Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

锥形血管中的血液流动

本文研究了带有锥度的血管的发展流动问题,导得了一组相应的速度分布、压力分布公式。分析表明,锥度角对血管流场是有影响的。当略去锥度角时,本文公式便变为和无锥度角的等圆截面直管的Targ公式相一致。     

复杂网络: 结构和动力学

(续本刊2006年第4期) 6 应用 本章将讨论前述理论在实际网络中的应用,包括网络的结构和动力学两方面的问题.首先回顾社会网络的某些结构并考虑两类社会网络(意见形成和博弈模型)的动态演化,然后探讨因特网和万维网的统计属性,最后集中讨论生物和医学复杂网络,如分子成分之间的相互作用网和神经网络.     

复杂网络:结构和动力学

耦合的生物化学系统、神经网络、相互作用的群居物种、互联网和万维网只是由大量高度相互连接的动态个体组成的系统的少数几个例子。获取这类系统的全局特征的首选方法是建立图模型——图中的点代表动态个体，边代表个体间的相互作用。一方面，科学家们需要处理结构问题如刻画一个复杂连线体系的拓扑结构、揭示建立在现实网络基础上的统一原理，以及完善模型从而模拟网络的增长和复制网络结构特性；另一方面，在研究复杂网络动力学时会产生许多相关问题，例如研究一个大的动态系统如何通过复杂连接的相互作用来表现集体行为的。我们回顾了近来在研究复杂网络的结构和动力学方面的主要概念以及取得的结果，总结了这些思想在许多不同学科包括从非线性科学到生物学、从统计力学到医药学以及工程学等领域的有关应用。     

Design of Vehicle Routing by Integrating Optimization and Simulated Annealing Approach

The vehicle routing problem (VRP) can be described as the problem of designing the optimal delivery or collection routes from one or several depots to a number of geographically scattered customers, subject to load constraints. The routing decision involves determining which of the demand s will be satisfied by each vehicle and what route each vehicle will follow in s erving its assigned demand in order to minimize total delivery cost. In this pap er, a methodology for the design of VRP by integrating...     

Mitochondrial protein phylogeny joins myriapods with chelicerates

The animal phylum Arthropoda is very useful for the study of body plan evolution given its abundance of morphologically diverse species and our profound understanding of Drosophila development. However, there is a lack of consistently resolved phylogenetic relationships between the four extant arthropod subphyla, Hexapoda, Myriapoda, Chelicerata and Crustacea. Recent molecular studies have strongly supported a sister group relationship between Hexapoda and Crustacea, but have not resolved the phylogenetic position of Chelicerata and Myriapoda. Here we sequence the mitochondrial genome of the centipede species Lithobius forficatus and investigate its phylogenetic information content. Molecular phylogenetic analysis of conserved regions from the arthropod mitochondrial proteome yields highly resolved and congruent trees. We also find that a sister group relationship between Myriapoda and Chelicerata is strongly supported. We propose a model to explain the apparently parallel evolution of similar head morphologies in insects and myriapods.     

复杂网络:结构与动力学

(续本刊2006年第3期) 　　3 静态与动态鲁棒性 　　网络的鲁棒性是指当网络中的部分节点或边被破坏时,网络仍然能够继续维持其功能的能力.这是一个具有明显实际意义的论题,因为它直接影响着任何发生在网络上的过程的效率,而且它也是复杂网络文献中最早被探索的论题之一.……     

Intracellular recordings from Deiters' neurons in response to saccular and oculomotor nucleus stimulations

Summary 2 populations of cells were found in the Deiters' nucleus responsive to direct electrical stimulation of the ipsilateral saccule. Only those Deiters' neurons activated monosynaptically from the saccule could be driven antidromically from the oculomotor nucleus. Such an intracellular study provides strong evidence for a tri-neuronal arc in the sacculo-ocular reflex for vertical eye movements.Acknowledgment. This study was supported by the Medical Faculty Research Grant No. 377/004/03, University of Hong Kong.     

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10(-8)). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.