A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease

With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.     

Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.     

A Functional Framework for Integrating eCRM with Workflow Management Based on Customer Value

Introduction No other inventions in recent years have had such a deep influence on how companies manage their customer relationships and how they do business as the Internet. Use of the Internet has changed customers’ purchase expectations to a totally n…     

Similiclava nivea (Cnidaria: Hydrozoa: Similiclavidae): a new family,genus and species of athecate hydroid from the Pacific coast of North America

The hydroid Similiclava nivea, gen. nov., sp. nov., is described from colonies collected in nearshore waters of southern British Columbia, Canada. It has been observed by divers, and recorded as Clava sp., several hundred times at locations between southeast Alaska and southern Oregon, USA. While resembling the hydractiniid Clava multicornis, tentacles of S. nivea are arranged in two close whorls in extended hydranths rather than being scattered over the distal end of the hydranth. Moreover, the hypostome is dome-shaped to flattened instead of being proboscidiform. Similiclava nivea also resembles species of the hydractiniid genera Stylactaria, Hydractinia and Podocoryna, but differs in being monomorphic, in lacking spines on the hydrorhiza and in having numerous (as many as 50 or more) sporosacs borne in a broad whorl below the tentacles on normal hydranths. Molecular analysis using the mitochondrial 16S gene sequences reveals that S. nivea is closer to Clathrozoellidae than to Hydractiniidae, although it is clearly distinct from both. A new family, Similiclavidae, is established to accommodate the species. Hydroids of S. nivea were observed at relatively shallow depths (10–30 m) on rocks and epibiota attached to rocky substrates. Colonies are conspicuous because of the relatively large surface area they occupy (up to 20 cm across, and in aggregations often exceeding 100 or more hydranths) together with the height (about 15 mm high when extended) and striking white colour of living hydranths. The cnidome consists of desmonemes, microbasic euryteles and microbasic mastigophores. A substrate generalist observed on rocks, algae, sponges, barnacles, bryozoans and other hydroids in cold-temperate waters, S. nivea is most prevalent in shallow subtidal areas swept by tidal currents.

http://zoobank.org/urn:lsid:zoobank.org:pub:2691E02E-7E14-4820-8D91-41D9E7E8BF62     

A TWO-PHASE APPROACH TO FUZZY SYSTEM IDENTIFICATION

A two-phase approach to fuzzy system identification is proposed. The first phase produces a baseline design to identify a prototype fuzzy system for a target system from a collection of input-output data pairs. It uses two easily implemented clustering techniques: the subtractive clustering method and the fuzzy c-means (FCM) clustering algorithm. The second phase (fine tuning) is executed to adjust the parameters identified in the baseline design. This phase uses the steepest descent and recursive least-squares estimation methods. The proposed approach is validated by applying it to both a function approximation type of problem and a classification type of problem. An analysis of the learning behavior of the proposed approach for the two test problems is conducted for further confirmation.     

Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.