Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH–mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum–associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.

In Neisseria meningitidis, iron-responsive gene regulation is mediated primarily by the ferric uptake regulator (Fur) protein. When complexed with iron, Fur represses gene expression by preventing transcription initiation. Fur can also indirectly activate gene expression via the repression of regulatory small RNAs (sRNA). One such Fur- and iron-regulated sRNA, NrrF, was previously identified in N. meningitidis and shown to repress expression of the sdhA and sdhC genes encoding subunits of the succinate dehydrogenase complex. In the majority of Gram-negative bacteria, sRNA-mediated regulation requires a cofactor RNA-binding protein (Hfq) for proper gene regulation and stabilization. In this study, we examined the role of Hfq in NrrF-mediated regulation of the succinate dehydrogenase genes in N. meningitidis and the effect of an hfq mutation on iron-responsive gene regulation more broadly. We first demonstrated that the stability of NrrF, as well as the regulation of sdhC and sdhA in vivo, was unaltered in the hfq mutant. Secondly, we established that iron-responsive gene regulation of the Fur-regulated sodB gene was dependent on Hfq. Finally, we demonstrated that in N. meningitidis, Hfq functions in a global manner to control expression of many ORFs and intergenic regions via iron-independent mechanisms. Collectively these studies demonstrate that in N. meningitidis, iron- and NrrF-mediated regulation of sdhC and sdhA can occur independently of Hfq, although Hfq functions more globally to control regulation of other N. meningitidis genes primarily by iron-independent mechanisms.

Background The link between chronic diseases and the Big 6 lifestyle risk behaviors (ie, poor diet, physical inactivity, smoking, alcohol use, sedentary recreational screen time, and poor sleep) is well established. It is critical to target these lifestyle risk behaviors, as they often co-occur and emerge in adolescence. Smartphones have become an integral part of everyday life, and many adolescents already use mobile apps to monitor their lifestyle behaviors and improve their health. Smartphones may be a valuable platform for engaging adolescents with interventions to prevent key chronic disease risk behaviors. Objective The aim of this paper is to describe the development, usability, and acceptability of the Health4Life app, a self-monitoring smartphone app for adolescents that concurrently targets the Big 6 lifestyle behaviors. Methods The development of the Health4Life app was an iterative process conducted in collaboration with adolescents and experts. The development process consisted of three stages: scoping the literature; end user consultations, which included a web-based survey (N=815; mean age 13.89, SD 0.89 years) and a focus group (N=12) among adolescents; and app development and beta testing. Following this development work, 232 adolescents were asked to rate the usability and acceptability of the app. Results The process resulted in a self-monitoring smartphone app that allows adolescent users to track and set goals for the Big 6 health behaviors, using in-app rewards and notifications to enhance engagement. The overall adolescent feedback was positive in terms of user-friendly design, content, relevance, and helpfulness. Commonly identified areas for improvement were to increase interactive features and display recorded health behaviors differently to improve interpretability. Conclusions The Health4Life app is a co-designed, self-monitoring smartphone app for adolescents that concurrently targets the Big 6 lifestyle behaviors. Adolescents rated the app as highly acceptable and usable. The app has the potential to efficiently and effectively modify important risk factors for chronic disease among young people and is currently being evaluated in a world-first trial of 6640 secondary school students in 71 schools across Australia.

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Background: Six core behavioural risk factors (poor diet, physical activity, sedentary behaviour, alcohol misuse, smoking and unhealthy sleep patterns) have been identified as strong determinants of chronic disease, such as cardiovascular disease, diabetes and cancers. Smartphones have the potential to provide a real-time, pervasive, unobtrusive and cost-effective way to measure health behaviours and deliver instant feedback to users. Despite this, validity of using smartphones to measure these six key behaviours is largely unknown. The proposed systematic review aims to address this gap by identifying existing smartphone-based approaches to measure these health behaviours and critically appraising, comparing and summarizing the quality of their measurement properties. Methods: A systematic search of the Ovid MEDLINE, Embase (Elsevier), Cochrane Library (Wiley), PsychINFO (EBSCOhost), CINAHL (EBSCOHost), Web of Science (Clarivate), SPORTDiscus (EBSCOhost) and IEEE Xplore Digital Library databases will be conducted from January 2007 to March 2020. Eligible studies will be those written in English that measure at least one of the six health behaviours of interest via a smartphone and report on at least one measurement property. The primary outcomes will be validity, reliability and/or responsiveness of these measurement approaches. A secondary outcome will be the feasibility (e.g. user burden, usability and cost) of identified approaches. No restrictions will be placed on the participant population or study design. Two reviewers will independently screen studies for eligibility, extract data and assess the risk of bias. The study methodological quality (or bias) will be appraised using an appropriate tool. Our results will be described in a narrative synthesis. If feasible, random effects meta-analysis will be conducted where appropriate.