Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Do patients with well-functioning total hip arthroplasty achieve typical sagittal plane hip kinematics? A proof of concept study

Background: Total hip arthroplasty (THA) patients have been shown to not achieve normal sagittal plane hip kinematics. However, previous studies have only conducted group level analysis and as such lack the sensitivity to highlight whether individual patients do achieve normal hip kinematics. As such this study looked to determine whether some patients with well-functioning THA achieve typical sagittal plane hip kinematics. Methods: Sagittal plane hip kinematics were collected on 11 well-functioning THA patients (Oxford Hip Score = 46 ± 3) and 10 asymptomatic controls using a 3-dimensional motion analysis system during self-paced walking. High-functioning THA patients were identified as those who displayed sagittal plane hip kinematics that were within the variance of the control group on average, and low-functioning patients as those who did not. Results: 5 THA patients were identified as high-functioning, displaying hip kinematics within the variance of the control group. High-functioning THA patients displayed peak hip flexion and extension values more closely aligned to asymptomatic control group than low-functioning patients. However, hip range of motion was comparable between high- and low-functioning total hip arthroplasty patients and reduced compared to controls. Conclusion: The presence of high-functioning THA patients who display comparable sagittal plane hip kinematics to controls suggests these patients do achieve normative function and challenges the conclusions of previous group level analysis. Understanding why some patients achieve better function post-operatively will aid pre- and post-operative practices to maximise functional recovery

Can programme theory be used as a 'translational tool’ to optimise health service delivery in a national early years’ initiative in Scotland: a case study

Background Theory-based evaluation (TBE) approaches are heralded as supporting formative evaluation by facilitating increased use of evaluative findings to guide programme improvement. It is essential that learning from programme implementation is better used to improve delivery and to inform other initiatives, if interventions are to be as effective as they have the potential to be. Nonetheless, few studies describe formative feedback methods, or report direct instrumental use of findings resulting from TBE. This paper uses the case of Scotland’s, National Health Service, early years’, oral health improvement initiative (Childsmile) to describe the use of TBE as a framework for providing feedback on delivery to programme staff and to assess its impact on programmatic action.<p></p> Methods In-depth, semi-structured interviews and focus groups with key stakeholders explored perceived deviations between the Childsmile programme 'as delivered’ and its Programme Theory (PT). The data was thematically analysed using constant comparative methods. Findings were shared with key programme stakeholders and discussions around likely impact and necessary actions were facilitated by the authors. Documentary review and ongoing observations of programme meetings were undertaken to assess the extent to which learning was acted upon.<p></p> Results On the whole, the activities documented in Childsmile’s PT were implemented as intended. This paper purposefully focuses on those activities where variation in delivery was evident. Differences resulted from the stage of roll-out reached and the flexibility given to individual NHS boards to tailor local implementation. Some adaptations were thought to have diverged from the central features of Childsmile’s PT, to the extent that there was a risk to achieving outcomes. The methods employed prompted national service improvement action, and proposals for local action by individual NHS boards to address this.<p></p> Conclusions The TBE approach provided a platform, to direct attention to areas of risk within a national health initiative, and to agree which intervention components were 'core’ to its hypothesised success. The study demonstrates that PT can be used as a 'translational tool’ to facilitate instrumental use of evaluative findings to optimise implementation within a complex health improvement programme.<p></p&gt

Psychosocial Factors Associated with Patterns of Smoking Surrounding Pregnancy in Fragile Families

Although research has documented factors associated with maternal smoking, we need a more in-depth understanding of the risk factors associated with changes in smoking behaviors during the postpartum period. We investigate smoking patterns during pregnancy and 1 year postpartum as a function of relevant psychosocial factors. We use data on 3,522 postpartum mothers from the Fragile Families and Child Wellbeing Study to analyze the predictors of smoking among mothers who did not smoke during pregnancy but smoked at 1 year postpartum, mothers who smoked both during pregnancy and postpartum, and mothers who did not smoke during either period. Our covariates are grouped into four categories of risk factors for smoking: socioeconomic status, health care, life course and health, and partner and social support. Postpartum mothers in our sample were more likely to smoke throughout or after their pregnancies if they had only a high school education or less, had a household income three or more times below the poverty line, had public or no health insurance, breastfed for less than 5 months, were not married to the infant’s father, if the infant’s father currently smoked, and if they attended religious services less than once a week. Mental health problems were consistently associated with an increased risk of constant and postpartum smoking relative to non-smoking. Psychosocial factors play a role in postpartum smoking, but they have a stronger effect in predicting smoking that persists throughout pregnancy and the first year postpartum

Forward Genetic Analysis of Visual Behavior in Zebrafish

The visual system converts the distribution and wavelengths of photons entering the eye into patterns of neuronal activity, which then drive motor and endocrine behavioral responses. The gene products important for visual processing by a living and behaving vertebrate animal have not been identified in an unbiased fashion. Likewise, the genes that affect development of the nervous system to shape visual function later in life are largely unknown. Here we have set out to close this gap in our understanding by using a forward genetic approach in zebrafish. Moving stimuli evoke two innate reflexes in zebrafish larvae, the optomotor and the optokinetic response, providing two rapid and quantitative tests to assess visual function in wild-type (WT) and mutant animals. These behavioral assays were used in a high-throughput screen, encompassing over half a million fish. In almost 2,000 F2 families mutagenized with ethylnitrosourea, we discovered 53 recessive mutations in 41 genes. These new mutations have generated a broad spectrum of phenotypes, which vary in specificity and severity, but can be placed into only a handful of classes. Developmental phenotypes include complete absence or abnormal morphogenesis of photoreceptors, and deficits in ganglion cell differentiation or axon targeting. Other mutations evidently leave neuronal circuits intact, but disrupt phototransduction, light adaptation, or behavior-specific responses. Almost all of the mutants are morphologically indistinguishable from WT, and many survive to adulthood. Genetic linkage mapping and initial molecular analyses show that our approach was effective in identifying genes with functions specific to the visual system. This collection of zebrafish behavioral mutants provides a novel resource for the study of normal vision and its genetic disorders

Degenerate Stars and Gravitational Collapse in AdS/CFT

We construct composite CFT operators from a large number of fermionic primary fields corresponding to states that are holographically dual to a zero temperature Fermi gas in AdS space. We identify a large N regime in which the fermions behave as free particles. In the hydrodynamic limit the Fermi gas forms a degenerate star with a radius determined by the Fermi level, and a mass and angular momentum that exactly matches the boundary calculations. Next we consider an interacting regime, and calculate the effect of the gravitational back-reaction on the radius and the mass of the star using the Tolman-Oppenheimer-Volkoff equations. Ignoring other interactions, we determine the "Chandrasekhar limit" beyond which the degenerate star (presumably) undergoes gravitational collapse towards a black hole. This is interpreted on the boundary as a high density phase transition from a cold baryonic phase to a hot deconfined phase.Comment: 75 page

Aidnogenesis via Leptogenesis and Dark Sphalerons

We discuss aidnogenesis, the generation of a dark matter asymmetry via new sphaleron processes associated to an extra non-abelian gauge symmetry common to both the visible and the dark sectors. Such a theory can naturally produce an abundance of asymmetric dark matter which is of the same size as the lepton and baryon asymmetries, as suggested by the similar sizes of the observed baryonic and dark matter energy content, and provide a definite prediction for the mass of the dark matter particle. We discuss in detail a minimal realization in which the Standard Model is only extended by dark matter fermions which form "dark baryons" through an SU(3) interaction, and a (broken) horizontal symmetry that induces the new sphalerons. The dark matter mass is predicted to be approximately 6 GeV, close to the region favored by DAMA and CoGeNT. Furthermore, a remnant of the horizontal symmetry should be broken at a lower scale and can also explain the Tevatron dimuon anomaly.Comment: Minor changes, discussion of present constraints expanded. 16 pages, 2 eps figures, REVTeX

Framework Report: The AIDS Accountability Workplace Scorecard, September 2011

The aim of the AIDS Accountability Workplace Scorecard is to improve HIV and AIDS workplace programmes in the countries and sectors most affected by the disease, and improve the health of employees, their families and communities. Through this initiative we will: / 1. Provide tools for HIV and AIDS workplace programme monitoring and evaluation AAI has developed scorecard tools for small, medium and large workplaces, which can be used to assess a global, regional or national HIV and AIDS programme or interventions at a specific workplace site. The scorecards can serve as both internal monitoring and evaluation tools and as assessments to present to stakeholders within and outside the organization. / 2. Publish annual Rankings of HIV and AIDS Workplace Programmes Scorecard users who wish to receive a ranking analysis and recommendations for how to improve their programmes can submit their scorecards to AAI. AAI ‘s ranking analysis will allow users to compare their performance with others and over time also measure their own progress. Respondents will be encouraged to publish their ranking in AAI’s yearly Ranking Reports. / 3. Share good practice The knowledge and good practices generated through the published rankings will be used to stimulate improved HIV and AIDS Workplace Programmes worldwide. Large networks of companies, trade union confederations, and national and international organizations can use the scorecard as a common framework for monitoring and evaluation of workplace programmes

Reliability of kinematic waveforms during gait analysis with total hip arthroplasty patients

Purpose The aim of the study was to determine the test-retest reliability of lower limb kinematic waveforms derived from 3D gait analysis (3DGA) in patients following total hip arthroplasty (THA). Methods Eight (7 ​M:1F; age: 70 ​± ​7 years; height: 1.68 ​± ​0.11 ​m; mass: 85 ​± ​20 ​kg) adults with a unilateral THA attended test and retest sessions. 3DGA was undertaken with participants walking at a self-selected pace along a 7 ​m walkway within each session. The standard error or the measurement (SEM) was calculated for hip, knee and ankle joint angles in all three planes, over the walking gait cycle. Results The SEM ranged from 2.9 to 4.1°, 2.7–3.7° and 1.9–3.9°, in the sagittal, frontal and traverse planes at the hip. At the knee the SEM ranged from 1.6 to 4.2°, 1.0–1.9° and 1.3–2.9° in the sagittal, frontal and transverse planes, respectively. While the SEM ranged from 0.7 to 2.0°, 1.2–2.3° and 2.9–4.0° in the sagittal, frontal and transverse planes at the ankle. Conclusions The findings demonstrate that 3DGA provides a reliable means of quantifying lower limb kinematics over the walking gait cycle in patients following THA, with all SEM values below the 5° threshold previously suggested to identify clinically meaningful differences. The SEM values reported may aid in the interpretation of changes in lower limb kinematics in patients following THA

Multiwavelength observations of nova SMCN 2016-10a --- one of the brightest novae ever observed

We report on multiwavelength observations of nova SMCN 2016-10a. The present observational set is one of the most comprehensive for any nova in the Small Magellanic Cloud, including: low, medium, and high resolution optical spectroscopy and spectropolarimetry from SALT, FLOYDS, and SOAR; long-term OGLE $V$- and $I$- bands photometry dating back to six years before eruption; SMARTS optical and near-IR photometry from $\sim$ 11 days until over 280 days post-eruption; $Swift$ satellite X-ray and ultraviolet observations from $\sim$ 6 days until 319 days post-eruption. The progenitor system contains a bright disk and a main sequence or a sub-giant secondary. The nova is very fast with $t_2 \simeq$ 4.0 $\pm$ 1.0 d and $t_3 \simeq$ 7.8 $\pm$ 2.0 d in the $V$-band. If the nova is in the SMC, at a distance of $\sim$ 61 $\pm$ 10 kpc, we derive $M_{V,\mathrm{max}} \simeq - 10.5$ $\pm$ 0.5, making it the brightest nova ever discovered in the SMC and one of the brightest on record. At day 5 post-eruption the spectral lines show a He/N spectroscopic class and a FWHM of $\sim$ 3500 kms$^{-1}$ indicating moderately high ejection velocities. The nova entered the nebular phase $\sim$ 20 days post-eruption, predicting the imminent super-soft source turn-on in the X-rays, which started $\sim$ 28 days post-eruption. The super-soft source properties indicate a white dwarf mass between 1.2 M$_{\odot}$ and 1.3 M$_{\odot}$ in good agreement with the optical conclusions