Description: Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from that of Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment in Escherichia coli , followed by whole-genome resequencing. Overexpression of the Hsp70 chaperone DnaK helps cells cope with mutational load and completely avoid the extinctions we observe in lineages evolving without chaperone overproduction. Additionally, our sequence data show that DnaK overexpression increases mutational robustness, the tolerance of its clients to nonsynonymous nucleotide substitutions. We also show that this elevated mutational buffering translates into differences in evolutionary rates on intermediate and long evolutionary time scales. Specifically, we studied the evolutionary rates of DnaK clients using the genomes of E. coli , Salmonella enterica , and 83 other gamma-proteobacteria. We find that clients that interact strongly with DnaK evolve faster than weakly interacting clients. Our results imply that all three major chaperone classes can buffer mutations and affect protein evolution. They illustrate how an individual protein like a chaperone can have a disproportionate effect on the evolution of a proteome.

Description: The quasar mode of active galactic nuclei (AGN) in the high-redshift Universe is routinely observed in gas-rich galaxies together with large-scale AGN-driven winds. It is crucial to understand how photons emitted by the central AGN source couple to the ambient interstellar medium to trigger large-scale outflows. By means of radiation–hydrodynamical simulations of idealized galactic discs, we study the coupling of photons with the multiphase galactic gas, and how it varies with gas cloud sizes, and the radiation bands included in the simulations, which are ultraviolet, optical, and infrared (IR). We show how a quasar with a luminosity of 10 46 erg s – 1 can drive large-scale winds with velocities of $10^2\text{--}10^3 \, \rm km \, s^{-1}$ and mass outflow rates around 10 3 M yr – 1 for times of the order of a few million years. IR radiation is necessary to efficiently transfer momentum to the gas via multiscattering on dust in dense clouds. However, IR multiscattering, despite being extremely important at early times, quickly declines as the central gas cloud expands and breaks up, allowing the radiation to escape through low gas density channels. The typical number of multiscattering events for an IR photon is only about a quarter of the mean optical depth from the centre of the cloud. Our models account for the observed outflow rates of ~500–1000 M yr – 1 and high velocities of ~ 10 3 km s – 1 , favouring winds that are energy driven via extremely fast nuclear outflows, interpreted here as being IR radiatively driven winds.

Description: Introduction Levels of stress in UK university students are high, with an increase in the proportion of students seeking help in recent years. Academic pressure is reported as a major trigger. Mindfulness training has been shown to reduce stress and is popular among students, but its effectiveness in this context needs to be ascertained. In this pragmatic randomised controlled trial, we hypothesise that the provision of a preventative mindfulness intervention in universities could reduce students' psychological distress during the examination period (primary outcome), improve their resilience to stress up to at least 1 year later, reduce their use of mental health support services and improve academic performance. Methods and analysis At least 550 University of Cambridge students free from active crises or severe mental illness will be randomised to joining an 8-week mindfulness course or to mental health provision as usual (one-to-one allocation rate). Psychological distress will be measured using the Clinical Outcomes in Routine Evaluation Outcome Measure at baseline, postintervention, examination term and 1-year follow-up. Other outcomes are use of mental health services, inability to sit examinations or special circumstance requests, examination grades, well-being, altruism and coping measured with ecological momentary assessment. Outcome assessment and intention-to-treat primary analysis using linear mixed models adjusted for baseline scores will be blind to intervention allocation. We will also conduct per-protocol, subgroup and secondary outcome analyses. An Independent Data Monitoring and Ethics Committee will be set up. We will systematically monitor for, and react to, possible adverse events. An advisory reference group will comprise student representatives, members of the University Counselling Service and other student welfare staff. Ethics and dissemination Approval has been obtained from Cambridge Psychology Research Ethics Committee (PRE.2015.060). Results will be published in peer-reviewed journals. A lay summary will be disseminated to a wider audience including other universities. Trial registration number ACTRN12615001160527 ; pre-results.

Description: Background This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. Patients and methods The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1–21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. Results Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2–18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8–43.5 months). The median OS was 25 months (95% CI 13.2–39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS ( P 〈 0.0001). Long-term safety profile is consistent with previous reports; hand–foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. Conclusions Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. Clinical trial number NCT01068769.

Description: The Large Magellanic Cloud (LMC) harbours a rich and diverse system of star clusters, whose ages, chemical abundances and positions provide information about the LMC history of star formation. We use Science Verification imaging data from the Dark Energy Survey (DES) to increase the census of known star clusters in the outer LMC and to derive physical parameters for a large sample of such objects using a spatially and photometrically homogeneous data set. Our sample contains 255 visually identified cluster candidates, of which 109 were not listed in any previous catalogue. We quantify the crowding effect for the stellar sample produced by the DES Data Management pipeline and conclude that the stellar completeness is 〈10 per cent inside typical LMC cluster cores. We therefore reanalysed the DES co-add images around each candidate cluster and remeasured positions and magnitudes for their stars. We also implement a maximum-likelihood method to fit individual density profiles and colour–magnitude diagrams. For 117 (from a total of 255) of the cluster candidates (28 uncatalogued clusters), we obtain reliable ages, metallicities, distance moduli and structural parameters, confirming their nature as physical systems. The distribution of cluster metallicities shows a radial dependence, with no clusters more metal rich than [Fe/H] ~= –0.7 beyond 8 kpc from the LMC centre. The age distribution has two peaks at ~=1.2 and ~=2.7 Gyr.

Description: We present the results of 3D relativistic hydrodynamic simulations of interaction of active galactic nucleus jets with a dense turbulent two-phase interstellar medium, which would be typical of high-redshift galaxies. We describe the effect of the jet on the evolution of the density of the turbulent interstellar medium (ISM). The jet-driven energy bubble affects the gas to distances up to several kiloparsecs from the injection region. The shocks resulting from such interactions create a multiphase ISM and radial outflows. One of the striking result of this work is that low-power jets ( P jet 10 43 ergs –1 ), although less efficient in accelerating clouds, are trapped in the ISM for a longer time and hence affect the ISM over a larger volume. Jets of higher power drill through with relative ease. Although the relativistic jets launch strong outflows, there is little net mass ejection to very large distances, supporting a galactic fountain scenario for local feedback.

Description: Objective In 2008, the Thai government introduced the ‘high-cost medicines E2 access program’ as a part of the National List of Essential Medicines to increase patient access to medicines, improve clinical outcomes and make medicines more affordable. Our objective was to examine whether the ‘high-cost medicines E2 access program’ achieved its goals. Design Interrupted time-series design study. Setting 3 tertiary hospitals in different regions of Thailand, January 2006 to December 2012. Participants Patients with target acute and chronic disease diagnoses who newly met E2 program criteria for selected study medicines. Intervention High-cost medicines E2 access program. Main outcomes measures Level and trend changes over time in the proportions of eligible patients who received the indicated E2 medicines and who improved clinically, as well as in costs of treatment. Results A total of 2024 patients were included in utilisation analyses and 1375 patients with selected acute diseases contributed to analyses of clinical outcome. After 1 year of the E2 program implementation, the percentage of eligible patients receiving the indicated E2 program medicines increased significantly (relative change 12.7% (95% CI 4.4% to 21.0%), especially among those insured by the government's universal coverage scheme (relative change 19.9% (95% CI 9.5% to 30.5%)). The increase in the proportion of clinically improved patients with acute conditions was not significant (relative change 6.2% (95% CI –1.9% to 15.1%)). Quarterly healthcare costs per patient dropped significantly (relative change –13.5% (95% CI –26.9% to –1.7%)). Conclusions In the study hospitals, the E2 access program seems to have facilitated patient access to specialty medicines, may have contributed to improved health outcomes, and decreased treatment costs. Routine monitoring is needed to assess effects of expanding the programme, including effects on quality of care and financial sustainability.

Description: Dietary isoflavones, a group of secondary plant compounds that exhibit phytoestrogenic properties, are primarily found in soy. Prunetin, a representative isoflavone, was recently found to affect cell signaling in cultured cells; however, in vivo effects remain elusive. In this study, the model organism Drosophila melanogaster was used to investigate the effects of prunetin in vivo with respect to lifespan, locomotion, body composition, metabolism, and gut health. Adult flies were chronically administered a prunetin-supplemented diet. Prunetin improved median survival by 3 d, and climbing activity increased by 54% in males. In comparison with the females, male flies exhibited lower climbing activity, which was reversed by prunetin intake. Furthermore, prunetin-fed males exhibited increased expression of the longevity gene Sirtuin 1 ( Sir2 ) (22%), as well as elevated AMPK activation (51%) and triglyceride levels (29%), whereas glucose levels decreased (36%). As females are long-lived compared with their male counterparts and exhibit higher triglyceride levels, prunetin apparently "feminizes" male flies via its estrogenicity. We conclude that the lifespan-prolonging effects of prunetin in the male fruit fly depend on changes in AMPK-regulated energy homeostasis via male "feminization." Collectively, we identified prunetin as a plant bioactive compound capable of improving health status and survival in male D. melanogaster .—Piegholdt, S., Rimbach, G., Wagner, A. E. The phytoestrogen prunetin affects body composition and improves fitness and lifespan in male Drosophila melanogaster.

Description: The Drug–Gene Interaction Database (DGIdb, www.dgidb.org ) is a web resource that consolidates disparate data sources describing drug–gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug–gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug–gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation.

Description: Background Despite the high prevalence of chronic venous insufficiency and varicose veins in the Western world, suitable pharmaceutical therapies for these venous diseases have not been explored to date. In this context, we recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins through the activation of the transcription factor activator protein 1. Methods and Results We investigated whether deleterious venous remodeling is suppressed by the pleiotropic effects of statins. In vitro, activator protein 1 activity was inhibited by two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, rosuvastatin and atorvastatin, in stretch-stimulated human venous smooth muscle cells. Correspondingly, both statins inhibited venous smooth muscle cell proliferation as well as mRNA expression of the activator protein 1 target gene monocyte chemotactic protein 1 ( MCP1 ). In isolated mouse veins exposed to an increased level of intraluminal pressure, statin treatment diminished proliferation of venous smooth muscle cells and protein abundance of MCP1 while suppressing the development of varicose veins in a corresponding animal model by almost 80%. Further analyses of human varicose vein samples from patients chronically treated with statins indicated a decrease in venous smooth muscle cell proliferation and MCP1 abundance compared with samples from untreated patients. Conclusions Our findings imply that both atorvastatin and rosuvastatin effectively inhibit the development of varicose veins, at least partially, by interfering with wall stress–mediated activator protein 1 activity in venous smooth muscle cells. For the first time, this study reveals a potential pharmacological treatment option that may be suitable to prevent growth of varicose veins and to limit formation of recurrence after varicose vein surgery.