De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.     

Stiffness, working stroke, and force of single-myosin molecules in skeletal muscle: elucidation of these mechanical properties via nonlinear elasticity evaluation

In muscles, the arrays of skeletal myosin molecules interact with actin filaments and continuously generate force at various contraction speeds. Therefore, it is crucial for myosin molecules to generate force collectively and minimize the interference between individual myosin molecules. Knowledge of the elasticity of myosin molecules is crucial for understanding the molecular mechanisms of muscle contractions because elasticity directly affects the working and drag (resistance) force generation when myosin molecules are positively or negatively strained. The working stroke distance is also an important mechanical property necessary for elucidation of the thermodynamic efficiency of muscle contractions at the molecular level. In this review, we focus on these mechanical properties obtained from single-fiber and single-molecule studies and discuss recent findings associated with these mechanical properties. We also discuss the potential molecular mechanisms associated with reduction of the drag effect caused by negatively strained myosin molecules.     

Experimental extraction of an entangled photon pair from two identically decohered pairs

Entanglement is considered to be one of the most important resources in quantum information processing schemes, including teleportation, dense coding and entanglement-based quantum key distribution. Because entanglement cannot be generated by classical communication between distant parties, distribution of entangled particles between them is necessary. During the distribution process, entanglement between the particles is degraded by the decoherence and dissipation processes that result from unavoidable coupling with the environment. Entanglement distillation and concentration schemes are therefore needed to extract pairs with a higher degree of entanglement from these less-entangled pairs; this is accomplished using local operations and classical communication. Here we report an experimental demonstration of extraction of a polarization-entangled photon pair from two decohered photon pairs. Two polarization-entangled photon pairs are generated by spontaneous parametric down-conversion and then distributed through a channel that induces identical phase fluctuations to both pairs; this ensures that no entanglement is available as long as each pair is manipulated individually. Then, through collective local operations and classical communication we extract from the two decohered pairs a photon pair that is observed to be polarization-entangled.     

Advances in Tube Hydroforming - An Enabling Technology for Low-Mass Vehicle Manufacturing-Material, Lubrication, Loading, Simulation Issues, and Alternatives

The tube hydroforming process (THF) has recently found a wide application opportunity in the automotive industry, and is of increasing interest to other industries as well. The increased interest stems from the fact that, through the THF process, manufacturers are able to produce complex, consolidated,lightweight parts with reduced number of post-processing than through alternative metal forming techniques.In order to fully realize the benefits of this technology, various aspects have been under investigation in academia and industry world-wide. In this paper, effect of loading path, incoming material variation, and lubrication on the robustness of the hydroforming process and final part specifications are summarized based on previous experimental and computational work. In addition, the simulation of hydroforming and examples are presented in comparison with experimental findings. Briefly, results emphasized the importance of the loading path design whereas material variation within the experimentally tested range was not found to be significantly effective on the final part specifications. Selection of a lubricant for hydroforming of a frame rail part was presented demonstrating several aspects of lubrication selection methodology. Results of friction experiments show that only thickness, axial feeding, and force measurements are good indications of lubricant performance as these are found to be strongly discriminative.     

Lakeward and downstream movements of age-0 arctic grayling ( Thymallus arcticus ) originating between a lake and a waterfall

Arctic grayling in Deer Lake, Montana spawn only in the 350-m segment of outlet stream between the lake and a waterfall. The purpose of this study was to examine consequences of and possible adaptations by this population to spawning above the falls, by determining the extent of loss over the falls of age-0 young, the daily and seasonal patterns of such losses, and the seasonal pattern of movement upstream into the lake by the remaining young. We measured fish movements during 1989 and 1990 with traps placed at the outlet and at the falls, from fry swimup in July until October or November. Young went over the falls predominantly as newly swimming fry at night. In 1989 about 5000-9000 were lost downstream, representing an estimated 4-7% or less of young produced. Most young thus appear adapted to maintaining their position above the falls. A few started entering the lake in August and September, but only 95 in 1989 and 23 in 1990 had done so by the time observations were ended by the onset of wintery conditions. Most movement into the lake appeared to occur sometime during the six to seven months of annual ice cover. This extended period of stream residence contrasts with early lakeward movements reported for other inlet-spawning, lacustrine grayling populations and may be an adaptation for avoiding predation by large conspecifics in Deer Lake.     

Mechanical properties of directionally solidified lead-antimony alloys

The Pb-17wt% Sb alloy was directionally solidified under two solidification conditions: with different temperature gradients (G=0.93–3.67 K/mm) at a constant growth rate (V=17.50 μm/s) and with different growth rates (V=8.3–497 μm/s) at a constant temperature gradient (G=3.67 K/mm) in a Bridgman furnace. Microstructure parameters, such as primary dendrite arm spacing (λ₁), secondary dendrite arm spacing (λ₂), and dendrite tip radius (R), were measured. The microhardness (Hv) and ultimate tensile strength (σ) of the directional solidification samples were also measured. The influences of solidification and microstructure parameters on Hv and σ were investigated. The results obtained in this work were compared with similar experimental researches in literatures. It is shown that the Hv and σ values increase with the increase of G and V, but decrease with the increase of λ₁, λ₂, and R.     

蒸发毛细弯液面热质传输特征及其稳定性分析

在基于增广杨拉普拉斯方程及Wayner界面传质方程的蒸发毛细弯液面薄膜区热质传输模型的基础上,利用数值计算分析方法,讨论了系统运行参数、几何参数、工质物性参数对界面热质传输能力和稳定性的影响.结果表明:高过热度和高弯液面温度下,弯液面具有较强的热传输能力,但稳定性下降;毛细通道几何参数对界面热质传输的影响较小,而选择不同的工质其界面热质传输特征会有较大差异.相对而言,高热质传输能力对应了较低的界面稳定性,故在毛细抽吸两相回路的设计中需综合考虑二者的关系.     

Directional solidification and physical properties measurements of the zinc-aluminum eutectic alloy

Zn-5wt% Al eutectic alloy was directionally solidified with different growth rates (5.32–250.0 μm/s) at a constant temperature gradient of 8.50 K/mm using a Bridgman-type growth apparatus. The values of eutectic spacing were measured from transverse sections of the samples. The dependences of the eutectic spacing and undercooling on growth rate are determined as λ=9.21V-0.53 and ΔT=0.0245V0.53, respectively. The results obtained in this work were compared with the Jackson-Hunt eutectic theory and the similar experimental results in the literature. Microhardness of directionally solidified samples was also measured by using a microhardness test device. The dependency of the microhardness on growth rate is found as Hv=115.64V0.13. Afterwards, the electrical resistivity (r) of the casting alloy changes from 40×10-9 to 108×10-9 Ω·m with the temperature rising in the range of 300–630 K. The enthalpy of fusion (ΔH) and specific heat (C_p) for the Zn-Al eutectic alloy are calculated to be 113.37 J/g and 0.309 J/(g·K), respectively by means of differential scanning calorimetry (DSC) from heating trace during the transformation from liquid to solid.     

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.     

Recessive LAMC3 mutations cause malformations of occipital cortical development

The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.