Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.     

Alpha 1-adrenoceptor subtypes linked to different mechanisms for increasing intracellular Ca2+ in smooth muscle

Receptor-mediated increases in intracellular Ca2+ levels can be caused by release from intracellular organelles and/or influx from the extracellular fluid. Noradrenaline (NA) released from sympathetic nerves acts on alpha 1-adrenoceptors to increase cytosolic Ca2+ and promote smooth muscle contraction. In many cells activation of alpha 1-adrenoceptors causes formation of inositol 1,4,5-trisphosphate which promotes Ca2+ release from intracellular stores. The mechanism by which receptor activation opens cell surface Ca2+ channels is not known, although in some cases it may be secondary to formation of inositol phosphates or release of stored intracellular Ca2+ (ref. 3). However, alpha 1-adrenoceptors have recently been shown to have different pharmacological properties in different tissues, and it has been proposed that different alpha 1-adrenoceptor subtypes may control mobilization of intracellular Ca2+ and gating of extracellular Ca2+ influx. We here report evidence for two subtypes of alpha 1-adrenoceptors which cause contractile responses through different molecular mechanisms. One subtype stimulates inositol phosphate (InsP) formation and causes contractions which are independent of extracellular Ca2+, and the other does not stimulate inositol phosphate formation and causes contractions which require the influx of extracellular Ca2+ through dihydropyridine-sensitive channels. These results suggest that neurotransmitters and hormones may control Ca2+ release from intracellular stores and influx through voltage-gated membrane channels through distinct receptor subtypes.     

Increasing dominance of large lianas in Amazonian forests

Ecological orthodoxy suggests that old-growth forests should be close to dynamic equilibrium, but this view has been challenged by recent findings that neotropical forests are accumulating carbon and biomass, possibly in response to the increasing atmospheric concentrations of carbon dioxide. However, it is unclear whether the recent increase in tree biomass has been accompanied by a shift in community composition. Such changes could reduce or enhance the carbon storage potential of old-growth forests in the long term. Here we show that non-fragmented Amazon forests are experiencing a concerted increase in the density, basal area and mean size of woody climbing plants (lianas). Over the last two decades of the twentieth century the dominance of large lianas relative to trees has increased by 1.7-4.6% a year. Lianas enhance tree mortality and suppress tree growth, so their rapid increase implies that the tropical terrestrial carbon sink may shut down sooner than current models suggest. Predictions of future tropical carbon fluxes will need to account for the changing composition and dynamics of supposedly undisturbed forests.     

Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.     

A comparison of official population projections with Bayesian time series forecasts for England and Wales

We compare official population projections with Bayesian time series forecasts for England and Wales. The Bayesian approach allows the integration of uncertainty in the data, models and model parameters in a coherent and consistent manner. Bayesian methodology for time-series forecasting is introduced, including autoregressive (AR) and stochastic volatility (SV) models. These models are then fitted to a historical time series of data from 1841 to 2007 and used to predict future population totals to 2033. These results are compared to the most recent projections produced by the Office for National Statistics. Sensitivity analyses are then performed to test the effect of changes in the prior uncertainty for a single parameter. Finally, in-sample forecasts are compared with actual population and previous official projections. The article ends with some conclusions and recommendations for future work.     

Genetic variation in selenoprotein S influences inflammatory response

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.