Evidence for in situ and in vitro association between beta-dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse.

The accumulation of dystrophin and associated proteins at the postsynaptic membrane of the neuromuscular junction and their co-distribution with nicotinic acetylcholine receptor (AChR) clusters in vitro suggested a role for the dystrophin complex in synaptogenesis. Co-transfection experiments in which alpha- and beta-dystroglycan form a complex with AChR and rapsyn, a peripheral protein required for AChR clustering (Apel, D. A., Roberds, S. L., Campbell, K. P., and Merlie, J. P. (1995) Neuron 15, 115-126), suggested that rapsyn functions as a link between AChR and the dystrophin complex. We have investigated the interaction between rapsyn and beta-dystroglycan in Torpedo AChR-rich membranes using in situ and in vitro approaches. Cross-linking experiments were carried out to study the topography of postsynaptic membrane polypeptides. A cross-linked product of 90 kDa was labeled by antibodies to rapsyn and beta-dystroglycan; this demonstrates that these polypeptides are in close proximity to one another. Affinity chromatography experiments and ligand blot assays using rapsyn solubilized from Torpedo AChR-rich membranes and constructs containing beta-dystroglycan C-terminal fragments show that a rapsyn-binding site is present in the juxtamembranous region of the cytoplasmic tail of beta-dystroglycan. These data point out that rapsyn and dystroglycan interact in the postsynaptic membrane and thus reinforce the notion that dystroglycan could be involved in synaptogenesis

Caveolin-3 Directly Interacts with the C-terminal Tail of β-Dystroglycan IDENTIFICATION OF A CENTRAL WW-LIKE DOMAIN WITHIN CAVEOLIN FAMILY MEMBERS

Caveolin-3, the most recently recognized member of the caveolin gene family, is muscle-specific and is found in both cardiac and skeletal muscle, as well as smooth muscle cells. Several independent lines of evidence indicate that caveolin-3 is localized to the sarcolemma, where it associates with the dystrophin-glycoprotein complex. However, it remains unknown which component of the dystrophin complex interacts with caveolin-3. Here, we demonstrate that caveolin-3 directly interacts with b-dystroglycan, an integral membrane component of the dystrophin complex. Our results indicate that caveolin-3 co-localizes, co-fractionates, and coimmunoprecipitates with a fusion protein containing the cytoplasmic tail of b-dystroglycan. In addition, we show that a novel WW-like domain within caveolin-3 directly recognizes the extreme C terminus of b-dystroglycan that contains a PPXY motif. As the WW domain of dystrophin recognizes the same site within b-dystroglycan, we also demonstrate that caveolin-3 can effectively block the interaction of dystrophin with b-dystroglycan. In this regard, interaction of caveolin-3 with b-dystroglycan may competitively regulate the recruitment of dystrophin to the sarcolemma. We discuss the possible implications of our findings in the context of Duchenne muscular dystrophy

Computerized clinical decision support systems for chronic disease management: A decision-maker-researcher partnership systematic review

<p>Abstract</p> <p>Background</p> <p>The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations).</p> <p>Methods</p> <p>We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes.</p> <p>Results</p> <p>Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported.</p> <p>Conclusions</p> <p>A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes.</p

Panta Rhei benchmark dataset: socio-hydrological data of paired events of floods and droughts

As the adverse impacts of hydrological extremes increase in many regions of the world, a better understanding of the drivers of changes in risk and impacts is essential for effective flood and drought risk management and climate adaptation. However, there is currently a lack of comprehensive, empirical data about the processes, interactions and feedbacks in complex human-water systems leading to flood and drought impacts. Here we present a benchmark dataset containing socio-hydrological data of paired events, i.e., two floods or two droughts that occurred in the same area. The 45 paired events occurred in 42 different study areas and cover a wide range of socio-economic and hydro-climatic conditions. The dataset is unique in covering both floods and droughts, in the number of cases assessed, and in the quantity of socio-hydrological data. The benchmark dataset comprises: 1) detailed review style reports about the events and key processes between the two events of a pair; 2) the key data table containing variables that assess the indicators which characterise management shortcomings, hazard, exposure, vulnerability and impacts of all events; 3) a table of the indicators-of-change that indicate the differences between the first and second event of a pair. The advantages of the dataset are that it enables comparative analyses across all the paired events based on the indicators-of-change and allows for detailed context- and location-specific assessments based on the extensive data and reports of the individual study areas. The dataset can be used by the scientific community for exploratory data analyses e.g. focused on causal links between risk management, changes in hazard, exposure and vulnerability and flood or drought impacts. The data can also be used for the development, calibration and validation of socio-hydrological models. The dataset is available to the public through the GFZ Data Services (Kreibich et al. 2023, link for review: https://dataservices.gfz-potsdam.de/panmetaworks/review/923c14519deb04f83815ce108b48dd2581d57b90ce069bec9c948361028b8c85/).</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements