Two sub-states of the red2 state of methyl-coenzyme M reductase revealed by high-field EPR spectroscopy

Methyl-coenzyme M reductase (MCR) catalyzes the formation of methane from methyl-coenzyme M and coenzyme B in methanogenic archaea. The enzyme has two structurally interlinked active sites embedded in an α2β2γ2 subunit structure. Each active site has the nickel porphyrinoid F430 as a prosthetic group. In the active state, F430 contains the transition metal in the Ni(I) oxidation state. The active enzyme exhibits an axial Ni(I)-based continuous wave (CW) electron paramagnetic resonance (EPR) signal, called red1a in the absence of substrates or red1c in the presence of coenzyme M. Addition of coenzyme B to the MCR-red1 state can partially and reversibly convert it into the MCR-red2 form, which shows a rhombic Ni(I)-based EPR signal (at X-band microwave frequencies of approximately 9.4GHz). In this report we present evidence from high-field/high-frequency CW EPR spectroscopy (W-band, microwave frequency of approximately 94GHz) that the red2 state consists of two substates that could not be resolved by EPR spectroscopy at X-band frequencies. At W-band it becomes apparent that upon addition of coenzyme B to MCR in the red1c state, two red2 EPR signals are induced, not one as was previously believed. The first signal is the well-characterized (ortho)rhombic EPR signal, thus far called red2, while the second previously unidentified signal is axial. We have named the two substates MCR-red2r and MCR-red2a after their rhombic and axial signals, respectivel

Biomarker Discovery in Serum from Patients with Carotid Atherosclerosis

www.karger.com/cee This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License (www.karger.com/OA-license), applicable to the online version of the article only. Distribution for non-commercial purposes only

Evidence for Two Populations of Classical Transneptunian Objects: The Strong Inclination Dependence of Classical Binaries

We have searched 101 Classical transneptunian objects for companions with the Hubble Space Telescope. Of these, at least 21 are binary. The heliocentric inclinations of the objects we observed range from 0.6-34 degrees. We find a very strong anticorrelation of binaries with inclination. Of the 58 targets that have inclinations of less than 5.5 degrees, 17 are binary, a binary fraction of 29 +7/-6%. All 17 are similar-brightness systems. On the contrary, only 4 of the 42 objects with inclinations greater than 5.5 degrees have satellites and only 1 of these is a similar-brightness binary. This striking dichotomy appears to agree with other indications that the low eccentricity, non-resonant Classical transneptunian objects include two overlapping populations with significantly different physical properties and dynamical histories.Comment: 32 pages, 4 figures, 2 tables in press for Icarus volume 194 Note added in proof and reference updates in this corrected versio

A curriculum to teach medical students to care for people with disabilities: development and initial implementation

<p>Abstract</p> <p>Background</p> <p>Lack of knowledge and skills, and negative attitudes towards patients with disabilities, may adversely affect the services available to this group and negatively affect their health outcomes. The objective of this paper is to describe the development and initial implementation of a curriculum for teaching medical students to care for patients with disabilities.</p> <p>Methods</p> <p>We followed the six-step approach for developing curricula for medical education: general needs assessment, specific needs assessment, defining goals and objectives, determining the educational strategies, planning the implementation, and developing an evaluation plan.</p> <p>Results</p> <p>The curriculum has well defined goals and objectives covering knowledge, attitudes and skills. It employs both traditional and non-traditional teaching strategies. The implementation is planned over the four-year medical school curriculum in collaboration with a number of academic departments and specialized community-based agencies. The curriculum evaluation includes an attitudinal survey which is administered using a controlled design (pre- and post- exposure to the curriculum). The initial implementation of the curriculum has been very successful.</p> <p>Conclusion</p> <p>We have developed a longitudinal curriculum to teach medical students to care for people with disabilities. A rigorous evaluation of the impact of the curriculum is needed.</p

A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity

<p>Abstract</p> <p>Background</p> <p>Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.</p> <p>Methods</p> <p>Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients.</p> <p>Results</p> <p>Significant heterogeneity was detected among these trials (<it>I</it>²= 37%; <it>p </it>= 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abbé plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (<it>p </it>< 0.0001) and homogeneous populations (<it>I</it>²= 0 and <it>p </it>> 0.5, for both). Cluster 1 studies (<it>n </it>= 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68–1.12, <it>p </it>= 0.28), while cluster 2 studies (<it>n </it>= 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07–0.33, <it>p </it>< 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (<it>p </it>= 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (<it>p </it>= 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; <it>p </it>= 0.42) did not suggest that NAC is beneficial.</p> <p>Conclusion</p> <p>This meta-analysis does not support the efficacy of NAC to prevent CIN.</p

How to specify healthcare process improvements collaboratively using rapid, remote consensus-building: a framework and a case study of its application

Abstract: Background: Practical methods for facilitating process improvement are needed to support high quality, safe care. How best to specify (identify and define) process improvements – the changes that need to be made in a healthcare process – remains a key question. Methods for doing so collaboratively, rapidly and remotely offer much potential, but are under-developed. We propose an approach for engaging diverse stakeholders remotely in a consensus-building exercise to help specify improvements in a healthcare process, and we illustrate the approach in a case study. Methods: Organised in a five-step framework, our proposed approach is informed by a participatory ethos, crowdsourcing and consensus-building methods: (1) define scope and objective of the process improvement; (2) produce a draft or prototype of the proposed process improvement specification; (3) identify participant recruitment strategy; (4) design and conduct a remote consensus-building exercise; (5) produce a final specification of the process improvement in light of learning from the exercise. We tested the approach in a case study that sought to specify process improvements for the management of obstetric emergencies during the COVID-19 pandemic. We used a brief video showing a process for managing a post-partum haemorrhage in women with COVID-19 to elicit recommendations on how the process could be improved. Two Delphi rounds were then conducted to reach consensus. Results: We gathered views from 105 participants, with a background in maternity care (n = 36), infection prevention and control (n = 17), or human factors (n = 52). The participants initially generated 818 recommendations for how to improve the process illustrated in the video, which we synthesised into a set of 22 recommendations. The consensus-building exercise yielded a final set of 16 recommendations. These were used to inform the specification of process improvements for managing the obstetric emergency and develop supporting resources, including an updated video. Conclusions: The proposed methodological approach enabled the expertise and ingenuity of diverse stakeholders to be captured and mobilised to specify process improvements in an area of pressing service need. This approach has the potential to address current challenges in process improvement, but will require further evaluation

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues