Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Sexual function in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

BACKGROUND: Despite its importance to sexual health and wellbeing, sexual function is given little attention in sexual health policy. Population-based studies are needed to understand sexual function across the life course. METHODS: We undertook a probability sample survey (the third National Survey of Sexual Attitudes and Lifestyles [Natsal-3]) of 15,162 individuals aged 16-74 years who lived in Britain (England, Scotland, and Wales). Interviews were done between Sept 6, 2010, and Aug 31, 2012. We assessed the distribution of sexual function by use of a novel validated measure (the Natsal-SF), which assessed problems with individual sexual response, sexual function in a relationship context, and self-appraisal of sex life (17 items; 16 items per gender). We assess factors associated with low sexual function (defined as the lowest quintile of distribution of Natsal-SF scores) and the distribution of components of the measure. Participants reporting one or more sexual partner in the past year were given a score on the Natsal-SF (11,690 participants). 4122 of these participants were not in a relationship for all of the past year and we employed the full information maximum likelihood method to handle missing data on four relationship items. FINDINGS: We obtained data for 4913 men and 6777 women for the Natsal-SF. For men and women, low sexual function was associated with increased age, and, after age-adjustment, with depression (adjusted odds ratio 3·70 [95% CI 2·90-4·72] for men and 4·11 [3·36-5·04] for women) and self-reported poor health status (2·63 [1·73-3·98] and 2·41 [1·72-3·39]). Low sexual function was also associated with experiencing the end of a relationship (1·52 [1·18-1·95] and 1·77 [1·44-2·17]), inability to talk easily about sex with a partner (2·36 [1·94-2·88] and 2·82 [2·28-3·48]), and not being happy in the relationship (2·89 [2·32-3·61] and 4·10 [3·39-4·97]). Associations were also noted with engaging in fewer than four sex acts in the past 4 weeks (3·13 [2·58-3·79] and 3·38 [2·80-4·09]), having had same sex partners (2·28 [1·56-3·35] and 1·60 [1·16-2·20]), paying for sex (in men only; 2·62 [1·46-4·71]), and higher numbers of lifetime sexual partners (in women only; 2·12 [1·68-2·67] for ten or more partners). Low sexual function was also associated with negative sexual health outcomes such as experience of non-volitional sex (1·98 [1·14-3·43] and 2·18 [1·79-2·66]) and STI diagnosis (1·50 [1·06-2·11] and 1·83 [1·35-2·47]). Among individuals reporting sex in the past year, problems with sexual response were common (41·6% of men and 51·2% of women reported one or more problem) but self-reported distress about sex lives was much less common (9·9% and 10·9%). For individuals in a sexual relationship for the past year, 23·4% of men and 27·4% of women reported an imbalance in level of interest in sex between partners, and 18·0% of men and 17·1% of women said that their partner had had sexual difficulties. Most participants who did not have sex in the past year were not dissatisfied, distressed, or avoiding sex because of sexual difficulties. INTERPRETATION: Wide variability exists in the distribution of sexual function scores. Low sexual function is associated with negative sexual health outcomes, supporting calls for a greater emphasis on sexual function in sexual health policy and interventions. FUNDING: Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health

The Value Relevance of Earnings and Nonearnings Information in Regulated and Deregulated Markets: The Case of the Airline Industry

Regulated markets, Valuation relevance, Earnings and nonearnings information, Airline industry,

Childhood obesity intervention studies: A narrative review and guide for investigators, authors, editors, reviewers, journalists, and readers to guard against exaggerated effectiveness claims.

Being able to draw accurate conclusions from childhood obesity trials is important to make advances in reversing the obesity epidemic. However, obesity research sometimes is not conducted or reported to appropriate scientific standards. To constructively draw attention to this issue, we present 10 errors that are commonly committed, illustrate each error with examples from the childhood obesity literature, and follow with suggestions on how to avoid these errors. These errors are as follows: using self-reported outcomes and teaching to the test; foregoing control groups and risking regression to the mean creating differences over time; changing the goal posts; ignoring clustering in studies that randomize groups of children; following the forking paths, subsetting, p-hacking, and data dredging; basing conclusions on tests for significant differences from baseline; equating no statistically significant difference with equally effective ; ignoring intervention study results in favor of observational analyses; using one-sided testing for statistical significance; and stating that effects are clinically significant even though they are not statistically significant. We hope that compiling these errors in one article will serve as the beginning of a checklist to support fidelity in conducting, analyzing, and reporting childhood obesity research