何理论与应用研究进展

信息几何是在Riemann流形上采用现代微分几何方法来研究统计学问题的基础性、前沿性学科,被誉为是继Shannon开辟现代信息理论之后的又一新的理论变革,在信息科学与系统理论研究领域展现出了巨大的发展潜力．本文首先从参数化概率分布族的内蕴几何结构特征与信息的几何性质出发,精炼了信息几何的科学内涵,指出信息几何相比于经典统计学与信息论的理论优势与方法的革新．然后简要阐述了信息几何与微分几何的联系,综述了信息几何理论的发展历史与近20年来信息几何在神经网络、统计推断、通信编码、系统理论、物理学和医学成像等各领域应用的研究现状,归纳和总结了其中所体现的信息几何的基本原理和基本方法,并对信息几何的发展给予注记．特别地,对信息几何在信号处理领域中的应用成果进行了较全面的总结和概括,阐述了信息几何在信号检测、参数估计与滤波等方面的最新研究成果．最后,展望信息几何的发展前景,提出了信息几何在信号处理领域中的若干开放性问题．     

Molecular mechanism on the energy transfer and conversion in the photosynthetic system

Zusammenfassung Auf molekularer Basis wird die Energieübertragung und die Energieumsetzung in einem primären photosynthetischen System untersucht. Die Energieübertragung in den Pigmenten und im Chlorophyll-A wird mit der Energieübergangswahrscheinlichkeit und dem Diffusionsmodell eines intramolekularen «Exitons» mit Dipol-Dipol-Wechselwirkung behandelt. Bei einer Chlorophyllkonzentration von 0.1M/1 wird die Diffusionskonstante des «Exitons»D _e 1.1 × 10^–3 cm²/sec und seine Diffusionslängel _e 250 Å. Als Energieumsetzung wird die Anregung eines – -Tripletts des Chlorophyll-A mit Hilfe eines paramagnetischen Metallenzyms vorgeschlagen und diskutiert.

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This work was supported by grants from the Japanese Society for the Promote of Science. The author wishes to express his gratitude to ProfessorM. Kotani of Tokyo University and ProfessorK. Oomori and ProfessorG. Tomita for their encouragement.     

Snake venom components and their applications in biomedicine

Snake envenomation is a socio-medical problem of considerable magnitude. About 2.5 million people are bitten by snakes annually, more than 100,000 fatally. However, although bites can be deadly, snake venom is a natural biological resource that contains several components of potential therapeutic value. Venom has been used in the treatment of a variety of pathophysiological conditions in Ayurveda, homeopathy and folk medicine. With the advent of biotechnology, the efficacy of such treatments has been substantiated by purifying components of venom and delineating their therapeutic properties. This review will focus on certain snake venom components and their applications in health and disease. Received 6 July 2006; received after revision 14 August 2006; accepted 28 September 2006     

Myocardial force production and energy turnover in anoxia

ATP turnover of isolated rabbit papillary muscles, contracting isometrically at 20 degrees C, was determined in oxygen and during 40 min of exposure to nitrogen (anoxia). Stimulus frequency was 0.2 hertz (Hz) in oxygen and 0.2 or 1.0 Hz in nitrogen. In oxygen, ATP turnover was determined from oxygen consumption using a P/O2 ratio of 6.3. The time-dependent rate of ATP turnover in nitrogen was found from the production of lactate, and the changes in adenine nucleotides and phosphocreatine, measured in rapidly frozen preparations at different time-points during the anoxic period. A P/lactate ratio of 1.5 was used. In muscles stimulated at 0.2 Hz, twitch force dropped during the anoxic period to 33% while force production of muscles stimulated at 1.0 Hz stopped completely. However, in the latter muscles, resting force rose to 19% of the twitch force in oxygen. The rate of ATP hydrolysis in anoxia depended strongly on stimulus frequency, indicating that it is not solely determined by the glycolytic capacity. In the 0.2 Hz-stimulated muscles the decrease in energy turnover occurred in parallel with the drop in force. However, the rise in resting force in muscles stimulated at 1.0 Hz occurred when ATP turnover was close to zero. It was concluded that anoxia hardly affects the energy required for twitch force production, but that the rise of resting force measured when twitch force had disappeared occurred when the rates of cross-bridge cycling and calcium turnover were very low.     

Myocardial function and energy metabolism in carnitine-deficient rats

Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.     

基于STDP规则和忆阻桥突触的神经网络及图像处理

忆阻器是具有记忆和类突触特性的非线性电路元件.基于此特性,文中提出了一个基于STDP（spike-time-dependent plasticity）学习规则的忆阻桥突触电路,它具有可以作为人工神经网络突触的优势.根据此优势,将这个新的电路与其他电路和网络结合,构成全新的电路和网络.首先将该忆阻桥突触电路和3个附加的晶体管结合在一起,实现神经网络的突触运算,并构建完整的忆阻桥突触神经网络.然后再将它与细胞神经网络结合用于图像去噪、边缘提取、角检测和汉字识别.最后,通过一系列的仿真实验证实了该方案的可行性,说明基于STDP学习规则的忆阻桥突触神经网络更具仿生特性,而且集成度更高、模板更易更换,有望解决实时的复杂的智能问题.     

Protein-O-mannosyltransferases in virulence and development

Protein-O-mannosyltransferases (Pmt proteins) catalyse the addition of mannose to serine or threonine residues of secretory proteins. This modification was described first for yeast and later for other fungi, mammals, insects and recently also for bacteria. O-mannosylation depends on specific isoforms of the three Pmt1, 2 and 4 subfamilies. In fungi, O-mannosylation determines the structure and integrity of cell walls, as well as cellular differentiation and virulence. O-mannosylation of specific secretory proteins of the human fungal pathogen Candida albicans and of the bacterial pathogen Mycobacterium tuberculosis contributes significantly to virulence. In mammals and insects, Pmt proteins are essential for cellular differentiation and development, while lack of Pmt activity causes Walker-Warburg syndrome (muscular dystrophy) in humans. The susceptibility of human cells to certain viruses may also depend on O-mannosyl chains. This review focuses on the various roles of Pmt proteins in cellular differentiation, development and virulence. Received 6 September 2007; received after revision 3 October 2007; accepted 5 October 2007     

Cytokinesis in development and disease: variations on a common theme

Cytokinesis is a crucial step in cell proliferation, and remarkably, it is also an important mechanism for developmental regulation in the generation of diverse cell types in eukaryotic organisms. Successful cytokinesis relies on the assembly and activation of an actomyosin-based contractile ring and membrane deposition/fusion in a spatially and temporally precise manner. As such, the molecular pathways governing cytokinesis are highly complex, involving a large number of components forming intricate interactive networks. The complexity of this system, however, may have also provided a rich platform for evolutionary ‘tinkering’ to achieve specific morphogenetic and developmental outcomes. Furthermore, failed or altered cytokinesis appears to contribute to the development of cancer in unexpected ways. Received 25 June 2007; received after revision 20 July 2007; accepted 16 August 2007     

Cyclotides: macrocyclic peptides with applications in drug design and agriculture

Cyclotides are disulfide-rich peptides from plants that are exceptionally stable as a result of their unique cyclic cystine knot structural motif. Their natural role is thought to be as plant defence agents, most notably against insect pests, but they also have potential applications in drug design and agriculture. This article identifies gaps in current knowledge on cyclotides and suggests future directions for research into this fascinating family of ultra-stable mini-proteins.     

A cautionary note on pentacyanoammonioferrate use for determining L-canavanine occurrence in biological materials

Summary Caution must be taken in the prevelant use of the pentacyanoammonioferrate reagent for the detection of L-canavanine in biological materias. This reagent reacts with L-histidine at neutral pH to form a pentacyanoammonioferate-histidine complex that is mistaken readily for its canavanine-containing counterpart.This work was supported by a grant from the National Science Foundation (PCM-78-20167). This is publication number 81-7-199 of the Kentucky Agriculatural Experiment Station, Lexington     

Extracellular microfibrils in development and disease

Fibrillins are the structural components of extracellular microfibrils that impart physical properties to tissues, alone or together with elastin as elastic fibers. Genetic studies in mice have revealed that fibrillin-rich microfibrils are also involved in regulating developmental programs and homeostatic processes through the modulation of TGF-β/BMP signaling events. A new paradigm has thus emerged whereby the spatiotemporal organization of microfibrils dictates both the cellular activities and physical properties of connective tissues. These observations have paved the way to novel therapeutic approaches aimed at counteracting the life-threatening complications in human conditions caused by dysfunctions of fibrillin-rich microfibrils. Received 2 April 2007; received after revision 23 May 2007; accepted 24 May 2007