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

Entangled Quantum States of Magnetic Dipoles

Free magnetic moments usually manifest themselves in Curie Laws, where weak external magnetic fields produce magnetizations diverging as the reciprocal 1/T of the temperature. for a variety of materials that do not disply static magnetism, including doped semiconductors and certain rare earth intermetallics, the 1/T law is changed to a power law T^-a with a<1. We report here that a considerably simpler material, namely an insulating magneticsalt can also display such a power law, and show via comparison to specific heat data and numerical simulations that quantum mechanics is crucial for its formation. Two quantum mechanical phenomena are needed, namely level splitting - which affects the spectrum of excited states - and entanglement - where the wavefunction of a system with several degrees of freedom cannot be written as a product of wavefunctions for each degree of freedom. Entanglement effects become visible for remarkably small tunnelling terms, and are turned on well before tunnelling has visible effects on the spectrum. Our work is significant because it illustrates that entanglement is at the very heart of a very simple experimental observation for an insulating quantum spin system.Comment: 17 pages, 4 figure

T Wave Alternans in high arrhythmic risk patients: Analysis in time and frequency domains: A pilot study

BACKGROUND: T wave alternans (TA) is a repolarisation phenomenon manifesting as a microvolt beat to beat change in the amplitude of the T wave and ST segment. TA has been shown to be a predictor of arrhythmic risk in unselected myocardial infarction populations. TA has not been used to differentiate risk within the ischaemic cardiomyopathy population. METHODS: The subjects investigated comprised, Group 1: 7 stable patients with remote (>20 months) extensive myocardial scarring and no arrhythmic events (NYHA 3 and 4). Group2: 9 post infarction patients with malignant arrhythmia and implantable defibrillator. During breath holding, 20 continuous QRST complexes from each patients X, Y and Z leads were digitally recorded. Time domain, resultant absolute difference vectors (ATA), were calculated for alternate resultant T wave sequences. Group differences between the magnitude and temporal distribution of mean ATAs and their spectral and cross-spectral analysis were compared. RESULTS: Group 1 v Group 2 mean ATAs were 10.7 (7.17) v 11.7 (8.48) respectively, not significant. Each group had a homogenous temporal distribution of ATAs. Both group's largest mean ATA frequency components were between 0 to 25 Hz, the largest ATA component being at the DC frequency. Cross spectral analysis showed no significant differences in group ATA frequency content. CONCLUSION: The frequency content and microvolt magnitude of T wave alternans was not significantly different in these two groups. The specificity of T wave alternans for differentiating arrhythmic risk in post infarction scarring and heart failure needs investigation

Vascular responses of the extremities to transdermal application of vasoactive agents in Caucasian and African descent individuals

This is an accepted manuscript of an article published by Springer in European Journal of Applied Physiology on 04/04/2015, available online: https://doi.org/10.1007/s00421-015-3164-2 The accepted version of the publication may differ from the final published version.© 2015, Springer-Verlag Berlin Heidelberg. Purpose: Individuals of African descent (AFD) are more susceptible to non-freezing cold injury than Caucasians (CAU) which may be due, in part, to differences in the control of skin blood flow. We investigated the skin blood flow responses to transdermal application of vasoactive agents. Methods: Twenty-four young males (12 CAU and 12 AFD) undertook three tests in which iontophoresis was used to apply acetylcholine (ACh 1 w/v %), sodium nitroprusside (SNP 0.01 w/v %) and noradrenaline (NA 0.5 mM) to the skin. The skin sites tested were: volar forearm, non-glabrous finger and toe, and glabrous finger (pad) and toe (pad). Results: In response to SNP on the forearm, AFD had less vasodilatation for a given current application than CAU (P = 0.027–0.004). ACh evoked less vasodilatation in AFD for a given application current in the non-glabrous finger and toe compared with CAU (P = 0.043–0.014) with a lower maximum vasodilatation in the non-glabrous finger (median [interquartile], AFD n = 11, 41[234] %, CAU n = 12, 351[451] %, P = 0.011) and non-glabrous toe (median [interquartile], AFD n = 9, 116[318] %, CAU n = 12, 484[720] %, P = 0.018). ACh and SNP did not elicit vasodilatation in the glabrous skin sites of either group. There were no ethnic differences in response to NA. Conclusion: AFD have an attenuated endothelium-dependent vasodilatation in non-glabrous sites of the fingers and toes compared with CAU. This may contribute to lower skin temperature following cold exposure and the increased risk of cold injuries experienced by AFD.Published versio

Religiosity and teen birth rate in the United States

<p>Abstract</p> <p>Background</p> <p>The children of teen mothers have been reported to have higher rates of several unfavorable mental health outcomes. Past research suggests several possible mechanisms for an association between religiosity and teen birth rate in communities.</p> <p>Methods</p> <p>The present study compiled publicly accessible data on birth rates, conservative religious beliefs, income, and abortion rates in the U.S., aggregated at the state level. Data on teen birth rates and abortion originated from the Center for Disease Control; on income, from the U.S. Bureau of the Census, and on religious beliefs, from the U.S. Religious Landscape Survey carried out by the Pew Forum on Religion and Public Life. We computed correlations and partial correlations.</p> <p>Results</p> <p>Increased religiosity in residents of states in the U.S. strongly predicted a higher teen birth rate, with r = 0.73 (p < 0.0005). Religiosity correlated negatively with median household income, with r = -0.66, and income correlated negatively with teen birth rate, with r = -0.63. But the correlation between religiosity and teen birth rate remained highly significant when income was controlled for via partial correlation: the partial correlation between religiosity and teen birth rate, controlling for income, was 0.53 (p < 0.0005). Abortion rate correlated negatively with religiosity, with r = -0.45, p = 0.002. However, the partial correlation between teen birth rate and religiosity remained high and significant when controlling for abortion rate (partial correlation = 0.68, p < 0.0005) and when controlling for both abortion rate and income (partial correlation = 0.54, p = 0.001).</p> <p>Conclusion</p> <p>With data aggregated at the state level, conservative religious beliefs strongly predict U.S. teen birth rates, in a relationship that does not appear to be the result of confounding by income or abortion rates. One possible explanation for this relationship is that teens in more religious communities may be less likely to use contraception.</p

Estimation of Recurrence of Colorectal Adenomas with Dependent Censoring Using Weighted Logistic Regression

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial

Impact of statins and ACE inhibitors on mortality after COPD exacerbations

<p>Abstract</p> <p>Background</p> <p>The purpose of our study was to examine the association of prior outpatient use of statins and angiotensin converting enzyme (ACE) inhibitors on mortality for subjects ≥ 65 years of age hospitalized with acute COPD exacerbations.</p> <p>Methods</p> <p>We conducted a retrospective national cohort study using Veterans Affairs administrative data including subjects ≥65 years of age hospitalized with a COPD exacerbation. Our primary analysis was a multilevel model with the dependent variable of 90-day mortality and hospital as a random effect, controlling for preexisting comorbid conditions, demographics, and other medications prescribed.</p> <p>Results</p> <p>We identified 11,212 subjects with a mean age of 74.0 years, 98% were male, and 12.4% of subjects died within 90-days of hospital presentation. In this cohort, 20.3% of subjects were using statins, 32.0% were using ACE inhibitors or angiotensin II receptor blockers (ARB). After adjusting for potential confounders, current statin use (odds ratio 0.51, 95% confidence interval 0.40–0.64) and ACE inhibitor/ARB use (0.55, 0.46–0.66) were significantly associated with decreased 90-day mortality.</p> <p>Conclusion</p> <p>Use of statins and ACE inhibitors prior to admission is associated with decreased mortality in subjects hospitalized with a COPD exacerbation. Randomized controlled trials are needed to examine whether the use of these medications are protective for those patients with COPD exacerbations.</p

Genetic and environmental influences on the stability of withdrawn behavior in children: A longitudinal, multi-informant twin study.

We examined the contribution of genetic and environmental influences on the stability of withdrawn behavior (WB) in childhood using a longitudinal multiple rater twin design. Maternal and paternal ratings on the withdrawn subscale of the Child Behavior Checklist (CBCL) were obtained from 14,889 families when the twins were 3, 7, 10 and 12 years old. A longitudinal psychometric model was fitted to the data and the fit of transmission and common factor models were evaluated for each variance component. WB showed considerable stability throughout childhood, with correlation coefficients ranging from about .30 for the 9-year time interval to .65 for shorter time intervals. Individual differences in WB as observed by the mother and the father were found to be largely influenced by genetic effects at all four time points, in both boys (50–66%) and girls (38–64%). Shared environmental influences explained a small to modest proportion (0–24%) of the variance at all ages and were slightly more pronounced in girls. Non-shared environmental influences were of moderate importance to the variance and slightly increased with age, from 22–28% at age 3 to 35–41% at age 12 years. The stability of WB was largely explained by genetic effects, accounting for 74% of stability in boys and 65% in girls. Shared environmental effects explained 7% (boys) and 17% (girls) of the behavioral stability. Most shared environmental effects were common to both raters, suggesting little influence of rater bias in the assessment of WB. The shared environmental effects common to both raters were best described by a common factor model, indicating that these effects are stable and persistent throughout childhood. Non-shared environmental effects accounted for the remaining covariance over time