The N–Terminal Tail of hERG Contains an Amphipathic α–Helix That Regulates Channel Deactivation

The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user

Accurate masses and radii of normal stars: modern results and applications

This paper presents and discusses a critical compilation of accurate, fundamental determinations of stellar masses and radii. We have identified 95 detached binary systems containing 190 stars (94 eclipsing systems, and alpha Centauri) that satisfy our criterion that the mass and radius of both stars be known to 3% or better. To these we add interstellar reddening, effective temperature, metal abundance, rotational velocity and apsidal motion determinations when available, and we compute a number of other physical parameters, notably luminosity and distance. We discuss the use of this information for testing models of stellar evolution. The amount and quality of the data also allow us to analyse the tidal evolution of the systems in considerable depth, testing prescriptions of rotational synchronisation and orbital circularisation in greater detail than possible before. The new data also enable us to derive empirical calibrations of M and R for single (post-) main-sequence stars above 0.6 M(Sun). Simple, polynomial functions of T(eff), log g and [Fe/H] yield M and R with errors of 6% and 3%, respectively. Excellent agreement is found with independent determinations for host stars of transiting extrasolar planets, and good agreement with determinations of M and R from stellar models as constrained by trigonometric parallaxes and spectroscopic values of T(eff) and [Fe/H]. Finally, we list a set of 23 interferometric binaries with masses known to better than 3%, but without fundamental radius determinations (except alpha Aur). We discuss the prospects for improving these and other stellar parameters in the near future.Comment: 56 pages including figures and tables. To appear in The Astronomy and Astrophysics Review. Ascii versions of the tables will appear in the online version of the articl

The Making of a Queen: TOR Pathway Is a Key Player in Diphenic Caste Development

Honey bees (Apis mellifera) provide a principal example of diphenic development. Excess feeding of female larvae results in queens (large reproductives). Moderate diet yields workers (small helpers). The signaling pathway that links provisioning to female developmental fate is not understood, yet we reasoned that it could include TOR (target of rapamycin), a nutrient- and energy-sensing kinase that controls organismal growth.Here, the role of Apis mellifera TOR (amTOR) in caste determination is examined by rapamycin/FK506 pharmacology and RNA interference (RNAi) gene knockdown. We show that in queen-destined larvae, the TOR inhibitor rapamycin induces the development of worker characters that are blocked by the antagonist FK506. Further, queen fate is associated with elevated activity of the Apis mellifera TOR encoding gene, amTOR, and amTOR gene knockdown blocks queen fate and results in individuals with worker morphology.A much-studied insect dimorphism, thereby, can be governed by the TOR pathway. Our results present the first evidence for a role of TOR in diphenic development, and suggest that adoption of this ancestral nutrient-sensing cascade is one evolutionary pathway for morphological caste differentiation in social insects

Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes

Minimum pricing of alcohol versus volumetric taxation:which policy will reduce heavy consumption without adversely affecting light and moderate consumers?

Background We estimate the effect on light, moderate and heavy consumers of alcohol from implementing a minimum unit price for alcohol (MUP) compared with a uniform volumetric tax. Methods We analyse scanner data from a panel survey of demographically representative households (n = 885) collected over a one-year period (24 Jan 2010–22 Jan 2011) in the state of Victoria, Australia, which includes detailed records of each household's off-trade alcohol purchasing. Findings The heaviest consumers (3% of the sample) currently purchase 20% of the total litres of alcohol (LALs), are more likely to purchase cask wine and full strength beer, and pay significantly less on average per standard drink compared to the lightest consumers (A$1.31 [95$2.21 [95% CI 2.10–2.31]). Applying a MUP of A$1 per standard drink has a greater effect on reducing the mean annual volume of alcohol purchased by the heaviest consumers of wine (15.78 LALs [95$393.60 [95% CI 374.19–413.00]) and beer ($108.26 [95$552.46 [95% CI 530.55–574.36] and $163.92 [95% CI 152.79–175.03], respectively). Both a MUP and uniform volumetric tax have little effect on changing the annual cost of wine and beer for light and moderate consumers, and likewise little effect upon their purchasing. Conclusions While both a MUP and a uniform volumetric tax have potential to reduce heavy consumption of wine and beer without adversely affecting light and moderate consumers, a MUP offers the potential to achieve greater reductions in heavy consumption at a lower overall annual cost to consumers

First isolation report of Arcobacter cryaerophilus from a human diarrhea sample in Costa Rica

ABSTRACT Arcobacter cryaerophilus is an emerging enteropathogen and potential zoonotic agent transmitted by food and water. In Costa Rica, this bacterium has not been associated with cases of human gastroenteritis, even though it has been isolated from farm animals, especially poultry. This paper reports the first isolation of A. cryaerophilus from a human case of bloody watery diarrhea and the virulence genes associated with this isolate

Lack of observational evidence for quantum structure of space-time at Plank scales

It has been noted (Lieu & Hillmann, 2002) that the cumulative affect of Planck-scale phenomenology, or the structure of space-time at extremely small scales, can be lead to the loss of phase of radiation emitted at large distances from the observer. We elaborate on such an approach and demonstrate that such an effect would lead to an apparent blurring of distant point-sources. Evidence of the diffraction pattern from the HST observations of SN 1994D and the unresolved appearance of a Hubble Deep Field galaxy at z=5.34 lead us to put stringent limits on the effects of Planck-scale phenomenology.Comment: 12 pages, 3 figures, accepter for ApJ

Factorial validity and measurement invariance across gender groups of the German version of the Interpersonal Reactivity Index

The Interpersonal Reactivity Index (IRI) is the most widely used measure of empathy, but its factorial validity has been questioned. The present research investigates the factorial validity of the German adaptation of the IRI, the "Saarbrücker Persönlichkeitsfragebogen SPF-IRI". Confirmatory Factor Analyses (CFA) and Exploratory Structural Equation Modeling (ESEM) were used to test the theoretically predicted four-factor model. Across two subsamples ESEM outperformed CFA. Substantial cross-loadings were evident in ESEM. Measurement invariance (MI) across gender groups was tested using ESEM in the combined sample. Strict MI (invariant factor loadings, intercepts, residuals) could be established, and variances and covariances were also equal. Differences for latent means were evident. Women scored higher on fantasy, empathic concern, and personal distress. No significant differences were found for perspective taking. Mean differences were due to real differences on latent variables and not a result of measurement bias. Results support the factorial validity of the German SPF-IRI. The heterogeneity of empathy and the unclear differentiation between cognitive and emotional aspects might be a source for the unclear differentiation of scales

Double blind randomized placebo-controlled trial on the effects of testosterone supplementation in elderly men with moderate to low testosterone levels: design and baseline characteristics [ISRCTN23688581]

In ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. We set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. We recruited 237 men with serum testosterone levels below 13.7 nmol/L and ages 60–80 years. They were randomized to either four capsules of 40 mg testosterone undecanoate (TU) or placebo daily for 26 weeks. Primary endpoints are functional mobility and quality of life. Secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. Effects on prostate, liver and hematological parameters will be studied with respect to safety. Measure of effect will be the difference in change from baseline visit to final visit between TU and placebo. We will study whether the effect of TU differs across subgroups of baseline waist girth (< 100 cm vs. ≥ 100 cm; testosterone level (<12 versus ≥ 12 nmol/L), age (< median versus ≥ median), and level of outcome under study (< median versus ≥ median). At baseline, mean age, BMI and testosterone levels were 67 years, 27 kg/m(2 )and 10.72 nmol/L, respectively