Oxidation of carbon compounds by Methylococcus capsulatus

The effect of various potential Inhibitors on methane oxidation was tested on whole-cell suspensions of Methylococcus capsulatus (strain Texas) (TRMC ) and Methylococcus capsulatus (strain Bath) (MC). Methane oxidation by TRMC was specifically inhibited by a large number of metal-chelating/binding agents and suggested the involvement of a metal ion(s) with the methane mono -oxygenase. The whole-cell results of MC showed a much more restricted specific inhibitor pattern for methane oxidation, which was confirmed by cell-free studies. The inhibitor pattern of MC was compared with that of TRMC and with reported patterns for other methane-utilisers. The effect of a number of acetylenic compounds on methane oxidation by MC was tested and the results discussed. The substrate specificity of the methane mono-oxygenase from MC was determined and found to be very non-specific. It catalysed the oxidation of various substituted methane derivatives, including methanol. C₁ -C₈ n-alkanes were hydroxylated to the corresponding 1- and 2-alcohols, carbon monoxide to carbon dioxide, terminal alkenes to the corresponding 1, 2-epoxides and internal alkenes to a variety of products. Ethers, alicyclic, aromatic and heterocyclic compounds were also oxidised. The significance of the various oxidations are discussed. Only NADPH could replace NADH as electron donor for methane mono-oxygenase activity. The subject of non-growth substrate oxidation by micro-organisms is discussed and the terminology of the area critically reviewed. Whole-cell oxidation studies with MC revealed five fortuitously oxidised non-growth substrates (chloromethane, bromomethane, dimethyl ether, ethene and propene) and seven cometabolic non-growth substrates (carbon monoxide, diethyl ether, ethane, propane, but-1 -ene, cis but-2-ene and trans but-2-ene). From these, dimethyl ether, bromomethane and carbon monoxide were selected to study in detail their effect on cellular metabolism of MC. During the oxidation studies it was suspected that an NAD(P)⁺ -linked aldehyde dehydrogenase was present. Confirmative tests proved positive. Activity in crude cell-free extracts was lost on dialysis, but could be restored by supplementing with inactive, heat-treated extract. The non-dialysable, heat-sensitive component was isolated and purified. The heat-stable component/co-factor was presumed to be a low molecular weight protein or polypeptide. The enzymic potential for an NAD(P)⁺ -linked cyclic scheme for the complete oxidation of formaldehyde was detected in crude cell- free extracts of MC. The relative Importance of the different formaldehyde oxidation systems found is discussed

Enhancing Multimedia Search Using Human Motion

Over the last few years, there has been an increase in the number of multimedia-enabled devices (e.g. cameras, smartphones, etc.) and that has led to a vast quantity of multimedia content being shared on the Internet. For example, in 2010 thirteen million hours of video uploaded to YouTube (http://www.youtube.com). To usefully navigate this vast amount of information, users currently rely on search engines, social networks and dedicated multimedia websites (such as YouTube) to find relevant content. Efficient search of large collections of multimedia requires metadata that is human-meaningful, but currently multimedia sites generally utilize metadata derived from user-entered tags and descriptions. These are often vague, ambiguous or left blank, which makes search for video content unreliable or misleading. Furthermore, a large majority of videos contain people, and consequently, human movement, which is often not described in the user entered metadata

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study

Background: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pound for the completion of postal questionnaires. Methods: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pound to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pound incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. Results: The response rate following reminders for the historical controls was 78.1% ( 82 of 105) compared with 88.0% ( 389 of 442) for those patients who received the 5 pound payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response ( adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial - the extra cost per additional respondent was almost 50 pound. Conclusion: The direct payment of 5 pound significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study

Effect of Self-monitoring and Medication Self-titration on Systolic Blood Pressure in Hypertensive Patients at High Risk of Cardiovascular Disease

IMPORTANCE: Self-monitoring of blood pressure with self-titration of antihypertensives (self-management) results in lower blood pressure in patients with hypertension, but there are no data about patients in high-risk groups. OBJECTIVE: To determine the effect of self-monitoring with self-titration of antihypertensive medication compared with usual care on systolic blood pressure among patients with cardiovascular disease, diabetes, or chronic kidney disease. DESIGN, SETTING, AND PATIENTS: A primary care, unblinded, randomized clinical trial involving 552 patients who were aged at least 35 years with a history of stroke, coronary heart disease, diabetes, or chronic kidney disease and with baseline blood pressure of at least 130/80 mm Hg being treated at 59 UK primary care practices was conducted between March 2011 and January 2013. INTERVENTIONS: Self-monitoring of blood pressure combined with an individualized self-titration algorithm. During the study period, the office visit blood pressure measurement target was 130/80 mm Hg and the home measurement target was 120/75 mm Hg. Control patients received usual care consisting of seeing their health care clinician for routine blood pressure measurement and adjustment of medication if necessary. MAIN OUTCOMES AND MEASURES: The primary outcome was the difference in systolic blood pressure between intervention and control groups at the 12-month office visit. RESULTS: Primary outcome data were available from 450 patients (81%). The mean baseline blood pressure was 143.1/80.5 mm Hg in the intervention group and 143.6/79.5 mm Hg in the control group. After 12 months, the mean blood pressure had decreased to 128.2/73.8 mm Hg in the intervention group and to 137.8/76.3 mm Hg in the control group, a difference of 9.2 mm Hg (95% CI, 5.7-12.7) in systolic and 3.4 mm Hg (95% CI, 1.8-5.0) in diastolic blood pressure following correction for baseline blood pressure. Multiple imputation for missing values gave similar results: the mean baseline was 143.5/80.2 mm Hg in the intervention group vs 144.2/79.9 mm Hg in the control group, and at 12 months, the mean was 128.6/73.6 mm Hg in the intervention group vs 138.2/76.4 mm Hg in the control group, with a difference of 8.8 mm Hg (95% CI, 4.9-12.7) for systolic and 3.1 mm Hg (95% CI, 0.7-5.5) for diastolic blood pressure between groups. These results were comparable in all subgroups, without excessive adverse events. CONCLUSIONS AND RELEVANCE: Among patients with hypertension at high risk of cardiovascular disease, self-monitoring with self-titration of antihypertensive medication compared with usual care resulted in lower systolic blood pressure at 12 months

High Magnetic Shear Gain in a Liquid Sodium Stable Couette Flow Experiment; A Prelude to an alpha-Omega Dynamo

The $\Omega$-phase of the liquid sodium $\alpha$-$\Omega$ dynamo experiment at NMIMT in cooperation with LANL has successfully demonstrated the production of a high toroidal field, $B_{\phi} \simeq 8\times B_r$ from the radial component of an applied poloidal magnetic field, $B_r$. This enhanced toroidal field is produced by rotational shear in stable Couette flow within liquid sodium at $Rm \simeq 120$. The small turbulence in stable Taylor-Couette flow is caused by Ekman flow where $(\delta v/v)^2 \sim 10^{-3}$. This high $\Omega$-gain in low turbulence flow contrasts with a smaller $\Omega$-gain in higher turbulence, Helmholtz-unstable shear flows. This result supports the ansatz that large scale astrophysical magnetic fields are created within semi-coherent large scale motions in which turbulence plays only a smaller diffusive role that enables magnetic flux linkage.Comment: 5 pages, 5 figures, submitted PRL revised version: add one author, minor typo'

The Met Office Unified Model Global Atmosphere 6.0/6.1 and JULES Global Land 6.0/6.1 configurations

We describe Global Atmosphere 6.0 and Global Land 6.0: the latest science configurations of the Met Office Unified Model and JULES land surface model developed for use across all timescales. Global Atmosphere 6.0 includes the ENDGame dynamical core, which significantly increases mid-latitude variability improving a known model bias. Alongside developments of the model’s physical parametrisations, ENDGame also increases variability in the tropics, which leads to an improved representation of tropical cyclones and other tropical phenomena. Further developments of the atmospheric and land surface parametrisations improve other aspects of model performance, including the forecasting of surface weather phenomena. We also describe Global Atmosphere 6.1 and Global Land 6.1, which include a small number of long-standing differences from our main trunk configurations that we continue to require for operational global weather prediction. Since July 2014, GA6.1/GL6.1 has been used by the Met Office for operational global NWP, whilst GA6.0/GL6.0 was implemented in its remaining global prediction systems over the following year

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study:A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments

Grant information: STRADL is supported by the Wellcome Trust through a Strategic Award (104036/Z/14/Z). GS:SFHS received core support from the CSO of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). ADM is supported by Innovate UK, the European Commission, the Scottish Funding Council via the Scottish Imaging Network SINAPSE, and the CSO. HCW is supported by a JMAS SIM Fellowship from the Royal College of Physicians of Edinburgh, by an ESAT College Fellowship from the University of Edinburgh, and has received previous funding from the Sackler Trust. LR has previously received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with schizophrenia and bipolar disorder. JDH is supported by the MRC. DJM is an NRS Clinician, funded by the CSO. RMR is supported by the British Heart Foundation. ISP-V and MRM are supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health; and MRM is also supported by the MRC MC_UU_12013/6). JMW is supported by MRC UK Dementia Research Institute and MRC Centre and project grants, EPSRC, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant agreement (666881). DJP is supported by Wellcome Trust Longitudinal Population Study funding (216767/Z/19/Z) the Eva Lester bequest to the University of Edinburgh. AMM is additionally supported by the MRC (MC_PC_17209, MC_PC_MR/R01910X/1, MR/S035818/1), The Wellcome Trust (216767/Z/19/Z ), The Sackler Trust, and has previously received research funding from Pfizer, Eli Lilly, and Janssen. Both AMM and IJD are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the BBSRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptPeer reviewedPublisher PD

REVERBa couples the circadian clock to hepatic glucocorticoid action.

The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p