FAD binding, cobinamide binding and active site communication in the corrin reductase (CobR)

Adenosylcobalamin, the coenzyme form of vitamin B12, is one Nature's most complex coenzyme whose de novo biogenesis proceeds along either an anaerobic or aerobic metabolic pathway. The aerobic synthesis involves reduction of the centrally chelated cobalt metal ion of the corrin ring from Co(II) to Co(I) before adenosylation can take place. A corrin reductase (CobR) enzyme has been identified as the likely agent to catalyse this reduction of the metal ion. Herein, we reveal how Brucella melitensis CobR binds its coenzyme FAD (flavin dinucleotide) and we also show that the enzyme can bind a corrin substrate consistent with its role in reduction of the cobalt of the corrin ring. Stopped-flow kinetics and EPR reveal a mechanistic asymmetry in CobR dimer that provides a potential link between the two electron reduction by NADH to the single electron reduction of Co(II) to Co(I)

Occupation and amyotrophic lateral sclerosis risk : a case-control study in the isolated island population of Malta

Objective: Amyotrophic lateral sclerosis (ALS) is a mostly sporadic neurodegenerative disease. The role of environmental factors has been extensively investigated but associations remain controversial. Considering that a substantial proportion of adult life is spent at work, identifying occupations and work-related exposures is considered an effective way to detect factors that increase ALS risk. This process may be further facilitated in population isolates due to environmental and genetic homogeneity. Our study investigated occupations and occupational exposures potentially associated with ALS risk in the isolated island population of Malta, using a case-control study design. Methods: Patients with ALS and randomly identified matched controls (1:1) were recruited throughout a four-year window, from 2017 through 2020. Data on educational level, residence, main occupation, smoking, and alcohol history were collected. Results: We found that compared to controls (44.4%), a higher percentage (73.7%) of ALS patients reported a blue-collar job as their main occupation (OR 2.04, 95% CI 1.2-3.72; p = 0.0072). Through regression analysis, craft and related trades occupations such as carpentry and construction (ISCO-08 major group 7), were found to be positively associated with ALS, with patients in this occupational category found to be more prone to develop bulbar-onset ALS (p = 0.0297). Overall, patients with ALS reported a significantly higher exposure to work-related strenuous physical activity (OR 2.35, 95% CI 1.53-3.59; p = 0.0002). Conclusion: Our findings suggest that manual workers particularly those working in the carpentry and construction industries have an increased ALS risk, possibly due to a history of intense or sustained physical activity.peer-reviewe

Paramedic clinical decision making during high acuity emergency calls: design and methodology of a Delphi study

<p>Abstract</p> <p>Background</p> <p>The scope of practice of paramedics in Canada has steadily evolved to include increasingly complex interventions in the prehospital setting, which likely have repercussions on clinical outcome and patient safety. Clinical decision making has been evaluated in several health professions, but there is a paucity of work in this area on paramedics. This study will utilize the Delphi technique to establish consensus on the most important instances of paramedic clinical decision making during high acuity emergency calls, as they relate to clinical outcome and patient safety.</p> <p>Methods and design</p> <p>Participants in this multi-round survey study will be paramedic leaders and emergency medical services medical directors/physicians from across Canada. In the first round, participants will identify instances of clinical decision making they feel are important for patient outcome and safety. On the second round, the panel will rank each instance of clinical decision making in terms of its importance. On the third and potentially fourth round, participants will have the opportunity to revise the ranking they assigned to each instance of clinical decision making. Consensus will be considered achieved for the most important instances if 80% of the panel ranks it as important or extremely important. The most important instances of clinical decision making will be plotted on a process analysis map.</p> <p>Discussion</p> <p>The process analysis map that results from this Delphi study will enable the gaps in research, knowledge and practice to be identified.</p

Terrestrial support of lake food webs: Synthesis reveals controls over cross-ecosystem resource use

Widespread evidence that organic matter exported from terrestrial into aquatic ecosystems supports recipient food webs remains controversial. A pressing question is not only whether high terrestrial support is possible but also what the general conditions are under which it arises. We assemble the largest data set, to date, of the isotopic composition (δ$^{2}$H, δ$^{13}$C, and δ$^{15}$N) of lake zooplankton and the resources at the base of their associated food webs. In total, our data set spans 559 observations across 147 lakes from the boreal to subtropics. By predicting terrestrial resource support from within-lake and catchment-level characteristics, we found that half of all consumer observations that is, the median were composed of at least 42% terrestrially derived material. In general, terrestrial support of zooplankton was greatest in lakes with large physical and hydrological connections to catchments that were rich in aboveground and belowground organic matter. However, some consumers responded less strongly to terrestrial resources where within-lake production was elevated. Our study shows that multiple mechanisms drive widespread cross-ecosystem support of aquatic consumers across Northern Hemisphere lakes and suggests that changes in terrestrial landscapes will influence ecosystem processes well beyond their boundaries.Support to organize the working group that produced this manuscript came from Natural Environment Research Council grant NE/M005968/1. B.W.K. also received travel support from the Natural Sciences and Engineering Research Council of Canada Collaborative Research and Training Experiencein Biodiversity Research at the University of British Columbia. J.K. received funding from the Swedish Research Council (2012–2015, funding number 621-2011-3908). M.L.P. acknowledges funding from the NSF Division of Environmental Biology (grant number 1456151)

Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Astrophysical Tests of Dark Matter with Maunakea Spectroscopic Explorer

We discuss how astrophysical observations with the Maunakea Spectroscopic Explorer (MSE), a high-multiplexity (about 4300 fibers), wide field-of-view (1.5 square degree), large telescope aperture (11.25 m) facility, can probe the particle nature of dark matter. MSE will conduct a suite of surveys that will provide critical input for determinations of the mass function, phase-space distribution, and internal density profiles of dark matter halos across all mass scales. N-body and hydrodynamical simulations of cold, warm, fuzzy and self-interacting dark matter suggest that non-trivial dynamics in the dark sector could have left an imprint on structure formation. Analysed within these frameworks, the extensive and unprecedented datasets produced by MSE will be used to search for deviations away from cold and collisionless dark matter model. MSE will provide an improved estimate of the local density of dark matter, critical for direct detection experiments, and will improve estimates of the J-factor for indirect searches through self-annihilation or decay into Standard Model particles. MSE will determine the impact of low mass substructures on the dynamics of Milky Way stellar streams in velocity space, and will allow for estimates of the density profiles of the dark matter halos of Milky Way dwarf galaxies using more than an order of magnitude more tracers. In the low redshift Universe, MSE will provide critical redshifts to pin down the luminosity functions of vast numbers of satellite systems, and MSE will be an essential component of future strong lensing measurements to constrain the halo mass function. Across nearly all mass scales, the improvements offered by MSE, in comparison to other facilities, are such that the relevant analyses are limited by systematics rather than statistics.Comment: 44 pages, 19 figures. To appear as a chapter for "The Detailed Science Case for the Maunakea Spectroscopic Explorer, 2019