Physical activity trajectories and mortality: population based cohort study.

OBJECTIVE: To assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer. DESIGN: Population based cohort study. SETTING: Adults from the general population in the UK. PARTICIPANTS: 14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment). MAIN EXPOSURE: Physical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels. RESULTS: During 171 277 person years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity. CONCLUSIONS: Middle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.The EPIC-Norfolk study is supported by programme grants from the Medical Research CouncilandCancer Research UKwith additional support from the Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and the Wellcome Trust. Alexander Mok was supported by the National Science Scholarship from Singapore, A*STAR (Agency for Science, Technology and Research).The work of Nick Wareham and Soren Brage was funded by the Medical Research Council UK [MC_UU_12015/1 and MC_UU_12015/3].The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the article for publication

Is occupational physical activity associated with mortality in UK Biobank?

BackgroundCurrent physical activity guidelines do not distinguish between activity accumulated in different behavioural domains but some studies suggest that occupational physical activity (OPA) may not confer health benefits and could even be detrimental. The purpose of this study was to investigate associations between OPA and mortality outcomes.MethodsFrom baseline (2006-2010), 460,901 UK Biobank participants (aged 40-69 years) were followed for a median 12.0 (IQR: 11.3-12.7) years. OPA was categorised by cross-tabulating degree of manual work and walking/standing work amongst those in paid employment (n = 267,765), and combined with categories of occupational status for those not in paid employment (n = 193,136). Cox proportional hazards models were used to estimate sex-stratified hazard ratios (HR) and 95% confidence intervals (CI) for mortality from all causes, CVD, and cancer by occupational group, and for working hours/week and non-occupational physical activity stratified by occupational group. Models included adjustment for age and a range of lifestyle, socio-economic and health-related covariates.ResultsDuring 5,449,989 person-years of follow-up, 28,740 deaths occurred. Compared to those reporting no heavy manual or walking/standing work (e.g. sedentary office workers) and adjusting for covariates, retirement was associated with lower mortality in women (HR = 0.62, CI: 0.53-0.72) and men (HR = 0.80, CI: 0.71-0.90), whereas unemployment was associated with higher mortality in men only (HR = 1.24, CI: 1.07-1.45). Within the working population, there was no evidence of differences in all-cause, CVD or cancer mortality by OPA group when comparing those reporting higher levels of OPA to the lowest OPA reference group for both women and men. Working ConclusionsJobs classified as higher levels of OPA may not be as active as reported, or the types of physical activity performed in those jobs are not health-enhancing. Irrespective of OPA category or employment status, non-occupational physical activity appears to provide health benefits

Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway

Rgs2, a regulator of G proteins, lowers blood pressure by decreasing signaling through Gαq. Human patients expressing Met-Leu-Rgs2 (ML-Rgs2) or Met-Arg-Rgs2 (MR-Rgs2) are hypertensive relative to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). We found that wild-type MQ-Rgs2 and its mutant, MR-Rgs2, were destroyed by the Ac/N-end rule pathway, which recognizes Nα-terminally acetylated (Nt-acetylated) proteins. The shortest-lived mutant, ML-Rgs2, was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. The latter pathway recognizes unacetylated N-terminal residues. Thus, the Nt-acetylated Ac-MX-Rgs2 (X = Arg, Gln, Leu) proteins are specific substrates of the mammalian Ac/N-end rule pathway. Furthermore, the Ac/N-degron of Ac-MQ-Rgs2 was conditional, and Teb4, an endoplasmic reticulum (ER) membrane-embedded ubiquitin ligase, was able to regulate G protein signaling by targeting Ac-MX-Rgs2 proteins for degradation through their N^α-terminal acetyl group

Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway

In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. In contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt-formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N-degrons, and identified the Psh1 ubiquitin ligase as the recognition component of this eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins

riboviz 2:A flexible and robust ribosome profiling data analysis and visualization workflow

MOTIVATION: Ribosome profiling, or Ribo-seq, is the state-of-the-art method for quantifying protein synthesis in living cells. Computational analysis of Ribo-seq data remains challenging due to the complexity of the procedure, as well as variations introduced for specific organisms or specialized analyses. RESULTS: We present riboviz 2, an updated riboviz package, for the comprehensive transcript-centric analysis and visualization of Ribo-seq data. riboviz 2 includes an analysis workflow built on the Nextflow workflow management system for end-to-end processing of Ribo-seq data. riboviz 2 has been extensively tested on diverse species and library preparation strategies, including multiplexed samples. riboviz 2 is flexible and uses open, documented file formats, allowing users to integrate new analyses with the pipeline. AVAILABILITY AND IMPLEMENTATION: riboviz 2 is freely available at github.com/riboviz/riboviz

Estimating the impact of achieving Turkey's non-communicable disease policy targets: A macro-simulation modelling study.

BACKGROUND: The Burden of non-communicable disease (NCDs) has continued to rise globally, particularly in low- and middle-income countries. In Turkey, NCDs account for 89% of all deaths, with nearly one in five deaths occurring before age 70. This study investigates the number of NCD deaths that could be prevented if Turkey met national and international targets for major modifiable NCD risk factors. METHODS: Preventable deaths were estimated using the World Health Organization (WHO) 'Preventable Risk Integrated ModEl' (PRIME), by combining: 1) Baseline exposure data for risk factors, referenced from national surveillance and cohort studies; 2) Aetiological associations from published meta-analyses; and 3) Demographic and mortality statistics obtained from the Turkish Statistical Institute (TurkStat). Confidence intervals were estimated using Monte Carlo simulations. FINDINGS: If Turkey met its NCD risk factor targets for reducing tobacco and salt consumption by 30%, and physical inactivity by 10% in 2017, an estimated 19,859 deaths (95%CI: 12,802 to 26,609) could have been prevented. Approximately two thirds of these preventable deaths were in men, and one in three were in adults below 75 years. A 30% relative reduction in the consumption of alcohol, tobacco, and salt, as well as physical inactivity, would prevent 180 (107 to 259); 4,786 (3,679 to 5,836); 13,112 (5,819 to 19,952); and 7,124 (5,053 to 9,212) deaths, respectively. INTERPRETATION: Among major modifiable NCD risk factors, population-level reductions in salt intake and physical inactivity present the greatest opportunity for reducing NCD mortality in Turkey. These findings can help Turkey prioritise interventions to meet the Sustainable Development Goal target of reducing NCD mortality by one third, by 2030

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON).

In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs). Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression. 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1. Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC

CRFs form protein–protein interactions with each other and with members of the cytokinin signalling pathway in Arabidopsis via the CRF domain

Cytokinin is a plant hormone essential for growth and development. The elucidation of its signalling pathway as a variant of the bacterial two-component signalling system (TCS) has led to a better understanding of how this hormone is involved in general plant processes. A set of cytokinin-regulated transcription factors known as cytokinin response factors (CRFs) have been described as a potential branch emanating from the TCS, yet little is known about how CRFs actually interact with each other and with members of the TCS pathway. Here the interactions of CRF proteins (CRF1–CRF8) using the yeast two-hybrid system and bimolecular fluorescence complementation in planta assays are described. It was found that CRFs are readily able to form both homo- and heterodimers with each other. The first analysis of CRF versus TCS pathway protein interactions is also provided, which indicates that CRFs (CRF1–CRF8) are able specifically to interact directly with most of the Arabidopsis histidine-phosphotransfer proteins (AHP1–AHP5) further solidifying their link to the cytokinin signalling pathway. In addition, the region of CRF proteins involved in these interactions was mapped and it was determined that the clade-specific CRF domain alone is sufficient for these interactions. This is the first described function for the CRF domain in plants

A Qualitative Analysis of Motivators to Participation in Suicide-Focused Research from a Community-Based Australian Sample

Suicide prevention strategies internationally appear to be falling short of making a meaningful impact on global suicide deaths. Increasing the rates of general community participation in suicide research may improve knowledge generalisability as it relates to suicidal behaviour and leads to new suicide prevention approaches. This study aims to explore the motivations of a community-based sample to participate in suicide research. A subsample of the Australian general population took part in an online survey which is part of a multilevel suicide prevention trial. The survey concluded with an optional open-text question asking about peoples' motivations for participating in the study; 532 participants left a response to this question. These responses were qualitatively analysed using Thematic Network Analysis. Motivations to participate in suicide research were represented by four global themes: altruism, solve systemic problems, lived experience, and personal benefit. Of these themes, three were focused on the benefit of others, while only the final theme articulated motivation to participate that was self-focused. The impact of suicide is felt throughout the wider community. This new understanding of the motivations of community-based samples to participate in suicide research should be used to increase participation rates and reach people who would not normally contribute their voice to suicide research