Genome editing provides new insights into receptor-controlled signalling pathways

Rapid developments in genome editing, based largely on CRISPR/Cas9 technologies, are offering unprecedented opportunities to eliminate the expression of single or multiple gene products in intact organisms and in model cell systems. Elimination of individual G protein-coupled receptors (GPCRs), both single and multiple G protein subunits, and arrestin adaptor proteins is providing new and sometimes unanticipated insights into molecular details of the regulation of cell signalling pathways and the behaviour of receptor ligands. Genome editing is certain to become a central component of therapeutic target validation, and will provide pharmacologists with new understanding of the complexities of action of novel and previously studied ligands, as well as of the transmission of signals from individual cell-surface receptors to intracellular signalling cascades

The pandemic toll and post-acute sequelae of SARS-CoV-2 in healthcare workers at a Swiss University Hospital.

Healthcare workers have potentially been among the most exposed to SARS-CoV-2 infection as well as the deleterious toll of the pandemic. This study has the objective to differentiate the pandemic toll from post-acute sequelae of SARS-CoV-2 infection in healthcare workers compared to the general population. The study was conducted between April and July 2021 at the Geneva University Hospitals, Switzerland. Eligible participants were all tested staff, and outpatient individuals tested for SARS-CoV-2 at the same hospital. The primary outcome was the prevalence of symptoms in healthcare workers compared to the general population, with measures of COVID-related symptoms and functional impairment, using prevalence estimates and multivariable logistic regression models. Healthcare workers (n=3,083) suffered mostly from fatigue (25.5%), headache (10.0%), difficulty concentrating (7.9%), exhaustion/burnout (7.1%), insomnia (6.2%), myalgia (6.7%) and arthralgia (6.3%). Regardless of SARS-CoV-2 infection, all symptoms were significantly higher in healthcare workers than the general population (n=3,556). SARS-CoV-2 infection in healthcare workers was associated with loss or change in smell, loss or change in taste, palpitations, dyspnea, difficulty concentrating, fatigue, and headache. Functional impairment was more significant in healthcare workers compared to the general population (aOR 2.28; 1.76-2.96), with a positive association with SARS-CoV-2 infection (aOR 3.81; 2.59-5.60). Symptoms and functional impairment in healthcare workers were increased compared to the general population, and potentially related to the pandemic toll as well as post-acute sequelae of SARS-CoV-2 infection. These findings are of concern, considering the essential role of healthcare workers in caring for all patients including and beyond COVID-19

Less is more

After decades of remarkable development, medicine is facing a tough economic reality and new challenges. These challenges include defining the values, objectives and tasks of sustainable medicine. In this context, the concept of "less is more" emerged in North America. "Less is more" is an invitation to recognize the potential risks of overuse of medical care that may result in harm rather than in better health. It is therefore necessary to drive unnecessary and costly practices by streamlining care without rationing

Interleukin-1 (IL-1) and the inflammasome in cancer

Inflammation is a hallmark of cancer and while exciting preclinical and clinical data has emerged implicating inflammation in the development and progression of certain cancer, our mechanistic understanding of how distinct inflammatory pathways are contributing to specific stages and types of cancer is still at an early stage. Malignancies are known to arise in areas of chronic inflammation and inflammation in the tumor microenvironment (often called tumor-promoting inflammation) is believed to allow cancer cells to evade immunosurveillance while promoting genetic instability, survival and progression. Among the strongest data suggesting a causal role for inflammation in cancer comes from the recent CANTOS trial which demonstrated that chronic IL-1β inhibition with canakinumab leads to a significant, dose-dependent decrease in incident lung cancer. This observation has launched a series of additional clinical studies to understand the role of IL-1β and inflammasome in cancer and when, during the course of disease progression, inhibition of IL-1β provides patients with disease altering benefit. In this article we will review recent data implicating IL-1β signaling and its upstream regulator NLRP3 in both solid tumor and hematologic malignancies. We will discuss the key preclinical observations and the current clinical landscape, and describe the pharmacologic tools which will be used to evaluate the effects of blocking tumor-promoting inflammation clinically

Anatomical Profiling of G Protein-Coupled Receptor Expression

SummaryG protein-coupled receptors (GPCRs) comprise the largest family of transmembrane signaling molecules and regulate a host of physiological and disease processes. To better understand the functions of GPCRs in vivo, we quantified transcript levels of 353 nonodorant GPCRs in 41 adult mouse tissues. Cluster analysis placed many GPCRs into anticipated anatomical and functional groups and predicted previously unidentified roles for less-studied receptors. From one such prediction, we showed that the Gpr91 ligand succinate can regulate lipolysis in white adipose tissue, suggesting that signaling by this citric acid cycle intermediate may regulate energy homeostasis. We also showed that pairwise analysis of GPCR expression across tissues may help predict drug side effects. This resource will aid studies to understand GPCR function in vivo and may assist in the identification of therapeutic targets

Evidence of active shortening along the eastern border of the San Rafael basement block: Characterization of the seismic source of the Villa Atuel earthquake (1929), Mendoza province, Argentina

ACLInternational audienceOn the 30 May 1929, a massive earthquake occurred in the San Rafael area (southern Mendoza province) leading to the destruction of the Villa Atuel and Las Malvinas towns. The region affected by the ground shaking covers a large part of southern South America. Although no surface breaks have been detected on the surface, several authors have pointed out active faults that could be related to the event of 1929. Using satellite imagery and field observations, we investigated two active faults situated on the eastern border of the San Rafael Block (SRB) close to or within the epicentral area. The most prominent faults are the c. 40 km long Las Malvinas and c. 30 km long Cerro Negro reverse faults which are located near the epicentral area. Geological and morphological observations allow us to describe late Pleistocene activity and estimate the long-term slip rates of these faults. Possible ruptures that match our observations and which are compatible with the cartographic length of these faults would account for a seismic moment magnitude of M0 = 2.8×1019 N m and a moment magnitude of MW = 6.9. The morphological signatures of these fault segments and the occurrence of the San Rafael earthquake suggests that the southern Mendoza Province is still currently submitted to shortening. © 2016 Cambridge University Press

From subduction to collision: Control of deep processes on the evolution of convergent plate boundary

International audienceUsing laboratory experiments, we investigate the dynamics of the collisional process that follows the closure of an oceanic basin. The evolution of these experiments systematically shows four successive episodes of deformation, which correspond to (1) the initiation of oceanic subduction, (2) a mature period of oceanic subduction, (3) an episode of continental subduction, during which the trench absorbs all the convergence and the superficial tectonic regime does not change significantly within the continental plates, and (4) continental collision that starts when the trench locks and convergence is absorbed by a system of thrust faults and folds. We observe that the amount of continental material that subducts before the onset of collision depends on the slab pull exerted by the subducted oceanic lithosphere. The slab-pull force, in turn, depends on the amount of subducted oceanic material, on the thickness of the convective mantle, and also on the rheology of the slab. Our experiments, indeed, suggest that parts of the oceanic slab may separate from the superficial slab to sink rapidly in the mantle, decreasing the slab-pull level and triggering the rapid onset of collision. We observe two possible modes of slab deformation: slab break-off and development of viscous instabilities. We define two dimensionless rheological numbers to characterize the possible occurrence of these modes of deformation. In all cases, oceanic closure is followed by episode of continental subduction during which the continental lithosphere may reach depths varying between 50 and 450 km, prior to the onset of continental collision

Exploring the Role of Tertiary Lymphoid Structures Using a Mouse Model of Bacteria-Infected Lungs

International audienceAnimal models can be helpful tools for deciphering the generation, maintenance, and role of tertiary lymphoid structures (TLS) during infections or tumor development. We describe here the establishment of a persistent lung infection in immune-competent mice by intratracheal instillation of agarose beads containing Pseudomonas aeruginosa or Staphylococcus aureus bacteria. After instillation, animals develop a chronic pulmonary infection, marked by the presence of TLS. This experimental setting allows the study of the function of TLS induced by bacteria encountered in patients with cystic fibrosis (CF) as P. aeruginosa and S. aureus are the two main bacterial strains that infect bronchi of adult CF patients. Additionally, we describe also how to manipulate the immune response in these infected animals by targeting immune cells involved in TLS function. Overall, this approach makes it possible to explore the role of chronic inflammation in the induction and maintenance of TLS in infected tissues

Geomorphology of the Northern Great Caucasus : investigating depth geometries from surface data

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