Evidence That a Lipolytic Enzyme—Hematopoietic-Specific Phospholipase C-β2—Promotes Mobilization of Hematopoietic Stem Cells by Decreasing Their Lipid Raft-Mediated Bone Marrow Retention and Increasing the Promobilizing Effects of Granulocytes

Hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment and are retained there by the interaction of membrane lipid raft-associated receptors, such as the α-chemokine receptor CXCR4 and the α4β1-integrin (VLA-4, very late antigen 4 receptor) receptor, with their respective specific ligands, stromal-derived factor 1 and vascular cell adhesion molecule 1, expressed in BM stem cell niches. The integrity of the lipid rafts containing these receptors is maintained by the glycolipid glycosylphosphatidylinositol anchor (GPI-A). It has been reported that a cleavage fragment of the fifth component of the activated complement cascade, C5a, has an important role in mobilizing HSPCs into the peripheral blood (PB) by (i) inducing degranulation of BM-residing granulocytes and (ii) promoting their egress from the BM into the PB so that they permeabilize the endothelial barrier for subsequent egress of HSPCs. We report here that hematopoietic cell-specific phospholipase C-β2 (PLC-β2) has a crucial role in pharmacological mobilization of HSPCs. On the one hand, when released during degranulation of granulocytes, it digests GPI-A, thereby disrupting membrane lipid rafts and impairing retention of HSPCs in BM niches. On the other hand, it is an intracellular enzyme required for degranulation of granulocytes and their egress from BM. In support of this dual role, we demonstrate that PLC-β2-knockout mice are poor mobilizers and provide, for the first time, evidence for the involvement of this lipolytic enzyme in the mobilization of HSPCs

Family Physicians’ Attitudes and Practices Regarding Assessments of Medical Fitness to Drive in Older Persons

BACKGROUND: Higher crash rates per mile driven in older drivers have focused attention on the assessment of older drivers. OBJECTIVE: To examine the attitudes and practices of family physicians regarding fitness-to-drive issues in older persons. DESIGN: Survey questionnaire. PARTICIPANTS: The questionnaire was sent to 1,000 randomly selected Canadian family physicians. Four hundred sixty eligible physicians returned completed questionnaires. MEASUREMENTS: Self-reported attitudes and practices towards driving assessments and the reporting of medically unsafe drivers. RESULTS: Over 45% of physicians are not confident in assessing driving fitness and do not consider themselves to be the most qualified professionals to do so. The majority (88.6%) feel that they would benefit from further education in this area. About 75% feel that reporting a patient as an unsafe driver places them in a conflict of interest and negatively impacts on the patient and the physician–patient relationship. Nevertheless, most (72.4%) agree that physicians should be legally responsible for reporting unsafe drivers to the licensing authorities. Physicians from provinces with mandatory versus discretionary reporting requirements are more likely to report unsafe drivers (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.58 to 4.91), but less likely to perform driving assessments (OR, 0.58; 95% CI, 0.39 to 0.85). Most driving assessments take between 10 and 30 minutes, with much variability in the components included. CONCLUSIONS: Family physicians lack confidence in performing driving assessments and note many negative consequences of reporting unsafe drivers. Education about assessing driving fitness and approaches that protect the physician–patient relationship when reporting occurs are needed

The effects of mutant Ras proteins on the cell signalome

The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells. © 2020, The Author(s)

Diversité et adaptabilité du fonctionnement spatio-temporel d'exploitations herbagères : premiers enseignements à partir d'une étude de cas dans le Cantal (Auvergne)

National audienceIn breeding areas of medium mountains, the fodder system of the farms is marked by agro-climatic and structural constraints. For future, one of the strong stakes is in the capacity of these farms to organize and articulate the land-uses of their farm territory. This is why we were interested in the characterization and understanding of the spatio-temporal organization of the land-uses in mountain farms of the Cantal French department. The elements presented in this paper relate to a phase of qualitative analysis on four contrasted farm-cases, having been then used to develop a more exhaustive and statistical reading these spatio-temporal organizations in farms of this department. The comparison of the four contrasted farms shows different linkages between the farming space entities, in terms of complexity, period, location, form... This organization also arises like an adjustment key to farms constraints. This type of approach should help in better characterizing and understanding the adaptation capacities of mountain breeding farms.Dans les zones d'élevage de moyennes montagnes, le système fourrager des exploitations est fortement marqué par des contraintes agro-climatiques et structurelles. Pour l'avenir, un des enjeux forts est dans la capacité de ces exploitations à organiser et articuler l'utilisation de leur parcellaire. C'est pourquoi nous nous sommes intéressés à la caractérisation et à la compréhension de l'organisation spatio-temporelle des usages du parcellaire d'exploitations de montagne dans le Cantal. Les éléments présentés dans ce papier concernent une phase d'analyse qualitative de quatre cas contrastés d'exploitations, ayant ensuite servi à mettre au point une lecture plus exhaustive et statistique des divers types de fonctionnement spatio-temporel des systèmes fourragers de petites régions agricoles de ce département. La comparaison de quatre exploitations contrastées montrent des différences d'articulations entre les entités spatiales du parcellaire, en termes de complexité, période, lieu... Cette organisation spatio-temporelle ressort aussi comme une variable d'ajustement essentielle vis-à-vis de contraintes de l'exploitation. Ce type d'approche devrait aider à mieux caractériser et comprendre les capacités d'adaptation des élevages de montagne