Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.     

High-Q microresonators on 4H-silicon-carbide-oninsulator platform for nonlinear photonics

The realization of high-quality (Q) resonators regardless of the underpinning material platforms has been a ceaseless pursuit, because the high-Q resonators pro...     

圆高强钢管UHPC梁抗弯性能研究

高强钢管高强混凝土的应用越来越广泛,但目前对于其徐变特性的试验研究较少。该文对15根不同含钢率的高强钢管高强混凝土轴压短柱进行了365 d的收缩和徐变测试,并将试验结果与常用的徐变预测模型MC90、ACI209和MC2010等进行了对比。试验结果表明：高强钢管高强混凝土的徐变系数远小于素混凝土,当加载365 d后,素混凝土的徐变系数是高强钢管高强混凝土的2倍以上;含钢率对钢管混凝土试件的徐变有一定影响,徐变系数随着含钢率的增大而减小。在对比的3种常用徐变预测模型中,MC2010模型的徐变预测结果与试验结果吻合最好,可推荐用于高强钢管高强混凝土的收缩和徐变效应计算。此外,还将高强钢管高强混凝土与普通钢管混凝土的徐变试验结果进行了对比,结果表明,钢管混凝土的徐变随着核心混凝抗压强度的增加而减小。研究成果可为高强钢管高强混凝土轴心受压构件在正常使用阶段的徐变预测及徐变变形控制提供依据。     

汽轮发电机转子匝间短路故障的有限元分析

以300 MW汽轮发电机为例,在建立其二维有限元数值模型基础上,对瞬变电磁场有限元分析过程进行了分析与推导。同时阐述了汽轮发电机在不同工况下磁场分布情况,以及转子绕组发生不同匝间短路故障时通过探测线圈波形进行计算与分析。     

大容量机组圆形烟道设计特点

针对大容量机组的烟道形式问题,结合顺德德胜电厂的烟道设计,对比了圆形和矩形两种烟道的特点和用料量,介绍了圆烟道的设计参数及加固肋设置情况,可供设计人员参考。     

Application of electrolyzed functional water on producing mung bean sprouts

Electrolyzed functional water possesses a wide variety of antimicrobial activities. Electrolyzed functional water, which used to take place of tap water in producing mung bean sprouts, was studied in this paper. The results showed that electrolyzed water can not only reduce the quantity of microorganism on the surface of mung bean sprouts, but also promote the growth of sprouts. Further research showed that electrolyte leakage rate of mung bean soaked in electrolyzed water was the lowest, while the catalase’s activity of mung bean soaked in electrolyzed water was the highest. All of these contribute to the high activity of mung bean.     

A Novel Method for Calculation of Eigenmodes of Gyrotron Resonators

A new method for calculating the eigenmodes of gyrotron resonators is presented. With this method, the resonant frequency, Q-factor and field profiles of the eigenmodes are determined through finding the minimum value of a function of two variables, namely the resonant frequency and the Q-factor. Compared with the traditional calculation method, the new method predicts a significantly higher Q-factor of the eigenmodes.     

Effect of Electromagnetic Stirring on Solidification Structure of Incoloy 825 Superalloy

Superalloy Inconel 825 has been extensively used in chemical industry and transportation industry due to its excellent creep rupture strength and prominent corrosion resistant properties under various circumstances.However,the mass production of this alloy by continuous casting method is restricted because of the serious macrosegregation and coarse grains in the billet.In current,a linear travelling magnetic field was introduced in the solidification process of Inconel 825 with the aim of changing the fmal microstructure by electromagnetic stirring(EMS)force.The results have indicated that the dendrite structure of Incoloy 825 is refined obviously with applying EMS,and the mechanism of dendrite refinement is presumed to the introduction of a forced convection within the solidifying melt.Moreover,The number and the size of precipitated phases including carbide and nitride were found to be significantly reduced with EMS,a phenomenon on the reduction of interdendritic segregation of titanium and molybdenum was simultaneously observed,which demonstrated that he release of interdendritic segregation by EMS inhibits the growth dynamic of carbide and nitride from the melt.     

A DCT-based multipoint video composition scheme

针对视频会议应用中传统的像素域多路视频混合方法存在运算复杂度高、画面质量损伤的问题,提出了一种基于压缩域的替代方法,并给出了详细的码流映射算法步骤.该方法按照混合后多画面的空间位置关系,通过对输入的多路码流中宏块编码次序的重排和语法元素的映射,在码流级别将多路视频合成到同一画面中,并采取提前量化策略消除可能出现的二次量化失真,从而可兼具处理速度快和高保真的双重优点.以H.263为例验证了此方法的有效性.实验结果表明,与编解码器级联的方法相比,此方法的峰值信噪比(PSNR)平均提高2dB,运算效率提高百倍以上.此研究工作有望为正在制定的国际视频编码标准H.265贡献一种视频混合解决方案.