Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension

Diverse heterozygous mutations of bone morphogenetic receptor type II (BMPR-II) underlie the inherited form of the vascular disorder primary pulmonary hypertension (PPH). As yet, the molecular detail of how such defects contribute to the pathogenesis of PPH remains unclear. BMPR-II is a member of the transforming growth factor-beta cell signalling superfamily. Ligand binding induces cell surface receptor complex formation and activates a cascade of phosphorylation events of intracellular intermediaries termed Smads, which initiate transcriptional regulation. Some 30% of PPH-causing mutations localize to exon 12, which may be spliced out forming an isoform depleted of the unusually long BMPR-II cytoplasmic tail. To further elucidate the consequences of BMPR2 mutation, we sought to characterize aspects of the cytoplasmic domain function by seeking intracellular binding partners. We now report that Tctex-1, a light chain of the motor complex dynein, interacts with the cytoplasmic domain of BMPR-II and demonstrate that Tctex-1 is phosphorylated by BMPR-II, a function disrupted by PPH disease causing mutations within exon 12. Finally we show that BMPR-II and Tctex-1 co-localize to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodelling in PPH. Taken together, these data demonstrate a discrete function for the cytoplasmic domain of BMPR-II and justify further investigation of whether the interaction with and phosphorylation of Tctex-1 contributes to the pathogenesis of PPH

Micromagnetic modeling of the heat-assisted switching process in high anisotropy FePt granular thin films

The dynamic process of assisted magnetic switchings has been simulated to investigate the associated physics. The model uses a Voronoi construction to determine the physical structure of the nanogranular thin film recording media, the Landau-Lifshitz-Bloch equation is solved to evolve the magnetic system in time. The reduction of the magnetization is determined over a range of peak system temperatures and for a number of anisotropy values. The results show that the heat-assisted magnetic recording process is not simply magnetization reversal over a thermally reduced energy barrier. To achieve full magnetization reversal (for all anisotropies investigated), an applied field strength of at least 6 kOe is required and the peak system temperature must reach at least the Curie point (T c). When heated to T c, the magnetization associated with each grain is destroyed, which invokes the non-precessional linear reversal mode. Reversing the magnetization through this linear reversal mode is favorable, as the reversal time is two orders of magnitude smaller than that associated with precession. Under these conditions, as the temperature decreases to ambient, the magnetization recovers in the direction of the applied field, completing the reversal process. Also, the model produces results that are consistent with the concept of thermal writability; when heating the media to T c, the smaller grains require a larger field strength to reverse the magnetization

Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). METHODS AND RESULTS: Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. CONCLUSIONS: The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension

Black carbon as an additional indicator of the adverse health effects of airborne particles compared with PM10 and PM2.5.

Current air quality standards for particulate matter (PM) use the PM mass concentration [PM with aerodynamic diameters ≤ 10 μm (PM(10)) or ≤ 2.5 μm (PM(2.5))] as a metric. It has been suggested that particles from combustion sources are more relevant to human health than are particles from other sources, but the impact of policies directed at reducing PM from combustion processes is usually relatively small when effects are estimated for a reduction in the total mass concentration

A tale of two cities: effects of air pollution on hospital admissions in Hong Kong and London compared.

The causal interpretation of reported associations between daily air pollution and daily admissions requires consideration of residual confounding, correlation between pollutants, and effect modification. If results obtained in Hong Kong and London--which differ in climate, lifestyle, and many other respects--were similar, a causal association would be supported. We used identical statistical methods for the analysis in each city. Associations between daily admissions and pollutant levels were estimated using Poisson regression. Nonparametric smoothing methods were used to model seasonality and the nonlinear dependence of admissions on temperature, humidity, and influenza admissions. For respiratory admissions (> or = 65 years of age), significant positive associations were observed with particulate matter < 10 microm in aerodynamic diameter (PM(10), nitrogen dioxide, sulfur dioxide, and ozone in both cities. These associations tended to be stronger at shorter lags in Hong Kong and at longer lags in London. Associations were stronger in the cool season in Hong Kong and in the warm season in London, periods during which levels of humidity are at their lowest in each city. For cardiac admissions (all ages) in both cities, significant positive associations were observed for PM(10), NO(2), and SO(2) with similar lag patterns. Associations tended to be stronger in the cool season. The associations with NO(2) and SO(2) were the most robust in two-pollutant models. Patterns of association for pollutants with ischemic heart disease were similar in the two cities. The associations between O(3) and cardiac admissions were negative in London but positive in Hong Kong. We conclude that air pollution has remarkably similar associations with daily cardiorespiratory admissions in both cities, in spite of considerable differences between cities in social, lifestyle, and environmental factors. The results strengthen the argument that air pollution causes detrimental short-term health effects

Gated pipelined folding ADC based low power sensor for large-scale radiometric partial discharge monitoring

Partial discharge is a well-established metric for condition assessment of high-voltage plant equipment. Traditional techniques for partial discharge detection involve physical connection of sensors to the device under observation, limiting sensors to monitoring of individual apparatus, and therefore, limiting coverage. Wireless measurement provides an attractive low-cost alternative. The measurement of the radiometric signal propagated from a partial discharge source allows for multiple plant items to be observed by a single sensor, without any physical connection to the plant. Moreover, the implementation of a large-scale wireless sensor network for radiometric monitoring facilitates a simple approach to high voltage fault diagnostics. However, accurate measurement typically requires fast data conversion rates to ensure accurate measurement of faults. The use of high-speed conversion requires continuous high-power dissipation, degrading sensor efficiency and increasing cost and complexity. Thus, we propose a radiometric sensor which utilizes a gated, pipelined, sample-and-hold based folding analogue-todigital converter structure that only samples when a signal is received, reducing the power consumption and increasing the efficiency of the sensor. A proof of concept circuit has been developed using discrete components to evaluate the performance and power consumption of the system

Short-term associations between particle oxidative potential and daily mortality and hospital admissions in London.

BACKGROUND: Particulate matter (PM) from traffic and other sources has been associated with adverse health effects. One unifying theory is that PM, whatever its source, acts on the human body via its capacity to cause damaging oxidation reactions related to its content of pro-oxidants components. Few epidemiological studies have investigated particle oxidative potential (OP) and health. We conducted a time series analysis to assess associations between daily particle OP measures and numbers of deaths and hospital admissions for cardiovascular and respiratory diseases. METHODS: During 2011 and 2012 particles with an aerodynamic diameter less than 2.5 and 10μm (PM2.5 and PM10 respectively) were collected daily on Partisol filters located at an urban background monitoring station in Central London. Particulate OP was assessed based on the capacity of the particles to oxidize ascorbate (OP(AA)) and glutathione (OP(GSH)) from a simple chemical model reflecting the antioxidant composition of human respiratory tract lining fluid. Particulate OP, expressed as % loss of antioxidant per μg of PM, was then multiplied by the daily concentrations of PM to derive the daily OP of PM mass concentrations (% loss per m(3)). Daily numbers of deaths and age- and cause-specific hospital admissions in London were obtained from national registries. Poisson regression accounting for seasonality and meteorology was used to estimate the percentage change in risk of death or admission associated with an interquartile increment in particle OP. RESULTS: We found little evidence for adverse associations between OP(AA) and OP(GSH) and mortality. Associations with cardiovascular admissions were generally positive in younger adults and negative in older adults with confidence intervals including 0%. For respiratory admissions there was a trend, from positive to negative associations, with increasing age although confidence intervals generally included 0%. CONCLUSIONS: Our study, the first to analyse daily particle OP measures and mortality and admissions in a large population over two years, found little evidence to support the hypothesis that short-term exposure to particle OP is associated with adverse health effects. Further studies with improved exposure assessment and longer time series are required to confirm or reject the role of particle OP in triggering exacerbations of disease

Measurement error in a multi-level analysis of air pollution and health: a simulation study.

BACKGROUND: Spatio-temporal models are increasingly being used to predict exposure to ambient outdoor air pollution at high spatial resolution for inclusion in epidemiological analyses of air pollution and health. Measurement error in these predictions can nevertheless have impacts on health effect estimation. Using statistical simulation we aim to investigate the effects of such error within a multi-level model analysis of long and short-term pollutant exposure and health. METHODS: Our study was based on a theoretical sample of 1000 geographical sites within Greater London. Simulations of "true" site-specific daily mean and 5-year mean NO2 and PM10 concentrations, incorporating both temporal variation and spatial covariance, were informed by an analysis of daily measurements over the period 2009-2013 from fixed location urban background monitors in the London area. In the context of a multi-level single-pollutant Poisson regression analysis of mortality, we investigated scenarios in which we specified: the Pearson correlation between modelled and "true" data and the ratio of their variances (model versus "true") and assumed these parameters were the same spatially and temporally. RESULTS: In general, health effect estimates associated with both long and short-term exposure were biased towards the null with the level of bias increasing to over 60% as the correlation coefficient decreased from 0.9 to 0.5 and the variance ratio increased from 0.5 to 2. However, for a combination of high correlation (0.9) and small variance ratio (0.5) non-trivial bias (> 25%) away from the null was observed. Standard errors of health effect estimates, though unaffected by changes in the correlation coefficient, appeared to be attenuated for variance ratios > 1 but inflated for variance ratios < 1. CONCLUSION: While our findings suggest that in most cases modelling errors result in attenuation of the effect estimate towards the null, in some situations a non-trivial bias away from the null may occur. The magnitude and direction of bias appears to depend on the relationship between modelled and "true" data in terms of their correlation and the ratio of their variances. These factors should be taken into account when assessing the validity of modelled air pollution predictions for use in complex epidemiological models

Workshop on Environmental Research Needs in Support of Potential Virginia Offshore Oil and Gas Activities

The MMS, a bureau within the Department of the Interior, sponsored a workshop on the environmental research needs in support of potential Virginia offshore oil and gas activities 3 and 4 December 2008, in Williamsburg, Virginia. The focus of the workshop was to assess the existing scientific knowledgebase along the Virginia Coast and the information gaps that need to 2 be addressed should a lease sale for oil and gas activities be held for the Virginia outer continental shelf. This report summarizes the outcome of the workshop