Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).     

Genome-wide association analysis identifies 20 loci that influence adult height

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.     

Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.     

Intrinsic protein disorder in oncogenic <Emphasis Type="Italic">KRAS</Emphasis> signaling

How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes anchoring in membranes, permits segments to fulfil multiple roles, and broadly is crucial for activation mechanisms and intensified oncogenic signaling. Here, we provide an overview illustrating some of the key mechanisms through which conformational disorder can promote oncogenesis, with K-Ras4B signaling serving as an example. We discuss (1) GTP-bound KRas4B activation through membrane attachment; (2) how farnesylation and palmitoylation can promote isoform functional specificity; (3) calmodulin binding and PI3K activation; (4) how Ras activates its RASSF5 cofactor, thereby stimulating signaling of the Hippo pathway and repressing proliferation; and (5) how intrinsically disordered segments in Raf help its attachment to the membrane and activation. Collectively, we provide the first inclusive review of the roles of intrinsic protein disorder in oncogenic Ras-driven signaling. We believe that a broad picture helps to grasp and formulate key mechanisms in Ras cancer biology and assists in therapeutic intervention.     

Application of Fast and Robust Equalization in Communication Technology

In this paper, the authors explore the potential of several popular equalization techniques while overcoming their disadvantages. First, extensive literature survey on equalization is conducted. The focus is on popular linear equalization algorithms such as the conventional least-meansquare (LMS) algorithm, the recursive least-squares ( RLS ) algorithm, the filtered-X LMS algorithm and their development. To overcome the slow convergence problem while keeping the simplicity of the LMS based algorithms, an H2 optimal initialization is proposed.     

Subcellular distribution of acetylcholinesterases in the neural lobe of the bovine pituitary gland

Summary Biochemical analysis of subcellular fractions of bovine neural lobe tissue indicated that non-specific acetylcholinesterase was principally associated with the pituicytes.     

Accumulation of 3H-dopamine by synaptic vesicles from rat striatum in an impermeant medium

The accumulation of 3H-dopamine by synaptic vesicles from rat striatum was significantly stabilized in a membrane impermeant medium. The characteristics of dopamine accumulation by striatal vesicles were quite similar to those reported for dopamine accumulation by a whole brain vesicle preparation in the same medium, and were significantly different from the characteristics previously reported for vesicular accumulation of norepinephrine.     

A Probability for Classification Based on the Dirichlet Process Mixture Model

In this paper we provide an explicit probability distribution for classification purposes when observations are viewed on the real line and classifications are to be based on numerical orderings. The classification model is derived from a Bayesian nonparametric mixture of Dirichlet process model; with some modifications. The resulting approach then more closely resembles a classical hierarchical grouping rule in that it depends on sums of squares of neighboring values. The proposed probability model for classification relies on a numerical procedure based on a reversible Markov chain Monte Carlo (MCMC) algorithm for determining the probabilities. Some numerical illustrations comparing with alternative ideas for classification are provided.     

The structural intolerance of the PrP α-fold for polar substitution of the helix-3 methionines

The conversion of the cellular prion protein (PrP^C) into its disease-associated form (PrP^Sc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity, reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206 and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes.