The minimized dead-end elimination criterion and its application to protein redesign in a hybrid scoring and search algorithm for computing partition functions over molecular ensembles

One of the main challenges for protein redesign is the efficient evaluation of a combinatorial number of candidate structures. The modeling of protein flexibility, typically by using a rotamer library of commonly-observed low-energy side-chain conformations, further increases the complexity of the redesign problem. A dominant algorithm for protein redesign is dead-end elimination (DEE), which prunes the majority of candidate conformations by eliminating rigid rotamers that provably are not part of the global minimum energy conformation (GMEC). The identified GMEC consists of rigid rotamers (i.e., rotamers that have not been energy-minimized) and is thus referred to as the rigid-GMEC. As a postprocessing step, the conformations that survive DEE may be energy-minimized. When energy minimization is performed after pruning with DEE, the combined protein design process becomes heuristic, and is no longer provably accurate: a conformation that is pruned using rigid-rotamer energies may subsequently minimize to a lower energy than the rigid-GMEC. That is, the rigid-GMEC and the conformation with the lowest energy among all energy-minimized conformations (the minimized-GMEC) are likely to be different. While the traditional DEE algorithm succeeds in not pruning rotamers that are part of the rigid-GMEC, it makes no guarantees regarding the identification of the minimized-GMEC. In this paper we derive a novel, provable, and efficient DEE-like algorithm, called minimized-DEE (MinDEE), that guarantees that rotamers belonging to the minimized-GMEC will not be pruned, while still pruning a combinatorial number of conformations. We show that MinDEE is useful not only in identifying the minimized-GMEC, but also as a filter in an ensemble-based scoring and search algorithm for protein redesign that exploits energy-minimized conformations. We compare our results both to our previous computational predictions of protein designs and to biological activity assays of predicted protein mutants. Our provable and efficient minimized-DEE algorithm is applicable in protein redesign, protein-ligand binding prediction, and computer-aided drug design.     

Elucidation of urinary metabolites of fluoxymesterone by liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry

The suitability of liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS) for the elucidation of fluoxymesterone metabolism has been evaluated. Electrospray ionization (ESI) and collision induced dissociation (CID) fragmentation in LC-MS/MS and electron impact spectra (EI) in GC-MS have been studied for fluoxymesterone and two commercially available metabolites. MS(n) experiments and accurate mass measurements performed by an ion-trap analyser and a QTOF instrument respectively have been used for the elucidation of the fragmentation pathway. The neutral loss scan of 20 Da (loss of HF) in LC-MS/MS has been applied for the selective detection of fluoxymesterone metabolites. In a positive fluoxymesterone doping control sample, 9 different analytes have been detected including the parent compound. Seven of these metabolites were also confirmed by GC-MS including 5 previously unreported metabolites. On the basis of the ionization, the CID fragmentation, the accurate mass of the product ions and the EI spectra of these analytes, a tentative elucidation as well as a proposal for the metabolic pathway of fluoxymesterone has been suggested. The presence of these compounds has also been confirmed by the analysis of five other positive fluoxymesterone urine samples.     

A definitive RNAA method for determination of selenium in biological samples: uncertainty evaluation and assessment of degree of accuracy

This article describes work on the development of a highly accurate RNAA method for determination of selenium in biological samples. The analytical post-irradiation procedure is based on a combination of cation-exchange and extraction chromatography with final selective and quantitative fixation of selenium on a column packed with 3,3′-diaminobenzidine (DAB) supported on Amberlite XAD4, followed by gamma-ray spectrometric measurement. The suitability and accuracy of the method was demonstrated by analysing CRMs with certified selenium content. The uncertainty budget for Se determination in standard reference material Peach Leaves NBS 1547 was estimated; the combined standard uncertainty was calculated as 1.7%. The described method fulfils all the criteria for definitive methods. It was subsequently used for determination of selenium in biological materials intended as new CRMs and proficiency test samples.     

Numerical analysis of the Gran methods. A comparative study

The paper concerns mainly the modified Gran methods, considered as extrapolative standard addition methods. Particularly, the approximation:

     

A frequency accurate spatial derivative finite difference approximation

We present a method for designing spatial derivative approximations that achieves a priori accuracy in the spatial frequency domain. We use a general, average value approximation with undetermined coefficients together with a set of constraints that ensure convergence and consistency to formulate a constrained optimal fitting problem. These constraints lead to a linear matrix formulation. We apply the method to the design of spatial approximations for simulating equations with wavelike solutions using both an explicit central difference approximation (which has no phase error) and an upwind design where the level of dissipation can be specified by the designer. © 1997 John Wiley & Sons, Inc. Numer Methods Partial Differential Eq 13: 549–560, 1997     

纳米材料用于放疗防护的研究进展

放射治疗是利用高能射线抑制癌细胞增殖的治疗方法, 已广泛用于恶性肿瘤的治疗. 但是, 高能射线不可避免地会对机体的正常组织造成损害, 产生放疗相关副作用. 尽管目前有一些小分子放疗防护药物已应用于临床或处于临床前研究, 但其较短的血液循环时间和较快的新陈代谢速度极大地削弱了其防护效果. 近20年来, 随着纳米技术在生物医学领域的飞速发展, 纳米放疗防护剂的出现为提高防护效果提供了新的选择. 通过合理地设计和开发纳米放疗防护剂, 有望解决现有小分子放疗防护药物的缺陷. 鉴于纳米放疗防护剂具有诸多优势, 本Review概述了纳米放疗防护材料的常见设计策略, 同时分析了放射诱导的常见疾病的致病机制和纳米放疗防护材料防治各种放射诱导疾病的研究现状. 最后, 还讨论了纳米材料用于放疗防护所面临的挑战和未来前景.     

三维空间二阶精度流体体积界面重构方法

给出三维空间网格模板含81个单元的最小二乘流体体积界面重构方法,并和Youngs方法及网格模板含125个单元的最小二乘流体体积界面重构方法进行比较.静态和动态的测试例子均表明:该方法能精确重构任意方向的平面界面,对C²光滑曲面它能达到二阶收敛精度.和网格模板含125个单元的最小二乘流体体积界面重构方法相比,在达到同样网格精度的条件下,减少了计算量,节省了计算时间,提高了计算效率.     

紫外域多纵模高光谱分辨率激光雷达探测气溶胶的技术实现和系统仿真

多纵模高光谱分辨率激光雷达是一种新型的高光谱分辨率激光雷达.本文在研究典型高功率Nd:YAG脉冲激光器的多纵模模式及其在大气中传输的气溶胶米散射和瑞利散射光谱的基础上,设计紫外域多纵模高光谱分辨率激光雷达系统,采用窄带干涉滤光片滤除太阳背景光的影响,设计可调谐马赫-曾德尔干涉仪,分离提取多纵模激光回波中的气溶胶米散射和瑞利散射光谱,并利用马赫-曾德尔干涉仪双通道输出的互补性原理,精确反演气溶胶光学参量.系统仿真结果表明,所设计的紫外域多纵模高光谱分辨率激光雷达能够实现10 km高度内的气溶胶光学参量精细探测.     

The comparison of the proton dose distribution calculated with the treatment planning system and measured with alanine detectors in the eye phantom irradiated under therapeutic conditions

The paper describes the applicability of commercially available alanine detectors produced by Synergy Health for verification of the dose distribution calculated by the treatment planning system (TPS) used in proton eye radiotherapy – Eclipse Ocular Proton Planning (EOPP) program, version 8.9.06, Varian Medical Systems. The TPS-planned dose distribution at selected points in the eye phantom is compared to the dose registered by alanine detectors at these points during a simulated therapeutic irradiation at the proton eye radiotherapy facility in the Henryk Niewodniczanski Institute of Nuclear Physics (IFJ PAN), Krakow, Poland. The phantom was irradiated to obtain, a typical for choroidal melanoma, fraction dose of 15 CGE (13,64 Gy) at the tumor location. The dose registered with alanine pellets located inside the simulated tumor volume demonstrates a good agreement with the TPS-planned dose. The typical for proton radiotherapy, steep dose fall-off outside the treated area is registered by the alanine pellets however, it is difficult to assess it quantitatively, because the dose related EPR signal is registered from the entire pellet volume.     

Out-of-field dose measurements in radiotherapy – An overview of activity of EURADOS Working Group 9: Radiation protection in medicine

This review of dosimetry for second cancer risk estimation introduces work carried out by Working Group 9 (WG9: Radiation Protection Dosimetry in Medicine) of the European Radiation Dosimetry Group (EURADOS). The work concentrates on the measurement of out-of-field doses in water phantoms using a variety of dosimeters to measure photon and neutron doses. These include optically stimulated luminescence (OSL), radiophotoluminescence (RPL) and thermoluminescence (TLD) dosimeters for photon dosimetry (together with ion chambers for reference measurements) and track etch and superheated emulsion detectors for neutron measurements. The motivation of WG 9 was to assess undue, non-target patient doses in radiotherapy and the related risks of second malignancy. Improvements in cancer treatment have increased survival times and thus increased incidence of second cancer may be expected in the future. In addition, increased whole body exposure may result from some developments in radiotherapy. This means that radiotherapy clinics will need to simulate their treatments in order to estimate and minimise doses to healthy tissues and organs. The proposed work is designed to generate a robust dataset of out-of-field dose measurements which can be used for the development and validation of dose algorithms.