Absorption of fermionic dark matter by nuclear targets

Absorption of fermionic dark matter leads to a range of distinct and novel signatures at dark matter direct detection and neutrino experiments. We study the possible signals from fermionic absorption by nuclear targets, which we divide into two classes of four Fermi operators: neutral and charged current. In the neutral current signal, dark matter is absorbed by a target nucleus and a neutrino is emitted. This results in a characteristically different nuclear recoil energy spectrum from that of elastic scattering. The charged current channel leads to induced β decays in isotopes which are stable in vacuum as well as shifts of the kinematic endpoint of β spectra in unstable isotopes. To confirm the possibility of observing these signals in light of other constraints, we introduce UV completions of example higher dimensional operators that lead to fermionic absorption signals and study their phenomenology. Most prominently, dark matter which exhibits fermionic absorption signals is necessarily unstable leading to stringent bounds from indirect detection searches. Nevertheless, we find a large viable parameter space in which dark matter is sufficiently long lived and detectable in current and future experiments

Ergodic properties of quasi-Markovian generalized Langevin equations with configuration dependent noise and non-conservative force

We discuss the ergodic properties of quasi-Markovian stochastic differential equations, providing general conditions that ensure existence and uniqueness of a smooth invariant distribution and exponential convergence of the evolution operator in suitably weighted $L^{\infty}$ spaces, which implies the validity of central limit theorem for the respective solution processes. The main new result is an ergodicity condition for the generalized Langevin equation with configuration-dependent noise and (non-)conservative force

Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

Who uses outpatient healthcare services under Ghana’s health protection scheme and why?

Background: The National Health Insurance Scheme (NHIS) was launched in Ghana in 2003 with the main objective of increasing utilisation to healthcare by making healthcare more affordable. Previous studies on the NHIS have repeatedly highlighted that cost of premiums is one of the major barriers for enrollment. However, despite introducing premium exemptions for pregnant women, older people, children and indigents, many Ghanaians are still not active members of the NHIS. In this paper we investigate why there is limited success of the NHIS in improving access to healthcare in Ghana and whether social exclusion could be one of the limiting barriers. The study explores this by looking at the Social, Political, Economic and Cultural (SPEC) dimensions of social exclusion. Methods: Using logistic regression, the study investigates the determinants of health service utilisation using SPEC variables including other variables. Data was collected from 4050 representative households in five districts in Ghana covering the 3 ecological zones (coastal, forest and savannah) in Ghana. Results: Among 16,200 individuals who responded to the survey, 54 % were insured. Out of the 1349 who sought health care, 64 % were insured and 65 % of them had basic education and 60 % were women. The results from the logistic regressions show health insurance status, education and gender to be the three main determinants of health care utilisation. Overall, a large proportion of the insured who reported ill, sought care from formal health care providers compared to those who had never insured in the scheme. Conclusion: The paper demonstrates that the NHIS presents a workable policy tool for increasing access to healthcare through an emphasis on social health protection. However, affordability is not the only barrier for access to health services. Geographical, social, cultural, informational, political, and other barriers also come into play

Physical activity monitoring in obese people in the real life environment

<p>Abstract</p> <p>Background</p> <p>Obesity is a major problem especially in western countries and several studies underline the importance of physical activity to enhance diet. Currently there is increasing interest in instruments for monitoring daily physical activity. The purpose of this pilot study was to appraise the qualitative and quantitative differences in physical activities and gait analysis parameters in control and obese subjects by means of an innovative tool for the monitoring of physical activity.</p> <p>Methods</p> <p>Twenty-six obese patients, 16 women and 10 men, aged 22 to 69 years with Body Mass Index (BMI) between 30 and 51.4 kg/m², were compared with 15 control subjects, 4 men and 11 women, aged 24 to 69 with BMI between 18 and 25 kg/m²during daily physical activities. The IDEEA device (Minisun, Fresno, CA), based on a wearable system of biaxial accelerometers and able to continuously record the physical activities and energy expenditure of a subject in time was used. Time spent in different physical activities such as standing, sitting, walking, lying, reclining, stepping, energy expenditure and gait parameters (velocity, stance duration, etc) were measured during a 24-hours period.</p> <p>Results</p> <p>A trend toward a reduced number of steps was present, associated to reduced speed, reduced cadence and reduced rate of single and double limb support (SLS/DLS). Moreover, obese people spent significant less time stepping, less time lying and more time in a sitting or reclined position during the night. The energy expenditure during a 24-hours period was higher in the obese compared to controls.</p> <p>Conclusions</p> <p>The study provided objective parameters to differentiate the daily motor activity of obese subjects with respect to controls, even a larger population is required to confirm these findings. The device used can be of support in programming educational activities for life style modification in obese people as well as for monitoring the results of various kinds of intervention in these patients concerning weight and physical performance.</p

Fortified breakfast cereal consumed daily for 12 wk leads to a significant improvement in micronutrient intake and micronutrient status in adolescent girls: a randomised controlled trial

Background: Poor micronutrient status is reported among adolescents across Europe and USA. This may be related to the well-documented decline in the regular consumption of breakfast by this group. The regular consumption of a breakfast cereal offers a possible means to improve micronutrient status; fortified cereal is likely to have enhanced benefit. A study was conducted to determine the efficacy of the regular consumption of a fortified cereal with milk, compared with unfortified cereal, consumed either as a breakfast or a supper, in improving micronutrient intake and micronutrient status of adolescent girls. Methods: A randomised, double-blind, placebo-controlled intervention trial was conducted in girls recruited at ages 16–19 years, from schools and colleges in Sheffield, UK. Girls were randomised to receive 50 g fortified or unfortified cereal, with 150 ml semi-skimmed milk, daily, for 12 weeks, as a breakfast or as a supper. Dietary intake was estimated using a 4-d food diary and blood collected for the assessment of nutritional status. Within-group changes were tested using a paired sample t test; two-way ANOVA was used to analyse effects of the intervention, with cereal type and time of consumption as factors, correcting for baseline values. The analysis was conducted on 71 girls who completed the study. Results: Consumption of unfortified cereal elicited an increase in the intake of vitamins B1, B2 and B6; consumption of fortified cereal elicited increases in vitamins B1, B2, B6, B12, folate and iron (P < 0.001) and of vitamin D (P = 0.007), all increases were significantly greater than for unfortified cereal. Consumption of the fortified cereal also led to a significant improvement in biomarkers of status for vitamins B2, B12, folate and of iron, compared with girls receiving the unfortified cereal, and maintained vitamin D status, in contrast with the girls receiving the unfortified cereal (P < 0.001). Conclusions: The daily consumption of cereal with milk for 12 weeks by adolescent girls, increased intakes of micronutrients. The consumption of fortified cereal elicited greater increases than for unfortified cereal and improved biomarkers of micronutrient status. The findings justify strategies to encourage the consumption of fortified cereal with milk by adolescents, either as a breakfast or a supper

Proteome Sampling by the HLA Class I Antigen Processing Pathway

The peptide repertoire that is presented by the set of HLA class I molecules of an individual is formed by the different players of the antigen processing pathway and the stringent binding environment of the HLA class I molecules. Peptide elution studies have shown that only a subset of the human proteome is sampled by the antigen processing machinery and represented on the cell surface. In our study, we quantified the role of each factor relevant in shaping the HLA class I peptide repertoire by combining peptide elution data, in silico predictions of antigen processing and presentation, and data on gene expression and protein abundance. Our results indicate that gene expression level, protein abundance, and rate of potential binding peptides per protein have a clear impact on sampling probability. Furthermore, once a protein is available for the antigen processing machinery in sufficient amounts, C-terminal processing efficiency and binding affinity to the HLA class I molecule determine the identity of the presented peptides. Having studied the impact of each of these factors separately, we subsequently combined all factors in a logistic regression model in order to quantify their relative impact. This model demonstrated the superiority of protein abundance over gene expression level in predicting sampling probability. Being able to discriminate between sampled and non-sampled proteins to a significant degree, our approach can potentially be used to predict the sampling probability of self proteins and of pathogen-derived proteins, which is of importance for the identification of autoimmune antigens and vaccination targets

Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor

G protein-coupled receptors (GPCRs) are physiologically important transmembrane signalling proteins that trigger intracellular responses upon binding of extracellular ligands. Despite recent breakthroughs in GPCR crystallography1–3, the details of ligand induced signal transduction are not well understood owing to missing dynamical information. In principle, such information can be provided by NMR4, but so far only limited data of functional relevance on few side-chain sites of eukaryotic GPCRs have been obtained 5–9. Here we show that receptor motions can be followed at virtually any backbone site in a thermostabilized mutant of the turkey β1-adrenergic receptor (β1AR) 10–12. Labelling with [15N] valine in a eukaryotic expression system provides over twenty resolved resonances that report on structure and dynamics in six ligand complexes and the apo form. The response to the various ligands is heterogeneous in the vicinity of the binding pocket, but gets transformed into a homogeneous readout at the intracellular side of helix 5 (TM5), which correlates linearly with ligand efficacy for the G protein pathway. The effect of several pertinent, thermostabilizing point mutations was assessed by reverting them to the native sequence. Whereas the response to ligands remains largely unchanged, binding of the G protein mimetic nanobody NB80 and G protein activation are only observed when two conserved tyrosines (Y227 and Y343) are restored. Binding of NB80 leads to very strong spectral changes throughout the receptor, including the extracellular ligand entrance pocket. This indicates that even the fully thermostabilized receptor undergoes activating motions in TM5, but that the fully active state is only reached in presence of Y227 and Y343 by stabilization with a G protein-like partner. The combined analysis of chemical shift changes from the point mutations and ligand responses identifies crucial connections in the allosteric activation pathway, and presents a general experimental method to delineate signal transmission networks at high resolution in GPCRs