Compound C inhibits nonsense-mediated RNA decay independently of AMPK

The nonsense mediated RNA decay (NMD) pathway safeguards the integrity of the transcriptome by targeting mRNAs with premature translation termination codons (PTCs) for degradation. It also regulates gene expression by degrading a large number of non-mutant RNAs (including mRNAs and noncoding RNAs) that bear NMD-inducing features. Consequently, NMD has been shown to influence development, cellular response to stress, and clinical outcome of many genetic diseases. Small molecules that can modulate NMD activity provide critical tools for understanding the mechanism and physiological functions of NMD, and they also offer potential means for treating certain genetic diseases and cancer. Therefore, there is an intense interest in identifying small-molecule NMD inhibitors or enhancers. It was previously reported that both inhibition of NMD and treatment with the AMPK-selective inhibitor Compound C (CC) induce autophagy in human cells, raising the possibility that CC may be capable of inhibiting NMD. Here we show that CC indeed has a NMD-inhibitory activity. Inhibition of NMD by CC is, however, independent of AMPK activity. As a competitive ATP analog, CC does not affect the kinase activity of SMG1, an essential NMD factor and the only known kinase in the NMD pathway. However, CC treatment down-regulates the protein levels of several NMD factors. The induction of autophagy by CC treatment is independent of ATF4, a NMD target that has been shown to promote autophagy in response to NMD inhibition. Our results reveal a new activity of CC as a NMD inhibitor, which has implications for its use in basic research and drug development

Tracer concentration profiles measured in central London as part of the REPARTEE campaign

There have been relatively few tracer experiments carried out that have looked at vertical plume spread in urban areas. In this paper we present results from two tracer (cyclic perfluorocarbon) experiments carried out in 2006 and 2007 in central London centred on the BT Tower as part of the REPARTEE (Regent’s Park and Tower Environmental Experiment) campaign. The height of the tower gives a unique opportunity to study vertical dispersion profiles and transport times in central London. Vertical gradients are contrasted with the relevant Pasquill stability classes. Estimation of lateral advection and vertical mixing times are made and compared with previous measurements. Data are then compared with a simple operational dispersion model and contrasted with data taken in central London as part of the DAPPLE campaign. This correlates dosage with non-dimensionalised distance from source. Such analyses illustrate the feasibility of the use of these empirical correlations over these prescribed distances in central London

Extending periodic eddy covariance latent heat fluxes through tree sap-flow measurements to estimate long-term total evaporation in a peat swamp forest

A combination of measurement and modelling was used to find a pragmatic solution to estimate the annual total evaporation from the rare and indigenous Nkazana Peat Swamp Forest (PSF) on the east coast of Southern Africa to improve the water balance estimates within the area. Actual total evaporation (ETa) was measured during three window periods (between 7 and 9 days each) using an eddy covariance (EC) system on a telescopic mast above the forest canopy. Sap flows of an understory tree and an emergent tree were measured using a low-maintenance heat pulse velocity system for an entire hydrological year (October 2009 to September 2010). An empirical model was derived, describing the relationship between ETa from the Nkazana PSF and sap-flow measurements. These overlapped during two of the window periods (R2 = 0.92 and 0.90), providing hourly estimates of ETa from the Nkazana PSF for a year, totalling 1125 mm (while rainfall was 650 mm). In building the empirical model, it was found that to include the understory tree sap flow provided no benefit to the model performance. In addition, the relationship between the emergent tree sap flow with ETa between the two field campaigns was consistent and could be represented by a single empirical model (R2 = 0.90; RMSE = 0.08 mm h−1). During the window periods of EC measurement, no single meteorological variable was found to describe the Nkazana PSF ETa satisfactorily. However, in terms of evaporation models, the hourly FAO Penman–Monteith reference evaporation (ETo) best described ETa during the August 2009 (R2 = 0.75), November 2009 (R2 = 0.85) and March 2010 (R2 = 0.76) field campaigns, compared to the Priestley–Taylor potential evaporation (ETp) model (R2 = 0.54, 0.74 and 0.62 during the respective field campaigns). From the extended record of ETa (derived in this study from sap flow) and ETo, a monthly crop factor (Kc) was derived for the Nkazana PSF, providing a method of estimating long-term swamp forest water-use from meteorological data. The monthly Kc indicated two distinct periods. From February to May, it was between 1.2 and 1.4 compared with June to January, when the crop factor was 0.8 to 1.0. The derived monthly Kc values were verified as accurate (to one significant digit) using historical data measured at the same site, also using EC, from a previous study. The measurements provided insights into the microclimate within a subtropical peat swamp forest and the contrasting sap flow of emergent and understory trees. They showed that expensive, high-maintenance equipment can be used during manageable window periods in conjunction with low-maintenance systems, dedicated to individual trees, to derive a model to estimate long-term ETa over remote heterogeneous forests. In addition, the contrast in annual ETa and rainfall emphasised the reliance of the Nkazana PSF on groundwater

Automated psychological therapy using immersive virtual reality for treatment of fear of heights: A single-blind, parallel-group, randomised controlled trial

Background Engaging, interactive, and automated virtual reality (VR) treatments might help solve the unmet needs of individuals with mental health disorders. We tested the efficacy of an automated cognitive intervention for fear of heights guided by an avatar virtual coach (animated using motion and voice capture of an actor) in VR and delivered with the latest consumer equipment. Methods We did a randomised trial of automated VR versus usual care. We recruited adults aged older than 18 years with a fear of heights by radio advertisements in Oxfordshire, UK. We diagnosed fear of heights if participants scored more than 29 on the Heights Interpretation Questionnaire (HIQ). We randomly allocated participants by computer in a 1:1 ratio to either automated VR delivered in roughly six 30-min sessions administered about two to three times a week over a 2-week period (intervention group) or to usual care (control group). Randomisation was stratified by severity of fear of heights. The research team, who were unaware of the random allocation, administered three fear-of-height assessments, at baseline (0 weeks), at the end of treatment (2 weeks), and at follow-up (4 weeks). The primary outcome measure was HIQ score (range 16–80, with higher scores indicating greater severity). This trial is registered with the ISRCTN registry, number ISRCTN11898283. Findings Between Nov 25, 2017, and Feb 27, 2018, 100 individuals were enrolled and underwent randomisation, of whom 49 were assigned to the VR treatment group and 51 to the control group. All participants completed the 4-week follow-up. The mean total treatment time in VR was 124·43 min (SD 34·23). Compared with participants in the control group, the VR treatment reduced fear of heights at the end of treatment (mean change score −24·5 [SD 13·1] in the VR group vs −1·2 [7·3] in the control group; adjusted difference −24·0, 95% CI −27·7 to −20·3; Cohen's d=2·0; p<0·0001). The benefit was maintained at follow-up (mean change score −25·1 [SD 13·9] in the VR group vs −1·5 [7·8] in the control group; adjusted difference −24·3, 95% CI −27·9 to −20·6; Cohen's d=2·0; p<0·0001). The number needed to treat to at least halve the fear of heights was 1·3. No adverse events were reported. Interpretation Psychological therapy delivered automatically by a VR coach can produce large clinical benefits. Evidence-based VR treatments have the potential to greatly increase treatment provision for mental health disorders

Doctor Referral of Overweight People to a Low-Energy Treatment (DROPLET) in primary care using total diet replacement products:A protocol for a randomised controlled trial

Introduction The global prevalence of obesity has risen significantly in recent decades. There is a pressing need to identify effective interventions to treat established obesity that can be delivered at scale. The aim of the Doctor Referral of Overweight People to a Low-Energy Treatment (DROPLET) study is to determine the clinical effectiveness, feasibility and acceptability of referral to a low-energy total diet replacement programme compared with usual weight management interventions in primary care. Methods and analysis The DROPLET trial is a randomised controlled trial comparing a low-energy total diet replacement programme with usual weight management interventions delivered in primary care. Eligible patients will be recruited through primary care registers and randomised to receive a behavioural support programme delivered by their practice nurse or a referral to a commercial provider offering an initial 810 kcal/d low-energy total diet replacement programme for 8 weeks, followed by gradual food reintroduction, along with weekly behavioural support for 24 weeks. The primary outcome is weight change at 12 months. The secondary outcomes are weight change at 3 and 6 months, the proportion of participants achieving 5% and 10% weight loss at 12 months, and change in fat mass, haemoglobin A1c, low-density lipoprotein cholesterol and systolic and diastolic blood pressure at 12 months. Data will be analysed on the basis of intention to treat. Qualitative interviews on a subsample of patients and healthcare providers will assess their experiences of the weight loss programmes and identify factors affecting acceptability and adherence. Ethics and dissemination This study has been reviewed and approved by the National Health ServiceHealth Research Authority (HRA)Research Ethics Committee (Ref: SC/15/0337). The trial findings will be disseminated to academic and health professionals through presentations at meetings and peer-reviewed journals and to the public through the media. If the intervention is effective, the results will be communicated to policymakers and commissioners of weight management services.</p

The equity impact of brief opportunistic interventions to promote weight loss in primary care:secondary analysis of the BWeL randomised trial

BACKGROUND:Guidelines recommend that clinicians should make brief opportunistic behavioural interventions to patients who are obese to increase the uptake of effective weight loss programmes. The objective was to assess the effect of this policy on socioeconomic equity. METHODS:One thousand eight hundred eighty-two consecutively attending patients with obesity and who were not seeking support for weight loss from their GP were enrolled in a trial. Towards the end of each consultation, GPs randomly assigned participants to one of two 30-s interventions. In the active intervention (support arm), the GP offered referral to a weight management group. In the control intervention (advice arm), the GP advised the patient that their health would benefit from weight loss. Agreement to attend a behavioural weight loss programme, attendance at the programme and weight loss at 12 months were analysed by socioeconomic status, measured by postcode using the Index of Multiple Deprivation (IMD). RESULTS:Mean weight loss was 2.43 kg (sd 6.49) in the support group and 1.04 kg (sd 5.50) for the advice only group, but these effects were moderated by IMD (p = 0.039 for the interaction). In the support arm, weight loss was greater in higher socioeconomic groups. Participants from lower socioeconomic backgrounds were more likely to accept the offer and equally likely to attend a weight loss referral but attended fewer sessions. Adjusting for these sequentially reduced the gradient for the association of socioeconomic status with weight loss from + 0.035 to - 0.001 kg/IMD point. In the advice only arm, 10% took effective action to promote weight loss. The decision to seek support for weight loss outside of the trial did not differ by socioeconomic status, but weight loss among deprived participants who used external support was greater than among more affluent participants (p = 0.025). CONCLUSION:Participants' responses to GPs' brief opportunistic interventions to promote weight loss differed by socioeconomic status and trial arm. In the support arm, more deprived people lost less weight because they attended fewer sessions at the programme. In the advice arm, more deprived people who sought and paid for support for weight loss themselves lost more weight than more affluent people who sought support. TRIAL REGISTRATION:This trial is registered with the ISRCTN registry, number ISRCTN26563137 . Date of registration: January 3, 2013; date of first participant recruited: June 4, 2014

Comparison of the genetic algorithm and incremental optimisation routines for a Bayesian inverse modelling based network design

The design of an optimal network of atmospheric monitoring stations for the observation of carbon dioxide (CO2) concentrations can be obtained by applying an optimisation algorithm to a cost function based on minimising posterior uncertainty in the CO2; fluxes obtained from a Bayesian inverse modelling solution. Two candidate optimisation methods assessed were the evolutionary algorithm: the Genetic Algorithm (GA), and the deterministic algorithm: the Incremental Optimisation (IO) routine. This paper assessed the ability of the IO routine in comparison to the more computationally demanding GA routine to optimise the placement of a five-member network of CO2 monitoring sites located in South Africa. The comparison considered the reduction in uncertainty of the overall flux estimate, the spatial similarity of solutions, and computational requirements. Although the IO routine failed to find the solution with the global maximum uncertainty reduction, the resulting solution had only fractionally lower uncertainty reduction compared with the GA, and at only a quarter of the computational resources used by the lowest specified GA algorithm. The GA solution set showed more inconsistency if the number of iterations or population size was small, and more so for a complex prior flux covariance matrix. If the GA completed with a sub-optimal solution, these solutions were similar in fitness to the best available solution. Two additional scenarios were considered, with the objective of creating circumstances where the GA may outperform the IO. The first scenario considered an established network, where the optimisation was required to add an additional five stations to an existing five-member network. In the second scenario the optimisation was based only on the uncertainty reduction within a subregion of the domain. The GA was able to find a better solution than the IO under both scenarios, but with only a marginal improvement in the uncertainty reduction. These results suggest that the best use of resources for the network design problem would be spent in improvement of the prior estimates of the flux uncertainties rather than investing these resources in running a complex evolutionary optimisation algorithm. The authors recommend that, if time and computational resources allow, that multiple optimisation techniques should be used as a part of a comprehensive suite of sensitivity tests when performing such an optimisation exercise. This will provide a selection of best solutions which could be ranked based on their utility and practicality.</p

Pan-cancer analysis reveals recurrent BCAR4 gene fusions across solid tumors

UNLABELLED: Chromosomal rearrangements often result in active regulatory regions juxtaposed upstream of an oncogene to generate an expressed gene fusion. Repeated activation of a common downstream partner-with differing upstream regions across a patient cohort-suggests a conserved oncogenic role. Analysis of 9,638 patients across 32 solid tumor types revealed an annotated long noncoding RNA (lncRNA), Breast Cancer Anti-Estrogen Resistance 4 (BCAR4), was the most prevalent, uncharacterized, downstream gene fusion partner occurring in 11 cancers. Its oncogenic role was confirmed using multiple cell lines with endogenous BCAR4 gene fusions. Furthermore, overexpressing clinically prevalent BCAR4 gene fusions in untransformed cell lines was sufficient to induce an oncogenic phenotype. We show that the minimum common region to all gene fusions harbors an open reading frame that is necessary to drive proliferation. IMPLICATIONS: BCAR4 gene fusions represent an underappreciated class of gene fusions that may have biological and clinical implications across solid tumors

Gender differences in response to an opportunistic brief intervention for obesity in primary care: Data from the BWeL trial

Weight loss programmes appeal mainly to women, prompting calls for gender-specific programmes. In the United Kingdom, general practitioners (GPs) refer nine times as many women as men to community weight loss programmes. GPs endorsement and offering programmes systematically could reduce this imbalance. In this trial, consecutively attending patients in primary care with obesity were invited and 1882 were enrolled and randomized to one of two opportunistic 30-second interventions to support weight loss given by GPs in consultations unrelated to weight. In the support arm, clinicians endorsed and offered referral to a weight loss programme and, in the advice arm, advised that weight loss would improve health. Generalized linear mixed effects models examined whether gender moderated the intervention. Men took effective weight loss action less often in both arms (support: 41.6% vs 60.7%; advice: 12.1% vs 18.3%; odds ratio (OR) = 0.38, 95% confidence interval (CI), 0.27, 0.52, P&#x2009;&lt;&#x2009;.001) but there was no evidence that the relative effect differed by gender (interaction P = .32). In the support arm, men accepted referral and attended referral less often, 69.3% vs 82.4%; OR = 0.48, 95% CI, 0.35, 0.66, P&#x2009;&lt;&#x2009;.001 and 30.4% vs 47.6%; OR = 0.48, 95% CI, 0.36, 0.63, P&#x2009;&lt;&#x2009;.001, respectively. Nevertheless, the gender balance in attending weight loss programmes closed to 1.6:1. Men and women attended the same number of sessions (9.7 vs 9.1 sessions, P = .16) and there was no evidence weight loss differed by gender (6.05&#x2009;kg men vs 4.37&#x2009;kg women, P = .39). Clinician-delivered opportunistic 30-second interventions benefits men and women equally and reduce most of the gender imbalance in attending weight loss programmes