Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4)

Attenuating the function of protein arginine methyltransferases (PRMTs) is an objective for the investigation and treatment of several diseases including cardiovascular disease and cancer. Bisubstrate inhibitors that simultaneously target binding sites for arginine substrate and the co-factor (S-adenosylmethionine (SAM)) have potential utility, but structural information on their binding is required for their development. Evaluation of bisubstrate inhibitors featuring an isosteric guanidine replacement with two prominent enzymes PRMT1 and CARM1 (PRMT4) by isothermal titration calorimetry (ITC), activity assays and crystallography are reported. Key findings are that 2-aminopyridine is a viable replacement for guanidine, providing an inhibitor that binds more strongly to CARM1 than PRMT1. Moreover, a residue around the active site that differs between CARM1 (Asn-265) and PRMT1 (Tyr-160) is identified that affects the side chain conformation of the catalytically important neighbouring glutamate in the crystal structures. Mutagenesis data supports its contribution to the difference in binding observed for this inhibitor. Structures of CARM1 in complex with a range of seven inhibitors reveal the binding modes and show that inhibitors with an amino acid terminus adopt a single conformation whereas the electron density for equivalent amine-bearing inhibitors is consistent with preferential binding in two conformations. These findings inform the molecular basis of CARM1 ligand binding and identify differences between CARM1 and PRMT1 that can inform drug discovery efforts

Hemigrapsus takanoi Asakura and Watanabe, 2005 (Crustacea: Decapoda: Brachyura: Grapsoidea): first records of the brush-clawed shore crab from Great Britain

The brush-clawed shore crab is reported from the River Medway, Kent and the River Colne, Essex, England. These represent the first records of Hemigrapsus takanoi Asakura and Watanabe, 2005 from Great Britain. If H. takanoi becomes established in GB, it may pose a threat to populations of the native shore crab Carcinus maenas

The highest frequency detection of a radio relic : 16 GHz AMI observations of the 'Sausage' cluster

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society: Letters. © 2014 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We observed the cluster CIZA J2242.8+5301 with the Arcminute Microkelvin Imager at 16 GHz and present the first high radio-frequency detection of diffuse, non-thermal cluster emission. This cluster hosts a variety of bright, extended, steep-spectrum synchrotron-emitting radio sources, associated with the intracluster medium, called radio relics. Most notably, the northern, Mpc-wide, narrow relic provides strong evidence for diffusive shock acceleration in clusters. We detect a puzzling, flat-spectrum, diffuse extension of the southern relic, which is not visible in the lower radio-frequency maps. The northern radio relic is unequivocally detected and measures an integrated flux of 1.2 ± 0.3 mJy. While the low-frequency (<2 GHz) spectrum of the northern relic is well represented by a power law, it clearly steepens towards 16 GHz. This result is inconsistent with diffusive shock acceleration predictions of ageing plasma behind a uniform shock front. The steepening could be caused by an inhomogeneous medium with temperature/density gradients or by lower acceleration efficiencies of high energy electrons. Further modelling is necessary to explain the observed spectrum.Peer reviewe

Ebola respons-ibility: moving from shared to multiple responsibilities

Combating threats of infectious diseases has been increasingly framed as a global shared responsibility for a multi-actor framework, of states, international organisations and non-governmental actors. However, the outbreak of Ebola Virus Disease (EVD) has shown that this governance framework has not been able to limit the spread of this virus, despite the normative and legislative changes to global disease control. By unbundling the concept of responsibility, this article will assess how global shared responsibility may have failed due to the fact that accountability does not fall on any one state or stakeholder, highlighting an inherent weakness with the global disease governance regime. As such, this paper concludes that a move towards multiple responsibilities may prove a more effective mechanism for ensuring global health security

Electric Field Effect in Ultrathin Films near the Superconductor-Insulator Transition

The effect of an electric field on the conductance of ultrathin films of metals deposited on substrates coated with a thin layer of amorphous Ge was investigated. A contribution to the conductance modulation symmetric with respect to the polarity of the applied electric field was found in regimes in which there was no sign of glassy behavior. For films with thicknesses that put them on the insulating side of the superconductor-insulator transition, the conductance increased with electric field, whereas for films that were becoming superconducting it decreased. Application of magnetic fields to the latter, which reduce the transition temperature and ultimately quench superconductivity, changed the sign of the reponse of the conductance to electric field back to that found for insulators. We propose that this symmetric response to capacitive charging is a consequence of changes in the conductance of the a-Ge layer, and is not a fundamental property of the physics of the superconductor-insulator transition as previously suggested.Comment: 4 pages text, 4 figure

Association Between Accelerometer-Assessed Physical Activity and Severity of COVID-19 in UK Biobank.

Funder: UKRI Science and Technology Facilities CouncilOBJECTIVE: To quantify the association between accelerometer-assessed physical activity and coronavirus disease 2019 (COVID-19) outcomes. METHODS: Data from 82,253 UK Biobank participants with accelerometer data (measured 2013-2015), complete covariate data, and linked COVID-19 data from March 16, 2020, to March 16, 2021, were included. Two outcomes were investigated: severe COVID-19 (positive test result from in-hospital setting or COVID-19 as primary cause of death) and nonsevere COVID-19 (positive test result from community setting). Logistic regressions were used to assess associations with moderate to vigorous physical activity (MVPA), total activity, and intensity gradient. A higher intensity gradient indicates a higher proportion of vigorous activity. RESULTS: Average MVPA was 48.1 (32.7) min/d. Physical activity was associated with lower odds of severe COVID-19 (adjusted odds ratio per standard deviation increase: MVPA, 0.75 [95% CI, 0.67 to 0.85]; total, 0.83 [0.74 to 0.92]; intensity, 0.77 [0.70 to 0.86]), with stronger associations in women (MVPA, 0.63 [0.52 to 0.77]; total, 0.76 [0.64 to 0.90]; intensity, 0.63 [0.53 to 0.74]) than in men (MVPA, 0.84 [0.73 to 0.97]; total, 0.88 [0.77 to 1.01]; intensity, 0.88 [0.77 to 1.00]). In contrast, when mutually adjusted, total activity was associated with higher odds of a nonsevere infection (1.10 [1.04 to 1.16]), whereas the intensity gradient was associated with lower odds (0.91 [0.86 to 0.97]). CONCLUSION: Odds of severe COVID-19 were approximately 25% lower per standard deviation (∼30 min/d) MVPA. A greater proportion of vigorous activity was associated with lower odds of severe and nonsevere infections. The association between total activity and higher odds of a nonsevere infection may be through greater community engagement and thus more exposure to the virus. Results support calls for public health messaging highlighting the potential of MVPA for reducing the odds of severe COVID-19

How common is truly benign MS in a UK population?

Objectives The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. Methods We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. Results Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). Conclusions Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term ‘benign’ in clinical settings

Body composition and physical activity in New Zealand Maori, Pacific and European children aged 5-14 years

Body fatness and the components of energy expenditure in children aged 5-14 years were investigated. In a group of seventy-nine healthy children (thirty-nine female, forty male), mean age 10-0 (SD 2-8) years, comprising twenty-seven Maori, twenty-six Pacific Island and twenty-six European, total energy expenditure (TEE) was determined over 10d using the doubly-labelled water method. Resting metabolic rate (RMR) was measured by indirect calorimetry and physical activity level (PAL) was calculated as TEE:RMR. Fat-free mass (FFM), and hence fat mass, was derived from the O-18-dilution space using appropriate values for FFM hydration in children. Qualitative information on physical activity patterns was obtained by questionnaire. Maori and Pacific children had a higher BMI than European children (P< 0.003), but % body fat was similar for the three ethnic groups. The % body fat increased with age for girls (r 0-42, P=0008), but not for boys. Ethnicity was not a significant predictor of RMR adjusted for FFM and fat mass. TEE and PAL, adjusted for body weight and age, were higher in Maori than European children (