Optimization of Thienopyrrole‐Based Finger‐Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase

Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40 , which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold.     

运用蚁群优化法对钢结构进行基于性能的抗震设计

运用蚁群优化法(ACO)对钢结构进行了基于性能的抗震设计。这个离散的数学运算法比其他算法更为有效并精确。采用了非线性分析以得到结构在各种地震性能水平下的结构响应,采用一个简单的计算机程序,对包含一阶弹性和二阶几何刚度的特性进行推覆分析。采用两个实例说明了ACO在轻钢结构中的应用,证明其可满足抗弯钢结构在多种地震性能水平下的要求,同时也与标准遗传算法的结果进行对比,表明ACO更适合解决此类优化问题。     

Topology optimization of trusses considering static and dynamic constraints using the CSS

Topology optimization of structures reveals outstanding advantages when compared to sectional optimization. Many unnecessary members and nodes may exist in a structure and a topology optimization provides an opportunity to remove them. This advantage will specially become apparent when comparatively large cost of the nodes is taken into account. Fundamental frequencies of a structure are important, easily obtained characteristics which allow the designer to keep out from the dangerous resonance phenomenon. When dynamic excitations are critical, these characteristics cannot be neglected. In this paper, topology optimization of truss structures is investigated considering stress, displacement, buckling and frequency constraints. To perform such an optimization is not simple because of large, highly nonlinear and non-convex search space. Here the newly developed charged system search algorithm is used to accomplish this optimization.     

A secure credit-based cooperation stimulating mechanism for MANETs using hash chains

One of the most challenging problems in self-organized mobile ad hoc networks (MANETs), which consist of autonomous and self-interested nodes, is to stimulate the nodes to cooperate in routing and packet forwarding. In this paper, we propose a novel credit-based cooperation mechanism that utilizes hash chains on messages to defend against cheating by the nodes. We show that it imposes a low workload on the nodes in comparison with the mechanisms that deploy digital signature schemes. Moreover, through a game-theoretic analysis, it is shown that any level of cooperation by a node will be attainable if the mechanism makes appropriate payments.     

Design of frames using genetic algorithm,force method and graph theory

In the process of discrete‐sizing optimal design of frame structures by genetic algorithm, analysis should be performed several times. In this article, the force method is employed for the analysis using subminimal cycle basis of their graph models. The advantage of employing this method lies in the fact that the matrices corresponding to particular and complementary solutions are formed once and independently of the mechanical properties of members. These matrices are then used several times in the process of the sequential analyses, increasing the speed of optimization. Copyright © 2004 John Wiley & Sons, Ltd.     

Voting Under Uncertainty: A Stochastic Framework for Analyzing Group Decision Making Problems

Water resources policy making often involves consideration of a broader scope of environmental, economic, and social issues. This inevitably complicates policy making since consensus among multiple stakeholders with different interests is needed to implement decisions. This work employs several practical and popular voting methods to solve a multi-stakeholder hydro-environmental management problem. Conventionally, voting methods or social choice rules have been applied for consensus development in small groups and elections. This work combines voting methods with a Monte-Carlo selection, in order to help with social choice making under uncertainty. This process is intended to aid decision-makers with understanding of the risks associated with potential decision alternatives. The Sacramento-San Joaquin Delta’s water export conflict is solved here as a benchmark problem to illustrate the proposed framework for social decision making and analysis under uncertainty.     

Monoclinic Zirconia Microfiltration Membranes: Preparation and Characterization

Microfiltration zirconia membranes were prepared by slip casting from two pure zirconia powders derived from different processing techniques. Powders had almost the same mean particle size but were different in surface area, particle size distribution and morphology. Rheology of zirconia slips was studied in order to prepare a well-dispersed slip suitable for slip casting. The powders showed different dispersibility in the preparation of slips by colloidal processing. The effect of sintering temperature and holding time on porosity, pore size distribution, phase composition, microhardness and microstructure of unsupported membranes are studied and discussed in relation to the membrane processing and properties of powders resulting from different processing routes. Pore size distribution of membranes reflected the differences in morphology of particles and the state of agglomeration in the green samples.Isothermal sintering at 1100°C resulted in some tetragonal phase retained at room temperature in the monoclinic structure. Cracking occurred in membranes sintered above 1150°C due to the volume change in phase transformation. Densification behavior, removal of porosity and the hardness property showed differences that are attributed to the differences in powder processing and characteristics of powders. Crackfree membranes can be prepared by sintering at 1100°C from both powders.     

Effect of deep cryogenic treatment on microstructure, creep and wear behaviors of AZ91 magnesium alloy

This paper focuses on the effect of deep cryogenic treatment (−196 °C) on microstructure and mechanical properties of AZ91 magnesium alloy. The execution of deep cryogenic treatment on samples changed the distribution of β precipitates. The tiny laminar β particles almost dissolved in the microstructure and the coarse divorced eutectic β phase penetrated into the matrix. This microstructural modification resulted in a significant improvement on mechanical properties of the alloy. The steady state creep rates were measured and it was found that the creep behavior of the alloy, which is dependent on the stability of the near grain boundary microstructure, was improved by the deep cryogenic treatment. For the AZ91 alloy, the results indicate a mixed mode of creep behavior, with some grain boundary effects contributing to the overall behavior. However for the deep cryogenic samples dislocation climb controlled creep is the dominant deformation mechanism. After the deep cryogenic treatment the sliding of grain boundaries was greatly suppressed due to morphological changes. As a result, the grain boundaries are less susceptible for grain boundary sliding at high temperatures. Dry sliding wear tests were also applied and the wear resistance of the alloy improved remarkably after deep cryogenic treatment.     

The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man

The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.     

Buckling load of symmetric plane frames using canonical forms and group theory

Summary The main objective of this article is to develop a methodology for an efficient calculation of buckling loads for symmetric frame structures in order to reduce the size of the eigensolution problems involved. This is achieved by decomposing a symmetric model into two submodels followed by their healing to obtain the factors of the model. The buckling load of the entire structure is then obtained by calculating the buckling loads of its factors. For each case, the results are approved using group theoretical approaches. The methods of the present paper provide a mathematical foundation and a logical means for dealing with symmetry, in place of looking for various boundary conditions to be imposed for symmetric structures, as in the traditional methods. Examples are provided to illustrate the simplicity and efficiency of the present method.