Improving (Q)SAR predictions by examining bias in the selection of compounds for experimental testing

ABSTRACT

Existing data on structures and biological activities are limited and distributed unevenly across distinct molecular targets and chemical compounds. The question arises if these data represent an unbiased sample of the general population of chemical-biological interactions. To answer this question, we analyzed ChEMBL data for 87,583 molecules tested against 919 protein targets using supervised and unsupervised approaches. Hierarchical clustering of the Murcko frameworks generated using Chemistry Development Toolkit showed that the available data form a big diffuse cloud without apparent structure. In contrast hereto, PASS-based classifiers allowed prediction whether the compound had been tested against the particular molecular target, despite whether it was active or not. Thus, one may conclude that the selection of chemical compounds for testing against specific targets is biased, probably due to the influence of prior knowledge. We assessed the possibility to improve (Q)SAR predictions using this fact: PASS prediction of the interaction with the particular target for compounds predicted as tested against the target has significantly higher accuracy than for those predicted as untested (average ROC AUC are about 0.87 and 0.75, respectively). Thus, considering the existing bias in the data of the training set may increase the performance of virtual screening.     

Linear stability of WENO schemes coupled with explicit Runge–Kutta schemes

This paper focuses on the results of the linear stability analysis of the finite‐difference weighted essentially non‐oscillatory (WENO) schemes with optimal weights. The standard WENO schemes between the third and 11th order, the order‐optimised WENO schemes of the sixth and eighth order and the bandwidth‐optimised WENO schemes of the third and fourth order are considered. Several explicit Runge–Kutta schemes including the recently published strong stability‐preserving explicit Runge–Kutta schemes are considered for time discretisation. The stability limits as well as dissipation and dispersion properties dependent on the Courant–Friedrichs–Lewy number are presented for a hyperbolic model equation. The different combinations of space and time discretisation schemes are compared in terms of their accuracy and efficiency. For a parabolic model equation, the viscous term is discretised with high‐order central differences. The stability limits for the parabolic problem are presented as well. Numerical results of linear test cases are shown. Copyright © 2011 John Wiley & Sons, Ltd.     

Higher-order time integration with a local Lax–Wendroff procedure for a central scheme on an overlapping grid

We have implemented a high-order Lax–Wendroff type time integration for a central scheme on an overlapping grid for conservation law problems. Using a local iterative approach presented by Dumbser et al. (JCP, 2008) [12], we extend a local high-order spatial reconstruction on each cell to a local higher-order space–time polynomial on the cell. We rewrite the central scheme in a fully discrete form to avoid volume integration in the space–time domain. The fluxes at cell interfaces are calculated directly via integrating a higher-order space–time reconstruction of the flux. We compare this approach with the corresponding multi-stage Runge–Kutta time integration (RK). Numerical results show that the new time integration is more cost-effective.     

Analysis of a meshless solver for high Reynolds number flow

In this paper, the extension of an upwind least‐square based meshless solver to high Reynolds number flow is explored, and the properties of the meshless solver are analyzed both theoretically and numerically. Existing works have verified the meshless solver mostly with inviscid flows and low Reynolds number flows, and in this work, we are interested in the behavior of the meshless solver for high Reynolds number flow, especially in the near‐wall region. With both theoretical and numerical analysis, the effects of two parameters on the meshless solver are identified. The first one is the misalignment effect caused by the significantly skewed supporting points, and it is found that the meshless solver still yields accurate prediction. It is a very interesting property and is opposite to the median‐dual control volume based vertex‐centered finite volume method, which is known to give degraded result with stretched triangular/tetrahedral cells in the near‐wall region. The second parameter is the curvature, and according to theoretical analysis, it is found in the region with both large aspect ratio and curvature, and the streamwise residual is less affected; however, the wall‐normal counterpart suffers from accuracy degradation. In this paper, an improved method that uses a meshless solver for the streamwise residual and finite difference for wall‐normal residual is developed. This method is proved to be less sensitive to the curvature and provides improved accuracy. This work presents an understanding of the meshless solver for high Reynolds number flow computation, and the analysis in this paper is verified with a series of numerical experiments. Copyright © 2012 John Wiley & Sons, Ltd.     

Halbwertszeiten von 135 Radionukliden

Für 135 Radionuklide werden in der Literatur veröffentlichte Werte der Halbwertszeit mit Angabe von 200 Zitaten zusammengestellt. Dabei sind vorzugsweise die neuesten und zuverlässigsten Werte – maximal 4 je Nuklid – berücksichtigt. Für jades Nuklid wird ferner ein wahrscheinlichster Wert der Halbwertszeit angegeben. Die Anwendung dieses Wertes wird insbesondere auch bei der Umrechnung von Aktivitätsangaben der vom ASMW bereitgestellten Normallösungen radioaktiver Nuklide empfohlen.     

Empirical Likelihood Estimation for the Two-Sample Mean under Density Ratio Models Using Auxiliary Information

Auxiliary population information is often available in finite population inference problems, and the empirical likelihood (EL) approach has been demonstrated to be flexible and useful for such problems. The present paper concerns EL when interest centers on inference for the mean of the baseline distribution under two-sample density ratio models. Although dual EL is a convenient technical tool since it has the same maximum point and maximum likelihood as DRM-based EL, it can not combine such auxiliary information into the likelihood conveniently and may have loss of efficiency. By contrast, the classical EL approach of Qin and Lawless\ucite{21} does not have this problem and incorporate seamlessly auxiliary information. Based on the EL using auxiliary information and the dual EL methods, we construct both point and interval estimations and make a careful comparison. Though the point estimation efficiency gain obtained by the former is not noticeable, we find that they may have different performances in interval estimation. In terms of coverage accuracy, the two intervals are comparable for not or moderate skewed populations, and the EL interval using auxiliary information can be much superior for severely skewed populations.     

富里叶级数的收敛速度

对正弦和余弦富立叶级数,通过合并相邻同号项,使其重排成交错级数.讨论了重排形成的交错级数的敛散性.指出根据自变量x的不同取值,该交错级数可能是单调递减或周期递减的级数.按照莱布尼茨判定法提出了不同精度要求的级数项数的计算公式.选取一到三阶收敛的富立叶级数计算了不同比值精度及差值精度要求的级数项数.计算表明,在x的取值为2π的等分点时,富立叶级数的部分和随项数的增加单调地逼近其收敛值.在x的取值为其它点时,富立叶级数的部分和随项数的增加围绕收敛值上下变动,周期地逼近其收敛值.低收敛阶富立叶级数的收敛速度较慢.要达到0.01%的精度,一收敛阶富立叶级数需要数万项,二收敛阶富立叶级数也需要数百项.在不同计算点处,要达到相同的计算精度,需要的级数项数差别较大.     

A high‐order element based adaptive mesh refinement strategy for three‐dimensional unstructured grid

Adaptive mesh refinement (AMR) shows attractive properties in automatically refining the flow region of interest, and with AMR, better prediction can be obtained with much less labor work and cost compared to manually remeshing or the global mesh refinement. Cartesian AMR is well established; however, AMR on hybrid unstructured mesh, which is heavily used in the high‐Reynolds number flow simulation, is less matured and existing methods may result in degraded mesh quality, which mostly happens in the boundary layer or near the sharp geometric features. User intervention or additional constraints, such as freezing all boundary layer elements or refining the whole boundary layer, are required to assist the refinement process. In this work, a novel AMR strategy is developed to handle existing difficulties. In the new method, high‐order unstructured elements are first generated based on the baseline mesh; then the refinement is conducted in the parametric space; at last, the mesh suitable for the solver is output. Generating refined elements in the parametric space with high‐order elements is the key of this method and this helps to guarantee both the accuracy and robustness. With the current method, 3‐dimensional hybrid unstructured mesh of huge size and complex geometry can be automatically refined, without user intervention nor additional constraints. With test cases including the 2‐dimensional airfoil and 3‐dimensional full aircraft, the current AMR method proves to be accurate, simple, and robust.     

锥孔滚压头的开发设计

为了解决泥浆泵液力端泵头1：6锥孔表面加工精度不高,在使用中出现锥孔表面剌蚀而报废的问题,本文介绍了一种性价比较高,简单易行,安全可靠的锥孔滚压工艺方法,通过该工艺方法的实施,提高了锥孔表面加工精度和硬度,达到了设计要求,保证了泵头质量,延长了泵头的使用寿命,减少了阀及阀组件更换频次,大大的降低了运行成本,为用户安全生产提供了优质的产品保障。     

光电成像导引察打一体无人机命中精度计算分析

针对采用电视或红外成像导引方式的自毁式侦察打击一体化无人机,在落点偏差正态分布假定下,根据相对目标的以圆概率误差（CEP）表示的命中精度的定义,忽略无人机滚转影响,对CEP与落点系统偏差和标准偏差的关系进行数学描述。结合系统工作原理和俯冲攻击流程,建立CEP和基于视频图像的跟踪导引系统和随机角误差及导引盲距（即最短有效导引距离）间的数学方程,并利用Mathcard数学软件举例计算分析。此方法可以用于依据给定CEP和导引盲距分解确定跟踪导引角误差参数,也可基于导引盲距和跟踪导引角误差预测CEP指标是否能够实现。