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

Preliminary Clinical Experience with Androgen Administration for Pre- and Postmenopausal Women with Hypoactive Sexual Desire.

The present study examined effects of testosterone on hypoactive sexual desire in pre- and postmenopausal women (treated) compared with an age-matched reference group (reference). Treated participants received 100 mg of testosterone cypionate in oil injected intramuscularly (i.m.) monthly for 3 months. We measured salivary testosterone and scores on the Sexual Desire Inventory pretreatment and posttreatment. Treated and reference participants' baseline testosterone was equivalent, however, treated participants exhibited higher testosterone levels than did reference participants posttreatment. As expected, treated participants exhibited lower baseline sexual desire than did reference participants and showed a significant increase in sexual desire posttreatment. This research suggests that testosterone may effectively alleviate hypoactive sexual desire, even in women with normal testosterone levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83870/1/preliminary_clinical_experience.pd

Adolescent Female Text Messaging Preferences to Prevent Pregnancy After an Emergency Department Visit: A Qualitative Analysis

Background: Over 15 million adolescents use the emergency department (ED) each year in the United States. Adolescent females who use the ED for medical care have been found to be at high risk for unintended pregnancy. Given that adolescents represent the largest users of text messaging and are receptive to receiving text messages related to their sexual health, the ED visit represents an opportunity for intervention. Objective: The aim of this qualitative study was to explore interest in and preferences for the content, frequency, and timing of an ED-based text message intervention to prevent pregnancy for adolescent females. Methods: We conducted semistructured, open-ended interviews in one urban ED in the United States with adolescent females aged 14-19 years. Eligible subjects were adolescents who were sexually active in the past 3 months, presented to the ED for a reproductive health complaint, owned a mobile phone, and did not use effective contraception. Using an interview guide, enrollment continued until saturation of key themes. The investigators designed sample text messages using the Health Beliefs Model and participants viewed these on a mobile phone. The team recorded, transcribed, and coded interviews based on thematic analysis using the qualitative analysis software NVivo and Excel. Results: Participants (n=14) were predominantly Hispanic (13/14; 93%), insured (13/14; 93%), ED users in the past year (12/14; 86%), and frequent text users (10/14; 71% had sent or received >30 texts per day). All were interested in receiving text messages from the ED about pregnancy prevention, favoring messages that were “brief,” “professional,” and “nonaccusatory.” Respondents favored texts with links to websites, repeated information regarding places to receive “confidential” care, and focused information on contraception options and misconceptions. Preferences for text message frequency varied from daily to monthly, with random hours of delivery to maintain “surprise.” No participant feared that text messages would violate her privacy. Conclusions: Adolescent female patients at high pregnancy risk are interested in ED-based pregnancy prevention provided by texting. Understanding preferences for the content, frequency, and timing of messages can guide in designing future interventions in the ED

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

Solution-based intramolecular singlet fission in cross-conjugated pentacene dimers

We show unambiguous and compelling evidence by means of pump–probe experiments, which are complemented by calculations using ab initio multireference perturbation theory, for intramolecular singlet fission (SF) within two synthetically tailored pentacene dimers with cross-conjugation, namely XC1 and XC2. The two pentacene dimers differ in terms of electronic interactions as evidenced by perturbation of the ground state absorption spectra stemming from stronger through-bond contributions in XC1 as confirmed by theory. Multiwavelength analysis, on one hand, and global analysis, on the other hand, confirm that the rapid singlet excited state decay and triplet excited state growth relate to SF. SF rate constants and quantum yields increase with solvent polarity. For example, XC2 reveals triplet quantum yields and rate constants as high as 162 ± 10% and (0.7 ± 0.1) × 1012 s−1, respectively, in room temperature solutions

Estimating uncertainty in ecosystem budget calculations

© The Authors, 2010. This article is distributed under the terms of the Creative Commons Attribution-Noncommercial License. The definitive version was published in Ecosystems 13 (2010): 239-248, doi:10.1007/s10021-010-9315-8.Ecosystem nutrient budgets often report values for pools and fluxes without any indication of uncertainty, which makes it difficult to evaluate the significance of findings or make comparisons across systems. We present an example, implemented in Excel, of a Monte Carlo approach to estimating error in calculating the N content of vegetation at the Hubbard Brook Experimental Forest in New Hampshire. The total N content of trees was estimated at 847 kg ha−1 with an uncertainty of 8%, expressed as the standard deviation divided by the mean (the coefficient of variation). The individual sources of uncertainty were as follows: uncertainty in allometric equations (5%), uncertainty in tissue N concentrations (3%), uncertainty due to plot variability (6%, based on a sample of 15 plots of 0.05 ha), and uncertainty due to tree diameter measurement error (0.02%). In addition to allowing estimation of uncertainty in budget estimates, this approach can be used to assess which measurements should be improved to reduce uncertainty in the calculated values. This exercise was possible because the uncertainty in the parameters and equations that we used was made available by previous researchers. It is important to provide the error statistics with regression results if they are to be used in later calculations; archiving the data makes resampling analyses possible for future researchers. When conducted using a Monte Carlo framework, the analysis of uncertainty in complex calculations does not have to be difficult and should be standard practice when constructing ecosystem budgets