Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Flow physics of normal and abnormal bioprosthetic aortic valves

Flow physics of transvalvular flows in the aorta with bioprosthetic valves are investigated using computational modelling. For the efficient simulations of flow-structure-interaction in transvalvular flows, a simplified, reduced degree of freedom valve model is employed with a sharp interface immersed boundary based incompressible flow solver. Simulations are performed for normal as well as abnormal valves with reduced leaflet motion that models the effect of early leaflet thrombosis. The structure of the aortic jet and the hemodynamic stresses on the aortic wall are analysed to understand the hemodynamic impacts and possible long-term clinical implications of sub-clinical, reduced leaflet motion. The simulation results have shown that the reduced leaflet motion tilts the direction of aortic jet and generates stronger flow separation and re-attachment on the aortic wall downstream from the reduced motion leaflets. The modified flow pattern increases the wall pressure fluctuation and average wall shear stress on the downstream aortic wall, and results in the asymmetric oscillatory shear index distributions, which may have long-term clinical implications such as aortic wall damage and remodelling.     

Photoelastic stress freezing analysis of total shoulder replacement systems

Photoelastic stress freezing analyses in the orthopaedic literature have, in the past, been limited to studies where bone-on-bone, bone-on-metal or ultra-high molecular weight polyethylene (UHMWPE)-on-metal constructs are modeled. In these cases photoelastic plastics are used to simulate either bone or UHMWPE as it interacts with a metal implant. In joints such as the shoulder, a UHMWPE component is often cemented directly into the scapula's glenoid concavity using polymethylmethacrylate (PMMA). While a photoelastic material can be used to simulate bone with proper load scaling, UHMWPE and PMMA have very different mechanical properties at elevated stress freezing temperatures as compared within vivo body temperature. In this study, materials were identified such that proper scaling of elastic properties at elevated temperatures was utilized to simulate the metal-UHMWPE-PMMA-bone construct. Stresses on orthogonal planes throughout the glenoid were compared for two different UHMWPE component anchoring geometries (keeled and pegged). High stresses were found at the neck of the glenoid and also at the component-bone interface beneath simulated PMMA inclusions.     

Optimal inspection and perfect repair

Models are developed for decision making about monitoring andmaintenance of systems whose performance through time is describedby a general stochastic process. The system is monitored andpreventive and corrective maintenance actions are carried outin response to the observed system state. The decision processis simplified by using the maximum process as a decision variable.The models developed generalize age replacement models and othersimple maintenance strategies. The approach can deal with failuresthat prevent the system functioning further, and also failuresthat are defined by regulation or economic considerations. Attentionis restricted to perfect repair and inspection, but the structureprovides the framework for further developments.     

Highly Effective Phenol Hydroxylation over Ti-ZSM-5 Catalyst Prepared Using B-ZSM-5 as Precursor 以B-ZSM-5为母体合成Ti-ZSM-5高效苯酚羟基化催化剂

 以改进方法合成的B-ZSM-5为母体,采用气固相同晶取代法合成了较小晶粒的Ti-ZSM-5分子筛. 考察了样品的物化性能和催化苯酚羟基化性能. 结果表明: 所合成的小晶粒Ti-ZSM-5具有较高的结晶度,尺寸为100~200 nm,且不含锐钛矿型TiO2,对苯酚羟基化反应的催化性能优异.     

Statistical replacement for systems with delta-correlated fluctuations

Nonlinear systems with stochastic parameters are approximated by simpler systems using a method that we call statistical replacement. This method is an extension of the previously developed AGREE which was restricted to systems with additive fluctuations. Statistical replacement incorporates the distinctions between globally stable thermodynamically closed systems and thermodynamically open systems that can be unstable.     

带缓冲串行生产系统预防性维护建模及运行参数优化研究

为了保证串行生产系统的产能和提高系统可靠性,提出了带缓冲区的串行生产系统预防性维护决策模型。首先,分析了生产线各执行单元可靠性和运行参数之间的关系,建立了考虑执行单元运行参数和缓冲库存的维护模型。在此基础上,结合串行生产线的特点,建立综合考虑维护成本、有效运行速度和缓冲库存的多目标优化函数。最后,构建启发式算法求解目标函数,并以串行包装生产线为例进行仿真实验分析,结果表明本文所建模型是有效且实用的。     

Molecular Replacement Studies of Cucurmosin from Cucurbita Moschata:Structure Homology with Trichosanthin

1 INTRODUCTION Many plants contain proteins that are capable of inactivating ribosomes and therefore are called ribosome-inactivating proteins or RIPs[1]. RIPs are RNA N-glycosidases that inactivate ribosomes through a site-specific deadenylation of the large ribosomal RNA[2, 3]. RIPs are also capable of inactivating many nonribosomal nucleic acid substrates and can be considered as polynucleotide: adenosine glycosidases[4～6]. There are two types of RIPs: type I, single chain pr…     

单层分散型Pd/Ni双金属催化剂的制备及其催化加氢性能

通过置换反应制备了Pd/Ni双金属催化剂,利用X射线衍射、CO化学吸附和吸附H2的程序升温脱附对其进行了表征,并测定了该催化剂对环己烯、苯乙烯和丙酮气相加氢反应的催化性能.结果发现,在这种催化剂中Pd原子单层分散在金属Ni的表面,因而该催化剂表现出比浸渍法制备的相同Pd含量的Pd/Ni-im和Pd/-γAl2O3催化剂更高的催化加氢活性.