Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

基于MM算法的脉冲串模糊函数设计方法

针对离散相位调制脉冲串信号的模糊函数优化问题,提出了一种基于MM算法的波形设计方法。MM算法是一种求解最优化问题的迭代算法,通过重复“构造辅助函数-求解辅助函数最优值”的过程,可以逐步逼近原问题的全局最优解。本文首先将脉冲串模糊函数设计问题建模为带约束四次型最优化问题,然后根据泰勒展开,给出了位于原函数上界的辅助函数的构造方法。其中,辅助函数的形式为带约束二次型最优化问题,可通过交替方向乘子法（ADMM）求解。最后通过计算机仿真说明了该方法的有效性。     

A water-assisted nucleophilic mechanism utilized by BphD,the meta-cleavage product hydrolase in biphenyl degradation

As members of the α/β-hydrolase superfamily, Meta-cleavage product (MCP) hydrolases generally utilize a Ser-His-Asp catalytic triad to hydrolyze the cleavage of CC bond during the aerobic catabolism of aromatic compounds by bacteria. BphD is one kind of MCP hydrolase that catalyzes the hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) to 2-hydroxypenta-2,4-dienoic acid (HPD) and benzoate. In this article, a combined quantum mechanics and molecule mechanics (QM/MM) approach has been employed to explore the reaction mechanism of BphD from Burkholderia xenovorans LB400. On the basis of the recently resolved crystal structures, three computational models have been constructed. Our calculation results reveal that BphD utilizes a water-assisted nucleophilic mechanism, which contains acylation and deacylation stages. In acylation reaction, an active site water molecule assists the proton transfer from Ser112 to the carbanion intermediate (substrate) by forming hydrogen bonds with Ser112 and His265, and this proton transfer is in concert with the nucleophilic attack of deprotonated Ser112 on the C6-carbonyl of substrate to form the acylated intermediate. In deacylation, the Asp237-His265 dyad acts as a general base to activate the hydrolytic water, whose nucleophilic attack leads to the collapses of acyl-enzyme intermediate. The acylation and deacylation process correspond to the highest energy barriers of 21.0 and 23.9 kcal/mol, respectively. During the catalytic reaction, the active site water and Asp237-His265 dyad play an important role for each elementary steps.     

基于MM430变频器的集中供热系统的控制

采用变频调速技术,调节集中供热系统中换热站的循环水流量以及补水定压,运行结果表明,系统达到了理想的控制效果,运行可靠,实现了节能降耗。     

马钢异形坯连铸火焰切割机改造

叙述了马钢异形坯火焰切割系统升级改造涉及更新设备的新特性、在系统中的作用以及编程调试中的经验。     

稳健MM估计在扩散张量成像中的应用

在扩散加权图像中存在由热噪声产生的高斯分布偏差和生理噪声产生的异常点,最小二乘(LS)法对于高斯分布偏差具有较好的估算效果,但是对异常点不稳健。为此,采用稳健MM估计方法对扩散张量成像(DTI)数据进行张量估算,将高失效点算法的估计结果作为初始估计值,进行两步M估计。模拟数据与真实数据的实验结果表明,该估计方法具有较好的稳健性,并能有效估算扩散张量。     

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole N^τ atom, and the produced N-methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of N-methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and N-methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of N-methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.     

基于小波基稀疏信号特征提取的轴承故障诊断

轴承弱故障振动信号中的瞬态成分极易被强背景噪声湮没而无法及时检测,结合稀疏表示原理提出一种基于小波基的稀疏信号特征提取方法,从而实现信号中瞬态特征成分的提取。通过构建原始信号瞬态成分稀疏表示模型,对原始信号采用相关滤波法获取最优小波原子,并构建最优冗余小波基底,实现小波基与信号故障特征的最优匹配;设计二次严格凸函数并运用MM(Majorization Minimization)算法求解模型中的目标函数,将信号中的瞬态冲击成分转化为稀疏表示系数,实现强背景噪声下弱特征的有效提取。仿真信号及轴承微弱故障试验验证了该方法能有效地检测和提取强背景噪声下的微弱瞬态成分。     

Flexible Expectile Regression in Reproducing Kernel Hilbert Spaces

Expectile, first introduced by Newey and Powell in 1987 Newey, W. K., and Powell, J. L. (1987), “Asymmetric Least Squares Estimation and Testing,” Econometrica, 55, 819–847.[Crossref], [Web of Science ®] , [Google Scholar] in the econometrics literature, has recently become increasingly popular in risk management and capital allocation for financial institutions due to its desirable properties such as coherence and elicitability. The current standard tool for expectile regression analysis is the multiple linear expectile regression proposed by Newey and Powell in 1987 Newey, W. K., and Powell, J. L. (1987), “Asymmetric Least Squares Estimation and Testing,” Econometrica, 55, 819–847.[Crossref], [Web of Science ®] , [Google Scholar]. The growing applications of expectile regression motivate us to develop a much more flexible nonparametric multiple expectile regression in a reproducing kernel Hilbert space. The resulting estimator is called KERE, which has multiple advantages over the classical multiple linear expectile regression by incorporating nonlinearity, nonadditivity, and complex interactions in the final estimator. The kernel learning theory of KERE is established. We develop an efficient algorithm inspired by majorization-minimization principle for solving the entire solution path of KERE. It is shown that the algorithm converges at least at a linear rate. Extensive simulations are conducted to show the very competitive finite sample performance of KERE. We further demonstrate the application of KERE by using personal computer price data. Supplementary materials for this article are available online.     

基于LIN总线的汽车后视镜控制模块设计

以MC9S12DG128为主控单元、MM908E622为后视镜单元,采用单主多从的总线控制方式,设计了一种基于LIN总线的汽车后视镜控制模块。主控单元以单片机MC9S12DG128为核心,通过LIN收发器MC33661实现对总线数据的收发,同时将液晶触摸信号转换为LIN指令以达到对后视镜单元的整体控制。后视镜单元以MM908E622作为从单元控制器,内置LIN收发器和电机驱动电路,具有优异的调控能力,适用于控制汽车高端后视镜。设计中体现了汽车车身电子的智能化和网络化,在汽车工业中有较高的应用价值。