Evidence of widespread selection on standing variation in Europe at height-associated SNPs

Strong signatures of positive selection at newly arising genetic variants are well documented in humans, but this form of selection may not be widespread in recent human evolution. Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation. By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P < 4.3 × 10(-4)). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ～10(-3)-10(-5) per allele) rather than genetic drift alone (P < 10(-15)).     

Molecular architecture of native HIV-1 gp120 trimers

The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.     

计算离散数学——Mathematica中的组合学与图论

Combinatorica是著名数学软件Mathemafica的一个重要扩展，是Mathelnatlca的一个重要软件包，专门用于求解分析离散数学问题。本书实际是对Combinatorica第2代版本的介绍，相当于Combinatorica的使用手册、向导。它把离散数学的知识与软件使用结合起来，在了解软件及其使用的同时，也可以帮助读者加深对离散数学的理解。     

Constructing optimal ultrametrics

Clique optimization (CLOPT) is a family of graph clustering procedures that construct parsimonious ultrametrics by executing a sequence of divisive and agglomerative operations. Every CLOPT procedure is associated with a distinct graph-partitioning heuristic. Seven HCS methods, a mathematical programming algorithm, and two CLOPT heuristics were evaluated on simulated data. These data were obtained by distorting ultrametric partitions and hierarchies. In general, internally optimal models yielded externally optimal models. By recovering near-optimal solutions more consistently, CLOPT2 emerged as the most robust technique.     

Robust estimation of conditional variance of time series using density power divergences

Suppose Z _t is the square of a time series Y _t whose conditional mean is zero. We do not specify a model for Y _t , but assume that there exists a p ×1 parameter vector Φ such that the conditional distribution of Z _t | Z _{t ?1} is the same as that of , where Z _{t ?1}=(Z _{t ?1},…,Z _{t ?p} )^T for some lag p ?1. Consequently, the conditional variance of Y _t is some function of . To estimate Φ , we propose a robust estimation methodology based on density power divergences (DPD) indexed by a tuning parameter α ∈[0,1], which yields a continuum of estimators, , where α controls the trade‐off between robustness and efficiency of the DPD estimators. For each α , is shown to be strongly consistent. We develop data‐dependent criteria for the selection of optimal α and lag p in practice. We illustrate the usefulness of our DPD methodology via simulation studies for ARCH‐type models, where the errors are drawn from a gross‐error contamination model and the conditional variance is a linear and/or nonlinear function of . Furthermore, we analyze the Chicago Board Options Exchange Dow Jones volatility index data and show that our DPD approach yields viable models for the conditional variance, which are as good as, or superior to, ARCH/GARCH models and two other divergence‐based models in terms of in‐sample and out‐of‐sample forecasts.     

Autonomic healing of polymer composites

Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mechanical degradation of fibre-reinforced polymer composites; in microelectronic polymeric components it can also lead to electrical failure. Microcracking induced by thermal and mechanical fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Experiments exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here we report a structural polymeric material with the ability to autonomically heal cracks. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymerization of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. Our fracture experiments yield as much as 75% recovery in toughness, and we expect that our approach will be applicable to other brittle materials systems (including ceramics and glasses).