Functional redundancy between RAP1 isoforms in murine platelet production and function

RAP GTPases, important regulators of cellular adhesion, are abundant signaling molecules in the platelet/megakaryocytic lineage. However, mice lacking the predominant isoform, RAP1B, display a partial platelet integrin activation defect and have a normal platelet count, suggesting the existence of a RAP1-independent pathway to integrin activation in platelets and a negligible role for RAP GTPases in megakaryocyte biology. To determine the importance of individual RAP isoforms on platelet production and on platelet activation at sites of mechanical injury or vascular leakage, we conditionally deleted Rap1a and/or Rap1b in the megakaryocytic lineage (mKO). Interestingly, Rap1a/b-mKO mice displayed a marked macrothrombocytopenia due to impaired pro- platelet formation by megakaryocytes. In platelets, RAP isoforms had both redundant and isoform-ˇspecific functions. Deletion of RAP1B, but not RAP1A, significantly reduced α- granule secretion and activation of the cytoskeleton regulator RAC1. Both isoforms significantly contributed to thromboxane A2 generation and the inside-out activation of platelet integrins. Combined deficiency of RAP1A and RAP1B markedly impaired platelet aggregation, spreading and clot retraction. Consistently, thrombus formation in physiological flow conditions was abolished in Rap1a/b-mKO, but not Rap1a-mKO or Rap1b-mKO platelets. Rap1a/b-mKO mice were strongly protected from experimental thrombosis and exhibited a severe defect in hemostasis after mechanical injury. Surprisingly, Rap1a/b-mKO platelets were indistinguishable from controls in their ability to prevent blood-lymphatic mixing during development and hemorrhage at sites of inflammation. In summary, our studies demonstrate an essential role for RAP1 signaling in platelet integrin activation and a critical role in platelet production. While important for hemostatic/thrombotic plug formation, platelet RAP1 signaling is dispensable for vascular integrity during development and inflammation

World Heart Federation Roadmap for Secondary Prevention of Cardiovascular Disease: 2023 Update.

BACKGROUND: Secondary prevention lifestyle and pharmacological treatment of atherosclerotic cardiovascular disease (ASCVD) reduce a high proportion of recurrent events and mortality. However, significant gaps exist between guideline recommendations and usual clinical practice. OBJECTIVES: Describe the state of the art, the roadblocks, and successful strategies to overcome them in ASCVD secondary prevention management. METHODS: A writing group reviewed guidelines and research papers and received inputs from an international committee composed of cardiovascular prevention and health systems experts about the article's structure, content, and draft. Finally, an external expert group reviewed the paper. RESULTS: Smoking cessation, physical activity, diet and weight management, antiplatelets, statins, beta-blockers, renin-angiotensin-aldosterone system inhibitors, and cardiac rehabilitation reduce events and mortality. Potential roadblocks may occur at the individual, healthcare provider, and health system levels and include lack of access to healthcare and medicines, clinical inertia, lack of primary care infrastructure or built environments that support preventive cardiovascular health behaviours. Possible solutions include improving health literacy, self-management strategies, national policies to improve lifestyle and access to secondary prevention medication (including fix-dose combination therapy), implementing rehabilitation programs, and incorporating digital health interventions. Digital tools are being examined in a range of settings from enhancing self-management, risk factor control, and cardiac rehab. CONCLUSIONS: Effective strategies for secondary prevention management exist, but there are barriers to their implementation. WHF roadmaps can facilitate the development of a strategic plan to identify and implement local and national level approaches for improving secondary prevention

World Heart Federation Cholesterol Roadmap 2022.

BACKGROUND: Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome. METHODS: Through a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these. RESULTS: Reducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies. CONCLUSIONS: The adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD

OptiProtec’Eau : Outil d’aide à la décision pour la définition optimisée des périmètres de protection des captages d’eau potable

International audienc

An artificial intelligence-aided virtual screening recipe for two-dimensional materials discovery

In recent years, artificial intelligence (AI) methods have prominently proven their use in solving complex problems. Across science and engineering disciplines, the data-driven approach has become the fourth and newest paradigm. It is the burgeoning of findable, accessible, interoperable, and reusable (FAIR) data generated by the first three paradigms of experiment, theory, and simulation that has enabled the application of AI methods for the scientific discovery and engineering of compounds and materials. Here, we introduce a recipe for a data-driven strategy to speed up the virtual screening of two-dimensional (2D) materials and to accelerate the discovery of new candidates with targeted physical and chemical properties. As a proof of concept, we generate new 2D candidate materials covering an extremely large compositional space, downselect 316,505 likely stable 2D materials, and predict the key physical properties of these new 2D candidates. Finally, we hone in on the most propitious candidates of functional 2D materials for energy conversion and storage

A new investigation method combining morphological observations and chemical analyses of surface waters to improve knowledge on flash karst floods genesis.

International audienc

Studies on new vegetable oil sources in the Amazon region of Peru. Investigations on the oil of umari (Poraqueiba sericea Tul.).

peer reviewe

Observations on how people in two locations of the plateau département of Southeast Benin perceive entomophagy:a study from West Africa

Abstract We surveyed the local populations of Kétou and Pobè in Southeast Benin through interviews and with the aid of a semi-structured questionnaire in order to understand how they currently perceive entomophagy, an age-old tradition in their communities. The study revealed that the majority of the population was familiar with the use of insects as food, and a sizable number of people were still interested in insect consumption. Gender differences were not apparent. Tradition or culture was identified as the most influential factor, followed by taste, as determinants for eating or rejecting insects. However, identifying the edible species and comparing practices how they were prepared for consumption, we found that the knowledge was not homogenous across the society of Benin, with differences depending on ethnicity, culture, respondent’s age, and educational background. Awareness and promotion of food insects in the society should help to preserve the practice of entomophagy and in turn could lead to the provision of much needed nutritional supplements to the poorer and disadvantaged sections of the society

First report of Zucchini yellow mosaic virus in cucurbits in Ivory Coast

International audienc