Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.     

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.     

软件定义网络下两阶段大象流识别算法

目的 针对数据中心网络(Data Center Network, DCN)中数据流量多导致大象流与老鼠流识别精确度低的问题,提出一种基于软件定义网络(Software Defined Networking, SDN)下两阶段大象流识别算法。方法 将SDN与DCN结合,第一阶段,采用高斯分布动态阈值优化算法,通过对数据包阈值的设定,计算大象流误检率与漏检率,不断优化得到最优阈值,以此识别出可疑大象流;第二阶段,在依据流传输速率与流持续时间精确得到大象流的基础上,提出阈值约束、流量检测机制、Count计数器等三方面改进对大象流识别阈值下限的约束,将网络中大象流的数据量与流持续时间进行周期内阈值计算,提高大象流的识别精确度。结果 实验结果表明：算法与已有相关算法相比,第一阶段可疑大象流平均字节数比网络流平均字节数多11.3%;不同阈值下的算法准确度提高1.7%,不同网络流量下的大象流平均检测时间降低至6 ms以内。结论 软件定义网络下两阶段大象流识别算法在第一阶段具有较强的大象流识别能力,同时算法的精确度有所提高,大象流的平均检测时间降低,提高了网络质量,能为进行网络流量调度策略的进一步研究...     

超声波场影响Langmuir吸附相平衡的机理分析

从分子动力学规律出发,建立了Langmuir吸附系统在外场作用下的吸附相平衡关系式,并根据超声条件下吸附相分子的受迫振动和非吸附相分子的波动,分别讨论了吸附相分子及非吸附相分子在超声波场中获得的能量,结果表明:在超声波场中,吸附相分子比非吸附相分子获得更多的能量是Langmuir吸附平衡等温线降低的本质所在.理论结果进一步表明:当超声波频率一定时,Langmuir平衡吸附量随超声波场能流的增大而减少;当超声波能流一定时,可通过调节超声波频率达到吸附相分子的固有频率而使吸附相分子获得最大的能量,从而使Langmuir平衡吸附量最小.     

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

Fluctuation and response in biology

In 1905, Albert Einstein proposed that the forces that cause the random Brownian motion of a particle also underlie the resistance to macroscopic motion when a force is applied. This insight, of a coupling between fluctuation (stochastic behavior) and responsiveness (non-stochastic behavior), founded an important branch of physics. Here we argue that his insight may also be relevant for understanding evolved biological systems, and we present a ‘fluctuation–response relationship’ for biology. The relationship is consistent with the idea that biological systems are similarly canalized to stochastic, environmental, and genetic perturbations. It is also supported by in silico evolution experiments, and by the observation that ‘noisy’ gene expression is often both more responsive and more ‘evolvable’. More generally, we argue that in biology there is (and always has been) an important role for macroscopic theory that considers the general behavior of systems without concern for their intimate molecular details.     

Cytoglobin: biochemical,functional and clinical perspective of the newest member of the globin family

Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry, functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various pathological conditions and potential clinical utility.     

Computer system reliability allocation method and supporting tool

This paper presents a computer system reliability allocation method that is based on the theory of statistic and Markovian chain, which can be used to allocate reliability to subsystem, to hybrid system and software modules. A relevant supporting tool built by us is introduced.