Long-term evolution and transmission dynamics of swine influenza A virus

Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12?years of systematic surveillance in this region, supplemented with data stretching back 34?years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans.     

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.     

Forecasting with leading indicators revisited

Transfer function or distributed lag models are commonly used in forecasting. The stability of a constant‐coefficient transfer function model, however, may become an issue for many economic variables due in part to the recent advance in technology and improvement in efficiency in data collection and processing. In this paper, we propose a simple functional‐coefficient transfer function model that can accommodate the changing environment. A likelihood ratio statistic is used to test the stability of a traditional transfer function model. We investigate the performance of the test statistic in the finite sample case via simulation. Using some well‐known examples, we demonstrate clearly that the proposed functional‐coefficient model can substantially improve the accuracy of out‐of‐sample forecasts. In particular, our simple modification results in a 25% reduction in the mean squared errors of out‐of‐sample one‐step‐ahead forecasts for the gas‐furnace data of Box and Jenkins. Copyright © 2003 John Wiley & Sons, Ltd.     

A simple interspike interval analyzer for study of neuronal spike trains.

A simple, low cost interspike interval analyzer for the analysis of trains of nerve impulses is described. The analyzer is built with readily available integrated circuits and has been used to analyze spike trains in the lateral vestibular nucleus of cats.     

Mechanisms of valence selectivity in biological ion channels

Transmembrane ion channels play a crucial role in the existence of all living organisms. They partition the exterior from the interior of the cell, maintain the proper ionic gradient across the cell membrane and facilitate signaling between cells. To perform these functions, ion channels must be highly selective, allowing some types of ions to pass while blocking the passage of others. Here we review a number of studies that have helped to elucidate the mechanisms by which ion channels discriminate between ions of differing charge, focusing on four channel families as examples: gramicidin, ClC chloride, voltage-gated calcium and potassium channels. The recent availability of high-resolution structural data has meant that the specific inter-atomic interactions responsible for valence selectivity can be pinpointed. Not surprisingly, electrostatic considerations have been shown to play an important role in ion specificity, although many details of the origins of this discrimination remain to be determined. Received 4 September 2005; received after revision 17 October 2005; accepted 2 November 2005     

Amyloid β-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity

Proteasome inhibition has been regarded as one of the mediators of Aβ neurotoxicity. In this study, we found that FOXRED2, a novel endoplasmic reticulum (ER) residential protein, is highly up-regulated by Aβ in rat cortical neurons and SH-SY5Y cells. Over-expression of FOXRED2 inhibits proteasome activity in the microsomal fractions containing ER and interferes with proteasome assembly, as evidenced by gel filtration and native gel electrophoresis analysis. In contrast, reduced expression of FOXRED2 rescues Aβ-induced inhibition of proteasome activity. FOXRED2 is an unstable protein with two degradation boxes and one KEN box, and its N-terminal oxidoreductase domain is required for proteasome inhibition. Ectopic expression of FOXRED2 induces ER stress-mediated cell death via caspase-12, which is inhibited by Salubrinal. Further, down-regulation of FOXRED2 expression attenuates Aβ-induced cell death and the ER stress response. These results suggest that up-regulated FOXRED2 inhibits proteasome activity by interfering with 26S proteasome assembly to contribute to Aβ neurotoxicity via an ER stress response.     

Statistical issues and approaches in endophenotype research

The endophenotype concept was initially proposed to enhance the power of genetic studies of complex disorders. It is closely related to the genetic component in a liability-threshold model; a perfect endophenotype should have a correlation of 1 with the genetic component of the liability to disease. In reality, a putative endophenotype is unlikely to be a perfect representation of the genetic component of disease liability. The magnitude of the correlation between a putative endophenotype and the genetic co...     

Genome-wide association identifies three new susceptibility loci for Paget's disease of bone

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study. Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 × 10(-14)), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 × 10(-11)) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 × 10(-10)). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 × 10(-17)) with PDB. These seven loci explained ～13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB.