Evolution of a Signaling Nexus Constrained by Protein Interfaces and Conformational States

Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The Gα subunit of the G protein, in particular, is highly constrained due to its many interactions with proteins that control or react to its conformational state. Various organisms contain differing sets of Gα-interacting proteins, clearly indicating that shifts in sequence and associated Gα functionality were acquired over time. These numerous interactions constrained much of Gα evolution; yet Gα has diversified, through poorly understood processes, into several functionally specialized classes, each with a unique set of interacting proteins. Applying a synthetic sequence-based approach to mammalian Gα subunits, we established a set of seventy-five evolutionarily important class-distinctive residues, sites where a single Gα class is differentiated from the three other classes. We tested the hypothesis that shifts at these sites are important for class-specific functionality. Importantly, we mapped known and well-studied class-specific functionalities from all four mammalian classes to sixteen of our class-distinctive sites, validating the hypothesis. Our results show how unique functionality can evolve through the recruitment of residues that were ancestrally functional. We also studied acquisition of functionalities by following these evolutionarily important sites in non-mammalian organisms. Our results suggest that many class-distinctive sites were established early on in eukaryotic diversification and were critical for the establishment of new Gα classes, whereas others arose in punctuated bursts throughout metazoan evolution. These Gα class-distinctive residues are rational targets for future structural and functional studies

Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons

<p>Abstract</p> <p>Background</p> <p>Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons.</p> <p>Methods</p> <p>Using provincial administrative databases, elderly Quebec residents were screened in 1989 for benzodiazepine use and non-users were followed for up to 5 years. Logistic regression models were used to evaluate potential predictors of new benzodiazepine use among patient baseline characteristics.</p> <p>Results</p> <p>In the 252,811 elderly patients who had no benzodiazepine prescription during the baseline year (1989), 174,444 (69%) never filled a benzodiazepine prescription and 78,367 (31%) filled at least one benzodiazepine prescription. In the adjusted analysis, several risk factors for falls were associated with statistically significant increases in the risk of receiving a new benzodiazepine prescription including the number of prescribing physicians seen at baseline (OR: 1.12; 95% CI 1.11–1.13), being female (OR: 1.20; 95% CI 1.18–1.22) or a diagnosis of arthritis (OR: 1.11; 95% CI 1.09–1.14), depression (OR: 1.42; 95% CI 1.35–1.49) or alcohol abuse (OR: 1.24; 95% CI 1.05–1.46). The strongest predictor for starting a benzodiazepine was the use of other medications, particularly anti-depressants (OR: 1.85; 95% CI 1.75–1.95).</p> <p>Conclusion</p> <p>Patients with pre-existing conditions that increase the risk of injurious falls are significantly more likely to receive a new prescription for a benzodiazepine. The strength of the association between previous medication use and new benzodiazepine prescriptions highlights an important medication safety issue.</p

From capture to immersive viewing of 3D HDR point clouds

International audienceThe collaborators of the ReVeRY project address the design of a specific grid of cameras, a cost-efficient system that acquires at once several viewpoints, possibly under several exposures and the converting of multiview, multiexposed, video stream into a high quality 3D HDR point cloud. In the last two decades, industries and researchers proposed significant advances in media content acquisition systems in three main directions: increase of resolution and image quality with the new ultra-high-definition (UHD) standard; stereo capture for 3D content; and high-dynamic range (HDR) imaging. Compression, representation, and interoperability of these new media are active research fields in order to reduce data size and be perceptually accurate. The originality of the project is to address both HDR and depth through the entire pipeline. Creativity is enhanced by several tools, which answer challenges at the different stages of the pipeline: camera setup, data processing, capture visualisation, virtual camera controller, compression, perceptually guided immersive visualisation. It is the experience acquired by the researchers of the project that is exposed in this tutorial