Behavior and Performance of Interactive Multi-Player Game Servers

With the recent explosion in deployment of services to large numbers of customers over the Internet and in global services in general, issues related to the architecture of scalable servers are becoming increasingly important. However, our understanding of these types of applications is currently limited, especially on how well they scale to support large numbers of users. One such, novel, commercial class of applications, are interactive, multi-player game servers. Multi-player games are both an important class of commercial applications (in the entertainment industry) and they can be valuable in understanding the architectural requirements of scalable services. They impose requirements on system performance, scalability, and availability, stressing multiple aspects of the system architecture (e.g., compute cycles and network I/O). Recently there has been a lot of interest on client side issues with respect to games. However, there has beenlittle or no work on the server side. In this paper we use a commercial game server to gain insight in this class of applications and the requirements they impose on modern architectures. We find that: (1) In terms of the benchmarking methodology, interactive game servers are very different from scientific workloads. We propose a methodology that deals with the related issues in benchmarking this class of applications. Our methodology bears many similarities with methodologies used in benchmarking online transaction processing (OLTP) systems. (2) Current, sequential game servers can support at most up to a few tens of users (60–100) on existing processors. (3) The bottleneck in the server is both game-related as well as network-related processing (about 50–50). (4) Network bandwidth requirements are not an important issue for the numbers of players we are interested in. (5) The processor achieves a surprisingly low IPC of 0.416.     

Side chain substitution benchmark for peptide/MHC interaction

The prediction of T-cell epitopes is an essential part in virtual immunology. Apart from sequence-based techniques, which achieve good results but fail to give insight into the binding behavior of a certain peptide binding to a major histocompatibility complex, structure-based approaches are another important technique. An essential step is the correct placement of the side chains for a given peptide in cases where no experimental data for the structure are available. To our knowledge, no benchmark for side chain substitution in the area of HLA has been reported in the literature. Here, we present a comparison of five different tools (SCWRL, SCATD, SPDBV, SCit, IRECS) applicable for side chain substitution. Each tool is tested on 29 different HLA-A2 structures with experimentally known side chain positions. Parts of the benchmark are correctness, reliability, runtime, and usability. For validation, the root mean square deviations between X-ray structures and predicted structures are used. All tools show different strengths and weaknesses.     

基于Wnt信号通路探讨氟砷混合暴露的生物暴露限值

慢性氟砷联合中毒是全世界的一个重大公共卫生问题,影响着数千万人.目前该病病因清楚,但发病机制未明,且无特效治疗方法,因此,早期预防尤为重要.生物暴露限值旨在探讨外源化学物引起机体有害效应的最高容许浓度.为了探讨氟砷混合暴露的生物暴露限值(BEL),本研究通过比较对照及氟砷联合暴露地区环境介质中的氟、砷含量,分析氟、砷与Wnt信号通路关键蛋白的剂量-效应及剂量-反应关系,利用基准剂量法估算氟砷混合暴露的生物暴露限值.结果表明: 氟砷联合暴露地区煤、黏土、室内空气、室外空气、辣椒、大米中的氟含量以及煤、黏土、室外空气、辣椒、大米中的砷含量均高于对照;随着氟、砷暴露水平的增加,糖原合酶激酶3β(GSK3β)、β-连环蛋白(β-catenin)含量以及Wnt/β连环蛋白信号通路拮抗蛋白(DKK1)、GSK3β、β-catenin的异常检出率逐渐增加,但DKK1含量显著降低;基于Wnt信号通路,氟砷混合暴露的生物暴露限值UF为0.52 mg·g^-1Cr,UAs为6.59 μg·g^-1Cr.本研究对于早期预防氟砷联合中毒引起的机体损伤具有重要的指导意义.     

基于水源涵养参照系的中国生态系统水源涵养功能优劣评估

为解决水源涵养优劣评估结果空间可比性差的问题,在拟合1990—2018年中国生态系统水源涵养动态数据基础上,构建基于参照系的水源涵养功能优劣等级评估方法体系,从全国和分区尺度揭示中国生态系统水源涵养功能优劣格局与演变规律,阐明该方法的优越性。结果表明：(1)2015年中国全国生态系统水源涵养功能以差级别占主导,约占总面积的44.8%,主要分布于西北、青藏高原、华北平原和东北平原。1990—2018年中国生态系统水源涵养功能中等级面积极显著降低,差等级面积显著增加,其余类型呈波动变化。(2)各气候区生态系统水源涵养优劣等级构成因气候、生态系统构成等差异而不同,一般为气候区愈湿润,其优良等级比重愈高。1990—2018年,共有10个气候区的优、良、中、低或差等级面积发生了显著变化,主要为优、良、中等级以显著降低为主,差等级全显著增加。(3)与其他方法相比,基于参照系的生态系统水源涵养功能优劣评估法因引入分区分类评估思想,评估结果更科学,空间可比性显著提高。     

Testing the use of best professional judgment to create biological benchmarks for habitat assessment of wetlands and oak savannas in northwestern Indiana

The Tolleston Strandplain at the southern end of Lake Michigan offers a unique “dune and swale” topography supporting oak savannas on the dunes and a mosaic of wetland communities in the swales. Following years of human degradation, sites in this area are now being restored. In this effort, assessments of vegetative quality have been necessary for proper management decisions. However, it is poorly understood what indices best reflect the vegetative quality of these oak savannas and wetlands. A potential method for determining the best indices for these community types is to use metric benchmarks that employ expert best professional judgment (BPJ). In order to confirm the viability and consistency of BPJ for creating benchmarks, Kappa analysis was used to determine the level of agreement among seven experts. They placed each of 63 transects from this unique landscape into one of four quality categories: (1) “good to very good,” (2) “medium,” (3) “poor,” and (4) “very poor.” While experts had good agreement about the quality of severely degraded riverine wetlands, they had fair agreement when assessing the swales, and poor agreement when assessing the oak savannas. Using discriminant analysis, follow-up questions, and a comparison of each expert's quality categories with remnant oak savanna metrics, varying perspectives of quality also were discovered which may have influenced the experts’ assessments of the sites. Therefore, BPJ must be used with caution when creating metric benchmarks.     

An introduction to biomolecular simulations and docking

The biomolecules in and around a living cell – proteins, nucleic acids, lipids and carbohydrates – continuously sample myriad conformational states that are thermally accessible at physiological temperatures. Simultaneously, a given biomolecule also samples (and is sampled by) a rapidly fluctuating local environment comprising other biopolymers, small molecules, water, ions, etc. that diffuse to within a few nanometres, leading to inter-molecular contacts that stitch together large supramolecular assemblies. Indeed, all biological systems can be viewed as dynamic networks of molecular interactions. As a complement to experimentation, molecular simulation offers a uniquely powerful approach to analyse biomolecular structure, mechanism and dynamics; this is possible because the molecular contacts that define a complicated biomolecular system are governed by the same physical principles (forces and energetics) that characterise individual small molecules, and these simpler systems are relatively well-understood. With modern algorithms and computing capabilities, simulations are now an indispensable tool for examining biomolecular assemblies in atomic detail, from the conformational motion in an individual protein to the diffusional dynamics and inter-molecular collisions in the early stages of formation of cellular-scale assemblies such as the ribosome. This text introduces the physicochemical foundations of molecular simulations and docking, largely from the perspective of biomolecular interactions.     

Flexible protein docking refinement using pose-dependent normal mode analysis

Modeling conformational changes in protein docking calculations is challenging. To make the calculations tractable, most current docking algorithms typically treat proteins as rigid bodies and use soft scoring functions that implicitly accommodate some degree of flexibility. Alternatively, ensembles of structures generated from molecular dynamics (MD) may be cross-docked. However, such combinatorial approaches can produce many thousands or even millions of docking poses, and require fast and sensitive scoring functions to distinguish them. Here, we present a novel approach called "EigenHex," which is based on normal mode analyses (NMAs) of a simple elastic network model of protein flexibility. We initially assume that the proteins to be docked are rigid, and we begin by performing conventional soft docking using the Hex polar Fourier correlation algorithm. We then apply a pose-dependent NMA to each of the top 1000 rigid body docking solutions, and we sample and re-score multiple perturbed docking conformations generated from linear combinations of up to 20 eigenvectors using a multi-threaded particle swarm optimization algorithm. When applied to the 63 "rigid body" targets of the Protein Docking Benchmark version 2.0, our results show that sampling and re-scoring from just one to three eigenvectors gives a modest but consistent improvement for these targets. Thus, pose-dependent NMA avoids the need to sample multiple eigenvectors and it offers a promising alternative to combinatorial cross-docking.     

Dose-response for retinoic acid-induced forelimb malformations and cleft palate: a comparison of computerized image analysis and visual inspection

BACKGROUND: The objectives of this study were to (1) compare two techniques (computerized image analysis and visual morphological evaluation) for the assessment of fetal forelimb malformations and (2) increase the robustness of the dose-response curve for forelimb and cleft palate malformations resulting from all-trans retinoic acid (RA) exposure in GD 11 mice. METHODS: Pregnant CD-1 mice were administered a single oral dose of all-trans RA (0, 2.5, 10, 30, 60, or 100 mg/kg) on GD 11. GD 18 fetuses were examined for malformations using visual morphological scoring and computerized image analysis. RESULTS: Dose-dependent changes occurred in the size and shape of the humerus, radius, and ulna based on both assessment methodologies. The most sensitive indicators for the lowest effect level (10 mg/kg) on forelimbs were roundness, a shape measurement determined by image analysis, and visual morphological scoring. For all other bone measurements (proximal and distal width, area, length, and perimeter), the lowest effect level was 30 mg/kg. The maximum effect for limb defects and total malformed fetuses was seen at 60 mg/kg and higher. Incidence of cleft palate increased over the entire range of administered doses reaching a maximum of 74% (100 mg/kg). CONCLUSIONS: Overall, results indicate that computerized image analysis was no more sensitive in detecting changes in the humerus, radius, and ulna than gross visual examination. Dose-response modeling of developmental endpoints yielded comparable benchmark dose levels for long bones and cleft palate that ranged from 0.24 to 7.6 mg/kg all-trans RA. Birth Defects Res B 71:289-295, 2004. Copyright 2004 Wiley-Liss, Inc.     

Benchmarking a computational design method for the incorporation of metal ion‐binding sites at symmetric protein interfaces

The design of novel metal‐ion binding sites along symmetric axes in protein oligomers could provide new avenues for metalloenzyme design, construction of protein‐based nanomaterials and novel ion transport systems. Here, we describe a computational design method, symmetric protein recursive ion‐cofactor sampling (SyPRIS), for locating constellations of backbone positions within oligomeric protein structures that are capable of supporting desired symmetrically coordinated metal ion(s) chelated by sidechains (chelant model). Using SyPRIS on a curated benchmark set of protein structures with symmetric metal binding sites, we found high recovery of native metal coordinating rotamers: in 65 of the 67 (97.0%) cases, native rotamers featured in the best scoring model while in the remaining cases native rotamers were found within the top three scoring models. In a second test, chelant models were crossmatched against protein structures with identical cyclic symmetry. In addition to recovering all native placements, 10.4% (8939/86013) of the non‐native placements, had acceptable geometric compatibility scores. Discrimination between native and non‐native metal site placements was further enhanced upon constrained energy minimization using the Rosetta energy function. Upon sequence design of the surrounding first‐shell residues, we found further stabilization of native placements and a small but significant (1.7%) number of non‐native placement‐based sites with favorable Rosetta energies, indicating their designability in existing protein interfaces. The generality of the SyPRIS approach allows design of novel symmetric metal sites including with non‐natural amino acid sidechains, and should enable the predictive incorporation of a variety of metal‐containing cofactors at symmetric protein interfaces.