Folding and insertion thermodynamics of the transmembrane WALP peptide

The anchor of most integral membrane proteins consists of one or several helices spanning the lipid bilayer. The WALP peptide, GWW(LA)$_n$(L)WWA, is a common model helix to study the fundamentals of protein insertion and folding, as well as helix-helix association in the membrane. Its structural properties have been illuminated in a large number of experimental and simulation studies. In this combined coarse-grained and atomistic simulation study, we probe the thermodynamics of a single WALP peptide, focusing on both the insertion across the water-membrane interface, as well as folding in both water and a membrane. The potential of mean force characterizing the peptide's insertion into the membrane shows qualitatively similar behavior across peptides and three force fields. However, the Martini force field exhibits a pronounced secondary minimum for an adsorbed interfacial state, which may even become the global minimum---in contrast to both atomistic simulations and the alternative PLUM force field. Even though the two coarse-grained models reproduce the free energy of insertion of individual amino acids side chains, they both underestimate its corresponding value for the full peptide (as compared with atomistic simulations), hinting at cooperative physics beyond the residue level. Folding of WALP in the two environments indicates the helix as the most stable structure, though with different relative stabilities and chain-length dependence.Comment: 12 pages, 5 figure

Reliable estimation of prediction uncertainty for physico-chemical property models

The predictions of parameteric property models and their uncertainties are sensitive to systematic errors such as inconsistent reference data, parametric model assumptions, or inadequate computational methods. Here, we discuss the calibration of property models in the light of bootstrapping, a sampling method akin to Bayesian inference that can be employed for identifying systematic errors and for reliable estimation of the prediction uncertainty. We apply bootstrapping to assess a linear property model linking the 57Fe Moessbauer isomer shift to the contact electron density at the iron nucleus for a diverse set of 44 molecular iron compounds. The contact electron density is calculated with twelve density functionals across Jacob's ladder (PWLDA, BP86, BLYP, PW91, PBE, M06-L, TPSS, B3LYP, B3PW91, PBE0, M06, TPSSh). We provide systematic-error diagnostics and reliable, locally resolved uncertainties for isomer-shift predictions. Pure and hybrid density functionals yield average prediction uncertainties of 0.06-0.08 mm/s and 0.04-0.05 mm/s, respectively, the latter being close to the average experimental uncertainty of 0.02 mm/s. Furthermore, we show that both model parameters and prediction uncertainty depend significantly on the composition and number of reference data points. Accordingly, we suggest that rankings of density functionals based on performance measures (e.g., the coefficient of correlation, r2, or the root-mean-square error, RMSE) should not be inferred from a single data set. This study presents the first statistically rigorous calibration analysis for theoretical Moessbauer spectroscopy, which is of general applicability for physico-chemical property models and not restricted to isomer-shift predictions. We provide the statistically meaningful reference data set MIS39 and a new calibration of the isomer shift based on the PBE0 functional.Comment: 49 pages, 9 figures, 7 table

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Accelerating Community College Graduation Rates: A Benefit–Cost Analysis

This article reports a benefit–cost evaluation of the Accelerated Study in Associate Programs (ASAP) of the City University of New York (CUNY). ASAP was designed to accelerate associate degree completion within 3 years of degree enrollment at CUNY’s community colleges. The program evaluation revealed that the completion rate for the examined cohort increased from 24.1% to 54.9%, and cost per graduate declined considerably (Levin & Garcia, 2012; Linderman & Kolenovic, 2012). The returns on investment to the taxpayer include the benefits from higher tax revenues and lower costs of spending on public health, criminal justice, and public assistance. For each dollar of investment in ASAP by taxpayers, the return was $3 to$4. For each additional graduate, the taxpayer gained an amount equal to a certificate of deposit with a value of $146,000 (net of the costs of the investment). Based on these estimated returns, a cohort of 1,000 students enrolled in ASAP would generate net fiscal benefits for the taxpayer of more than$46 million relative to enrolling in the conventional degree program. ASAP results demonstrate that an effective educational policy can generate returns to the taxpayer that vastly exceed the public investment required

Effect of medication review and cognitive behaviour treatment by community pharmacists of patients discharged from the hospital on drug related problems and compliance: design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Drug related problems (DRPs) are common among elderly patients who are discharged from the hospital and are using several drugs for their chronic diseases. Examples of drug related problems are contra-indications, interactions, adverse drug reactions and inefficacy of treatment. Causes of these problems include prescription errors and non-compliance with treatment. The aim of this study is to examine the effect of <it>medication review </it>and <it>cognitive behaviour therapy </it>of discharged patients by community pharmacists to minimize the occurrence of drug related problems.</p> <p>Methods/Design</p> <p>A randomized controlled trial will be performed. Community pharmacists will be randomized into a control group and an intervention group. 342 Patients, aged over 60 years, discharged from general and academic hospitals, using five or more prescription drugs for their chronic disease will be asked by their pharmacy to participate in the study.</p> <p>Patients randomized to the control group will receive usual care according to the Dutch Pharmacy Standard. The medication of patients randomised to the intervention group will be reviewed by the community pharmacist with use of the national guidelines for the treatment of diseases, when patients are discharged from the hospital. The Pharmaceutical Care network Europe Registration form will be used to record drug related problems. Trained pharmacy technicians will counsel patients at home at baseline and at 1,3,6,9 and 12 months, using Cognitive Behaviour Treatment according to the Theory of Planned Behaviour. The patient's attitude towards medication and patient's adherence will be subject of the cognitive behaviour treatment. The counselling methods that will be used are <it>motivational interviewing </it>and <it>problem solving treatment</it>. Patients adherence towards drug use will be determined with use of the Medication Adherence Report Scale Questionnaire. There will be a follow-up of 12 months.</p> <p>The two primary outcome measures are the difference in occurrence of DRPs between intervention and control group and adherence with drug use. Secondary endpoints are attitude towards drug use, incidence of Re-hospitalisations related to medicines, functional status of the patient, quality of life and the cost-effectiveness of this intervention.</p> <p>Discussion</p> <p>Combining both medication review and Cognitive Behaviour Treatment may decrease DRPs and may result in more compliance with drug use among patients discharged from the hospital and using 5 or more chronic drugs.</p> <p>Trial registration</p> <p>Dutch Trial Register NTR1194</p

A bootstrap approach for assessing the uncertainty of outcome probabilities when using a scoring system

Background: Scoring systems are a very attractive family of clinical predictive models, because the patient score can be calculated without using any data processing system. Their weakness lies in the difficulty of associating a reliable prognostic probability with each score. In this study a bootstrap approach for estimating confidence intervals of outcome probabilities is described and applied to design and optimize the performance of a scoring system for morbidity in intensive care units after heart surgery. Methods: The bias-corrected and accelerated bootstrap method was used to estimate the 95% confidence intervals of outcome probabilities associated with a scoring system. These confidence intervals were calculated for each score and each step of the scoring-system design by means of one thousand bootstrapped samples. 1090 consecutive adult patients who underwent coronary artery bypass graft were assigned at random to two groups of equal size, so as to define random training and testing sets with equal percentage morbidities. A collection of 78 preoperative, intraoperative and postoperative variables were considered as likely morbidity predictors. Results: Several competing scoring systems were compared on the basis of discrimination, generalization and uncertainty associated with the prognostic probabilities. The results showed that confidence intervals corresponding to different scores often overlapped, making it convenient to unite and thus reduce the score classes. After uniting two adjacent classes, a model with six score groups not only gave a satisfactory trade-off between discrimination and generalization, but also enabled patients to be allocated to classes, most of which were characterized by well separated confidence intervals of prognostic probabilities. Conclusions: Scoring systems are often designed solely on the basis of discrimination and generalization characteristics, to the detriment of prediction of a trustworthy outcome probability. The present example demonstrates that using a bootstrap method for the estimation of outcome-probability confidence intervals provides useful additional information about score-class statistics, guiding physicians towards the most convenient model for predicting morbidity outcomes in their clinical context

The RESOLVE Survey Atomic Gas Census and Environmental Influences on Galaxy Gas Reservoirs

We present the H i mass inventory for the REsolved Spectroscopy Of a Local VolumE (RESOLVE) survey, a volume-limited, multi-wavelength census of >1500 z = 0 galaxies spanning diverse environments and complete in baryonic mass down to dwarfs of ~109 ${M}_{\odot }$. This first 21 cm data release provides robust detections or strong upper limits (1.4M H i 1012 ${M}_{\odot }$) halos, suggesting that gas stripping and/or starvation may be induced by interactions with larger halos or the surrounding cosmic web. We find that the detailed relationship between G/S and environment varies when we examine different subvolumes of RESOLVE independently, which we suggest may be a signature of assembly bias

Strongly exchange-coupled triplet pairs in an organic semiconductor

From biological complexes to devices based on organic semiconductors, spin interactions play a key role in the function of molecular systems. For instance, triplet-pair reactions impact operation of organic light-emitting diodes as well as photovoltaic devices. Conventional models for triplet pairs assume they interact only weakly. Here, using electron spin resonance, we observe long-lived, strongly-interacting triplet pairs in an organic semiconductor, generated via singlet fission. Using coherent spin-manipulation of these two-triplet states, we identify exchange-coupled (spin-2) quintet complexes co-existing with weakly coupled (spin-1) triplets. We measure strongly coupled pairs with a lifetime approaching 3 µs and a spin coherence time approaching 1 µs, at 10 K. Our results pave the way for the utilization of high-spin systems in organic semiconductors.Gates-Cambridge Trust, Winton Programme for the Physics of Sustainability, Freie Universität Berlin within the Excellence Initiative of the German Research Foundation, Engineering and Physical Sciences Research Council (Grant ID: EP/G060738/1)This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nphys3908