Fast and accurate genotype imputation in genome-wide association studies through pre-phasing

The 1000 Genomes Project and disease-specific sequencing efforts are producing large collections of haplotypes that can be used as reference panels for genotype imputation in genome-wide association studies (GWAS). However, imputing from large reference panels with existing methods imposes a high computational burden. We introduce a strategy called 'pre-phasing' that maintains the accuracy of leading methods while reducing computational costs. We first statistically estimate the haplotypes for each individual within the GWAS sample (pre-phasing) and then impute missing genotypes into these estimated haplotypes. This reduces the computational cost because (i) the GWAS samples must be phased only once, whereas standard methods would implicitly repeat phasing with each reference panel update, and (ii) it is much faster to match a phased GWAS haplotype to one reference haplotype than to match two unphased GWAS genotypes to a pair of reference haplotypes. We implemented our approach in the MaCH and IMPUTE2 frameworks, and we tested it on data sets from the Wellcome Trust Case Control Consortium 2 (WTCCC2), the Genetic Association Information Network (GAIN), the Women's Health Initiative (WHI) and the 1000 Genomes Project. This strategy will be particularly valuable for repeated imputation as reference panels evolve.     

A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.     

The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.     

The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR. These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein 1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism. Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength. Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms independent of NMDAR.     

流域与中国城市群空间分布规律研究

以中国(大陆)为例,把12个公认的城市群空间分布与10大河流流域空间分布叠加,结果表明两点:一是流域与城市群形成了较好的空间对应关系;二是城市群的中心城市一般在流域的最佳区位.     

Universal Distributed Estimation Scheme for a Bandwidth Constrained Ad Hoc Sensor Network

This paper describes a distributed estimation scheme (DES) for a bandwidth constrained ad hoc sensor network.The DES is universal in the sense that operations on all sensors are identical and independent of noise distribution.The scheme requires each sensor to transmit just a 1-bit message per observation.Simulation results show that the scheme achieves much better mean-squares error (MSE) performance than the simplified isotropic universal DES and even outperforms the isotropic universal DES which requires more than twice the bandwidth of this scheme.     

智能型电冰箱断电延迟保护器

本文介绍了一种智能型电冰箱断电保护器的电路、工作原理及其优点。     

试论散手运动中蹬腿技术的特点及其训练

散手运动中蹬腿技术有杀伤力大,有利于近距离击打,隐蔽性强,不易被对方防守等特点,其训练方法包括基本技术训练、针对性训练和实战性训练三个步骤.     

Response ofPhloeotribus scarabaeoides (Coleoptera,Scolytidae) to ethylene in an olfactometer

The role of ethylene, pure or in formulation, in the colonization behaviour of the olive bark beetle,Phloeotribus scarabaeoides (Coleoptera, Scolytidae) has been investigated in the laboratory. Ethylene has been found to be attractive in both sexes; the formulation ethrel 48 was active in an olfactometer up to several months. Ethylene, whose concentration varies with the developmental stage or the condition of the tree or its wood, may play an important role in the primary attraction of these scolytids to their host.