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     

The PREPL A protein, a new member of the prolyl oligopeptidase family, lacking catalytic activity

The PREPL (previously called KIAA0436) gene encodes a putative serine peptidase from the prolyl oligopeptidase family. A chromosomal deletion involving the PREPL gene leads to a severe syndrome with multiple symptoms. Homology with oligopeptidase B suggested that the enzyme cleaves after an arginine or lysine residue. Several PREPL splice variants have been identified, and a 638-residue variant (PREPL A) was expressed in Escherichia coli and purified. Its secondary structure was similar to that of oligopeptidase B, but differential-scanning calorimetry indicated a higher conformational stability. Dimerization may account for the enhanced stability. Unexpectedly, the PREPL A protein did not cleave peptide substrates containing a P1 basic residue, but did slowly hydrolyse an activated ester substrate, and reacted with diisopropyl fluorophosphate. These results indicated that the catalytic serine is a reactive residue. However, the negligible hydrolytic activity suggests that the function of PREPL A is different from that of the other members of the prolyl oligopeptidase family.     

Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons

Many have hypothesized that cell death in Parkinsons disease is via apoptosis and, specifically, by the mitochondrial-mediated apoptotic pathway. We tested this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, challenged with the Parkinsonism-causing neurotoxin MPP⁺ (1-methyl-4-phenylpyridinium ion). Apoptosis was the main mode of cell death when the cells were subjected to MPP⁺ treatment under serum-free conditions for 24 h. Caspase-3 and caspase-9, however, were not activated, thus indicating the existence of alternate or compensatory cell death pathway(s) in dopaminergic neuronal cells. Using caspase inhibitors, we demonstrated that these pathways involve caspase-2, –8, –6 and –7. A time-course study indicated that activation of caspase-2 and –8 occurred upstream of caspase-6 and caspase-7. Upon MPP⁺ challenge, the apoptosis-inducing factor was translocated from the mitochondria into the MN9D cytosol and nucleus. These results suggest the existence of alternative apoptotic pathways in dopaminergic neurons.Received 20 September 2004; received after revision 5 November 2004; accepted 22 November 2004     

From Cybernetics and VSD to Management and Action

This paper uses Stafford Beer's Viable Systems Diagnosis (VSD) to suggest that the development of a model for actionable theory in organizations would take the form of a three-step process. The first step involves the definition and explanation of an appropriate theory base, the second theory interpretation into a coherent set of action principles and the third contextual action in organizations. We contend that even for a well-informed and widely read manager gleaning the theoretical basis for this process from the recognized Beer trilogy “Brain of the Firm,” “The Heart of the Enterprise” and “Diagnosing the System” is difficult to justify in terms of time, understanding, and action. We maintain that a sound set of action principles emanating from Beer's primary work must be considered before tackling the noted trilogy. We use Beer's initial text “Cybernetics and Management” to trace some fundamental operational research and the interdisciplinary tripartite science of cybernetics. We commence our action model process with some introductory thoughts into operational research, cybernetics, VSD, and contextual action. Our first step toward action involves some primary definitions and principles of cybernetic theory and the prospect of controlling overwhelming variety. Our second step provides our set of coherent potential action principles fundamental to cybernetic theory. The paper is written in a journalistic rather than academic style reflecting the need to couch the interpretation of the theory in a language that the well-informed manager may readily translate into third step contextual practice.     

生物序列分析

这次演讲将回顾近 1 0多年来应用某些随机模型于生物序列分析的研究工作 .这些模型本身有很长的历史 ,可追溯到 3 0多年以前 ,尽管从那时起 ,这些模型已经产生了很多新的变种 .在生物序列分析中模型的作用是归总那些涉及到在生物信息学中已知的模体 (motif)或域 (domain)的信息 ,并且提供一种工具在另一序列片段中寻找模体或域的实例 (instance) .我们将逐步介绍模体模型 ,从非常简单的 ,非随机情况开始 ,进而是更复杂的情况 ,直至近来的关于模体的剖面隐马氏模型 .第二个例子是来自利用一个或两个物种的序列数据进行基因发现 ,其中广义隐马氏模型或广义成对 (pair)隐马氏模型已被证实非常有效     

Fabrication and Properties of CoSm-Based Multilayer Thin Films

In recent years, SmCo series thin films have been found to be good candidates for fabricating integrated electromagnetic components and ultrahigh density magnetic recording media[1,2]. Up to now,intensive studies of such films have been carried out in order to obtain appropriate microstructure, crystallographic orientation and other properties. Substitution of Cu or Ni for Co in SmCo/Cr series films leads to a decrease of the saturation magnetization, magnetic switching volume, and to an increase of uniaxial anisotropy and coercivity[3-5].Various deposition conditions have also been investigated[6]. The large increase in coercivity for the annealed SmCo/Cr films is due to the growth of crystallitest[7,8]. In this article, we report a study of the deposition process,structure, and magnetic behavior of sputtered Sm (Co,Cu, Ti)/Cr series thin films.