Splice variants of Na(V)1.7 sodium channels have distinct β subunit-dependent biophysical properties.

Genes encoding the α subunits of neuronal sodium channels have evolutionarily conserved sites of alternative splicing but no functional differences have been attributed to the splice variants. Here, using Na(V)1.7 as an exemplar, we show that the sodium channel isoforms are functionally distinct when co-expressed with β subunits. The gene, SCN9A, encodes the α subunit of the Na(V)1.7 channel, and contains both sites of alternative splicing that are highly conserved. In conditions where the intrinsic properties of the Na(V)1.7 splice variants were similar when expressed alone, co-expression of β1 subunits had different effects on channel availability that were determined by splicing at either site in the α subunit. While the identity of exon 5 determined the degree to which β1 subunits altered voltage-dependence of activation (P = 0.027), the length of exon 11 regulated how far β1 subunits depolarised voltage-dependence of inactivation (P = 0.00012). The results could have a significant impact on channel availability, for example with the long version of exon 11, the co-expression of β1 subunits could lead to nearly twice as large an increase in channel availability compared to channels containing the short version. Our data suggest that splicing can change the way that Na(V) channels interact with β subunits. Because splicing is conserved, its unexpected role in regulating the functional impact of β subunits may apply to multiple voltage-gated sodium channels, and the full repertoire of β subunit function may depend on splicing in α subunits

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study

<p><b>Background:</b> Antioxidant vitamins are often described as having “independent” associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors.</p> <p><b>Methods and Findings:</b> Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30–59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (α-carotene, β-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3–6.0] to 38.8% [49.9–25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7–13.5]) and waist hip ratio for vitamin E (9.5% [4.8–14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels.</p> <p><b>Conclusions:</b> Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.</p&gt

Rupture by damage accumulation in rocks

The deformation of rocks is associated with microcracks nucleation and propagation, i.e. damage. The accumulation of damage and its spatial localization lead to the creation of a macroscale discontinuity, so-called "fault" in geological terms, and to the failure of the material, i.e. a dramatic decrease of the mechanical properties as strength and modulus. The damage process can be studied both statically by direct observation of thin sections and dynamically by recording acoustic waves emitted by crack propagation (acoustic emission). Here we first review such observations concerning geological objects over scales ranging from the laboratory sample scale (dm) to seismically active faults (km), including cliffs and rock masses (Dm, hm). These observations reveal complex patterns in both space (fractal properties of damage structures as roughness and gouge), time (clustering, particular trends when the failure approaches) and energy domains (power-law distributions of energy release bursts). We use a numerical model based on progressive damage within an elastic interaction framework which allows us to simulate these observations. This study shows that the failure in rocks can be the result of damage accumulation

Expression of a Serine Protease Gene prC Is Up-Regulated by Oxidative Stress in the Fungus Clonostachys rosea: Implications for Fungal Survival

BACKGROUND: Soil fungi face a variety of environmental stresses such as UV light, high temperature, and heavy metals. Adaptation of gene expression through transcriptional regulation is a key mechanism in fungal response to environmental stress. In Saccharomyces cerevisiae, the transcription factors Msn2/4 induce stress-mediated gene expression by binding to the stress response element. Previous studies have demonstrated that the expression of extracellular proteases is up-regulated in response to heat shock in fungi. However, the physiological significance of regulation of these extracellular proteases by heat shock remains unclear. The nematophagous fungus Clonostachys rosea can secret an extracellular serine protease PrC during the infection of nematodes. Since the promoter of prC has three copies of the stress response element, we investigated the effect of environmental stress on the expression of prC. METHODOLOGY/PRINCIPAL FINDINGS: Our results demonstrated that the expression of prC was up-regulated by oxidants (H(2)O(2) or menadione) and heat shock, most likely through the stress response element. After oxidant treatment or heat shock, the germination of conidia in the wild type strain was significantly higher than that in the prC mutant strain in the presence of nematode cuticle. Interestingly, the addition of nematode cuticle significantly attenuated the production of reactive oxygen species (ROS) induced by oxidants and heat shock in the wild type strain, but not in prC mutant strain. Moreover, low molecule weight (<3 kD) degradation products of nematode cuticle suppressed the inhibitory effect of conidial germination induced by oxidants and heat shock. CONCLUSIONS/SIGNIFICANCE: These results indicate that PrC plays a protective role in oxidative stress in C. rosea. PrC degrades the nematode cuticle to produce degradation products, which in turn offer a protective effect against oxidative stress by scavenging ROS. Our study reveals a novel strategy for fungi to adapt to environmental stress

Gas gangrene and osteomyelitis of the foot in a diabetic patient treated with tea tree oil

Diabetic foot wounds represent a class of chronic non-healing wounds that can lead to the development of soft tissue infections and osteomyelitis. We reviewed the case of a 44-year-old female with a diabetic foot wound who developed gas gangrene while treating her wound with tea tree oil, a naturally derived antibiotic agent. This case report includes images that represent clinical examination and x-ray findings of a patient who required broad-spectrum antibiotics and emergent surgical consultation. Emergency Department (ED) detection of these complications may prevent loss of life or limb in these patients

Model of Yield Response of Corn to Plant Population and Absorption of Solar Energy

Biomass yield of agronomic crops is influenced by a number of factors, including crop species, soil type, applied nutrients, water availability, and plant population. This article is focused on dependence of biomass yield (Mg ha−1 and g plant−1) on plant population (plants m−2). Analysis includes data from the literature for three independent studies with the warm-season annual corn (Zea mays L.) grown in the United States. Data are analyzed with a simple exponential mathematical model which contains two parameters, viz. Ym (Mg ha−1) for maximum yield at high plant population and c (m2 plant−1) for the population response coefficient. This analysis leads to a new parameter called characteristic plant population, xc = 1/c (plants m−2). The model is shown to describe the data rather well for the three field studies. In one study measurements were made of solar radiation at different positions in the plant canopy. The coefficient of absorption of solar energy was assumed to be the same as c and provided a physical basis for the exponential model. The three studies showed no definitive peak in yield with plant population, but generally exhibited asymptotic approach to maximum yield with increased plant population. Values of xc were very similar for the three field studies with the same crop species

Theoretical survey of tidal-charged black holes at the LHC

We analyse a family of brane-world black holes which solve the effective four-dimensional Einstein equations for a wide range of parameters related to the unknown bulk/brane physics. We first constrain the parameters using known experimental bounds and, for the allowed cases, perform a numerical analysis of their time evolution, which includes accretion through the Earth. The study is aimed at predicting the typical behavior one can expect if such black holes were produced at the LHC. Most notably, we find that, under no circumstances, would the black holes reach the (hazardous) regime of Bondi accretion. Nonetheless, the possibility remains that black holes live long enough to escape from the accelerator (and even from the Earth's gravitational field) and result in missing energy from the detectors.Comment: RevTeX4, 12 pages, 4 figures, 5 tables, minor changes to match the accepted version in JHE

The Number and Transmission of [PSI+] Prion Seeds (Propagons) in the Yeast Saccharomyces cerevisiae

Yeast (Saccharomyces cerevisiae) prions are efficiently propagated and the on-going generation and transmission of prion seeds (propagons) to daughter cells during cell division ensures a high degree of mitotic stability. The reversible inhibition of the molecular chaperone Hsp104p by guanidine hydrochloride (GdnHCl) results in cell division-dependent elimination of yeast prions due to a block in propagon generation and the subsequent dilution out of propagons by cell division.Analysing the kinetics of the GdnHCl-induced elimination of the yeast [PSI+] prion has allowed us to develop novel statistical models that aid our understanding of prion propagation in yeast cells. Here we describe the application of a new stochastic model that allows us to estimate more accurately the mean number of propagons in a [PSI+] cell. To achieve this accuracy we also experimentally determine key cell reproduction parameters and show that the presence of the [PSI+] prion has no impact on these key processes. Additionally, we experimentally determine the proportion of propagons transmitted to a daughter cell and show this reflects the relative cell volume of mother and daughter cells at cell division.While propagon generation is an ATP-driven process, the partition of propagons to daughter cells occurs by passive transfer via the distribution of cytoplasm. Furthermore, our new estimates of n(0), the number of propagons per cell (500-1000), are some five times higher than our previous estimates and this has important implications for our understanding of the inheritance of the [PSI+] and the spontaneous formation of prion-free cells

A randomised controlled trial of nurse-managed trial conclusion following early phase cancer trial participation

The effect of a nurse-managed intervention, for early phase cancer trial participants at trial conclusion, on psychosocial outcomes was evaluated at two cancer centres in the Midlands, England using a randomised controlled trial. It involved 117 patients who were participating in an early phase cancer clinical trial. It was a nurse-managed trial exit, which included a trial exit interview, trial feedback information leaflet and telephone follow-up compared with standard care at trial conclusion. Psychological distress at 1 week and 4–6 weeks post-trial conclusion, patient's knowledge and understanding and patient's satisfaction were assessed. The results showed there was no significant difference between the two groups regarding scores for anxiety and depression at time one and time two. There is some suggestion that the intervention reduced anxiety from trial conclusion to follow-up (P=0.27). Patients in both groups felt they had contributed to cancer research through trial participation. However, intervention patients were more likely to feel that they knew how the trial was going (P<0.001), knew how other people in the trial were doing (P=0.001), had all the feedback they needed about the trial they took part in (P<0.01) and knew how they would be followed up (P=0.02). Patient satisfaction with the intervention was high (median score=4.5 where 5 is greatest satisfaction). In conclusion, nurse-managed trial conclusion led to positive outcomes for patients who had recently completed a clinical trial

The equity dimension in evaluations of the quality and outcomes framework: A systematic review

<p>Abstract</p> <p>Background</p> <p>Pay-for-performance systems raise concerns regarding inequity in health care because providers might select patients for whom targets can easily be reached. This paper aims to describe the evolution of pre-existing (in)equity in health care in the period after the introduction of the Quality and Outcomes Framework (QOF) in the UK and to describe (in)equities in exception reporting. In this evaluation, a theory-based framework conceptualising equity in terms of equal access, equal treatment and equal treatment outcomes for people in equal need is used to guide the work.</p> <p>Methods</p> <p>A systematic MEDLINE and Econlit search identified 317 studies. Of these, 290 were excluded because they were not related to the evaluation of QOF, they lacked an equity dimension in the evaluation, their qualitative research focused on experiences or on the nature of the consultation, or unsuitable methodology was used to pronounce upon equity after the introduction of QOF.</p> <p>Results</p> <p>None of the publications (n = 27) assessed equity in access to health care. Concerning equity in treatment and (intermediate) treatment outcomes, overall quality scores generally improved. For the majority of the observed indicators, all citizens benefit from this improvement, yet the extent to which different patient groups benefit tends to vary and to be highly dependent on the type and complexity of the indicator(s) under study, the observed patient group(s) and the characteristics of the study. In general, the introduction of QOF was favourable for the aged and for males. Total QOF scores did not seem to vary according to ethnicity. For deprivation, small but significant residual differences were observed after the introduction of QOF favouring less deprived groups. These differences are mainly due to differences at the practice level. The variance in exception reporting according to gender and socio-economic position is low.</p> <p>Conclusions</p> <p>Although QOF seems not to be socially selective at first glance, this does not mean QOF does not contribute to the inverse care law. Introducing different targets for specific patient groups and including appropriate, non-disease specific and patient-centred indicators that grasp the complexity of primary care might refine the equity dimension of the evaluation of QOF. Also, information on the actual uptake of care, information at the patient level and monitoring of individuals' health care utilisation tracks could make large contributions to an in-depth evaluation. Finally, evaluating pay-for-quality initiatives in a broader health systems impact assessment strategy with equity as a full assessment criterion is of utmost importance.</p