L’épidémie de Covid-19, au-delà de mettre en évidence l’obésité comme facteur pronostique important, modifie grandement la prise en charge de cette maladie chronique. L’expérimentation article 51 ...Espace médical nutrition et obésité (EMNO) a dû intégrer des outils numériques pour maintenir les parcours de soins. Cette démarche a également été enrichie par l’apport d’un outil d’éducation thérapeutique digital. L’ensemble du processus de prise en charge a ainsi été réalisé malgré la situation, avec un retour très positif des patients inclus dans l’expérimentation. En contexte épidémique, le maintien des parcours de soins d’une maladie chronique comme l’obésité peut ainsi être assuré avec l’apport du numérique tout en dépassant le simple cadre de la téléconsultation et du suivi en y associant une approche pédagogique digitale.
The Covid-19 outbreak has not only brought evidence for obesity as an important prognostic factor, it also modifies this chronic disease management. The Article 51 Espace Médical Nutrition et Obésité (EMNO) experiment has had to include digital tools to ensure care pathway maintenance. The response of patients included in the experiment is, in this context, very positive. The procedure has also been enriched with the contribution of a digital therapeutic education tool. The care process has been maintained, despite the situation, with a positive response from patients. In the epidemic context, the maintenance of care pathways for a chronic disease such as obesity can be done with the contribution of digital tools, going beyond teleconsultations or tracking, by adding a digital education approach.
The BOLD contrast mechanism has a complex relationship with functional brain activity, oxygen metabolism, and neurovascular factors. Accurate interpretation of the BOLD signal for neuroscience and ...clinical applications necessitates a clear understanding of the sources of BOLD contrast and its relationship to underlying physiology. This review describes the physiological components that contribute to the BOLD signal and the steady-state calibrated BOLD models that enable quantification of functional changes with a separate challenge paradigm. The principles derived from these biophysical models are then used to interpret BOLD measurements in different neurological disorders in the presence of confounding vascular factors related to disease.
•Physiological sources of the BOLD fMRI contrast.•Dynamic and steady-state biophysical models of the BOLD signal.•Baseline oxygenation models (calibrated, qBOLD and fingerprinting).•BOLD signal and models in disease.
The plasma membrane represents a physical inelastic barrier with a given area that adheres to the underlying cytoskeleton. The tension in the membrane physically affects cell functions and recent ...studies have highlighted that this physical signal orchestrates complex aspects of trafficking and motility. Despite its undeniable importance, little is known about the mechanisms by which membrane tension regulates cell functions or stimulates signals. The maintenance of membrane tension is also a matter of debate, particularly the nature of the membrane reservoir and trafficking pathways that buffer tension. In this review we discuss the importance of membrane area and of tension as a master integrator of cell functions, particularly for membrane traffic.
We present a method allowing determination of resting cerebral oxygen metabolism (CMRO2) from MRI and end-tidal O2 measurements acquired during a pair of respiratory manipulations producing different ...combinations of hypercapnia and hyperoxia. The approach is based on a recently introduced generalization of calibrated MRI signal models that is valid for arbitrary combinations of blood flow and oxygenation change. Application of this model to MRI and respiratory data during a predominantly hyperoxic gas manipulation yields a specific functional relationship between the resting BOLD signal M and the resting oxygen extraction fraction OEF0. Repeating the procedure using a second, primarily hypercapnic, manipulation provides a different functional form of M vs. OEF0. These two equations can be readily solved for the two unknowns M and OEF0. The procedure also yields the resting arterial O2 content, which when multiplied by resting cerebral blood flow provides the total oxygen delivery in absolute physical units. The resultant map of oxygen delivery can be multiplied by the map of OEF0 to obtain a map of the resting cerebral metabolic rate of oxygen consumption (CMRO2) in absolute physical units.
Application of this procedure in a group of seven human subjects provided average values of 0.35±0.04 and 6.0±0.7% for OEF0 and M, respectively in gray-matter (M valid for 30ms echo-time at 3T). Multiplying OEF0 estimates by the individual values of resting gray-matter CBF (mean 52±5ml/100g/min) and the measured arterial O2 content gave a group average resting CMRO2 value of 145±30μmol/100g/min. The method also allowed the generation of maps depicting resting OEF, BOLD signal, and CMRO2.
Focal adhesions are mechanosensitive elements that enable mechanical communication between cells and the extracellular matrix. Here, we demonstrate a major mechanosensitive pathway in which α-actinin ...triggers adhesion maturation by linking integrins to actin in nascent adhesions. We show that depletion of the focal adhesion protein α-actinin enhances force generation in initial adhesions on fibronectin, but impairs mechanotransduction in a subsequent step, preventing adhesion maturation. Expression of an α-actinin fragment containing the integrin binding domain, however, dramatically reduces force generation in depleted cells. This behavior can be explained by a competition between talin (which mediates initial adhesion and force generation) and α-actinin for integrin binding. Indeed, we show in an in vitro assay that talin and α-actinin compete for binding to β ₃ integrins, but cooperate in binding to β ₁ integrins. Consistently, we find opposite effects of α-actinin depletion and expression of mutants on substrates that bind β ₃ integrins (fibronectin and vitronectin) versus substrates that only bind β ₁ integrins (collagen). We thus suggest that nascent adhesions composed of β ₃ integrins are initially linked to the actin cytoskeleton by talin, and then α-actinin competes with talin to bind β ₃ integrins. Force transmitted through α-actinin then triggers adhesion maturation. Once adhesions have matured, α-actinin recruitment correlates with force generation, suggesting that α-actinin is the main link transmitting force between integrins and the cytoskeleton in mature adhesions. Such a multistep process enables cells to adjust forces on matrices, unveiling a role of α-actinin that is different from its well-studied function as an actin cross-linker.
Cell migration and spreading involve the coordination of membrane trafficking, actomyosin contraction, and modifications to plasma membrane tension and area. The biochemical or biophysical basis for ...this coordination is however unknown. In this study, we show that during cell spreading, lamellipodia protrusion flattens plasma membrane folds and blebs and, once the plasma membrane area is depleted, there is a temporary increase in membrane tension by over twofold that is followed by activation of exocytosis and myosin contraction. Further, an artificial increase in plasma membrane tension stopped lamellipodia protrusion and activated an exocytotic burst. Subsequent decrease in tension restored spreading with activation of contraction. Conversely, blebbistatin inhibition of actomyosin contraction resulted in an even greater increase in plasma membrane tension and exocytosis activation. This spatiotemporal synchronization indicates that membrane tension is the signal that coordinates membrane trafficking, actomyosin contraction, and plasma membrane area change. We suggest that cells use plasma membrane tension as a global physical parameter to control cell motility.
A key molecular link between cells and the extracellular matrix is the binding between fibronectin and integrins α₅β₁ and αvβ₃. However, the roles of these different integrins in establishing ...adhesion remain unclear. We tested the adhesion strength of fibronectin-integrin-cytoskeleton linkages by applying physiological nanonewton forces to fibronectin-coated magnetic beads bound to cells. We report that the clustering of fibronectin domains within 40 nm led to integrin α₅β₁ recruitment, and increased the ability to sustain force by over six-fold. This force was supported by α₅β₁ integrin clusters. Importantly, we did not detect a role of either integrin αvβ₃ or talin 1 or 2 in maintaining adhesion strength. Instead, these molecules enabled the connection to the cytoskeleton and reinforcement in response to an applied force. Thus, high matrix forces are primarily supported by clustered α₅β₁ integrins, while less stable links to αvβ₃ integrins initiate mechanotransduction, resulting in reinforcement of integrin-cytoskeleton linkages through talin-dependent bonds.
Phagocytes clear the body of undesirable particles such as infectious agents and debris. To extend pseudopods over the surface of targeted particles during engulfment, cells must change shape through ...extensive membrane and cytoskeleton remodeling. We observed that pseudopod extension occurred in two phases. In the first phase, pseudopods extended rapidly, with actin polymerization pushing the plasma membrane forward. The second phase occurred once the membrane area from preexisting reservoirs was depleted, leading to increased membrane tension. Increased tension directly altered the small Rho GTPase Rac1, 3′-phosphoinositide, and cytoskeletal organization. Furthermore, it activated exocytosis of vesicles containing GPI-anchored proteins, increasing membrane area and phagocytosis efficiency for large particles. We thus propose that, during phagocytosis, membrane remodeling, cytoskeletal organization, and biochemical signaling are orchestrated by the mechanical signal of membrane tension. These results put a simple mechanical signal at the heart of understanding immunological responses.
Fundamental biological processes such as morphogenesis and wound healing involve the closure of epithelial gaps. Epithelial gap closure is commonly attributed either to the purse-string contraction ...of an intercellular actomyosin cable or to active cell migration, but the relative contribution of these two mechanisms remains unknown. Here we present a model experiment to systematically study epithelial closure in the absence of cell injury. We developed a pillar stencil approach to create well-defined gaps in terms of size and shape within an epithelial cell monolayer. Upon pillar removal, cells actively respond to the newly accessible free space by extending lamellipodia and migrating into the gap. The decrease of gap area over time is strikingly linear and shows two different regimes depending on the size of the gap. In large gaps, closure is dominated by lamellipodium-mediated cell migration. By contrast, closure of gaps smaller than 20 μm was affected by cell density and progressed independently of Rac, myosin light chain kinase, and Rho kinase, suggesting a passive physical mechanism. By changing the shape of the gap, we observed that low-curvature areas favored the appearance of lamellipodia, promoting faster closure. Altogether, our results reveal that the closure of epithelial gaps in the absence of cell injury is governed by the collective migration of cells through the activation of lamellipodium protrusion.
Cell migration is dependent on adhesion dynamics and actin cytoskeleton remodeling at the leading edge. These events may be physically constrained by the plasma membrane. Here, we show that the ...mechanical signal produced by an increase in plasma membrane tension triggers the positioning of new rows of adhesions at the leading edge. During protrusion, as membrane tension increases, velocity slows, and the lamellipodium buckles upward in a myosin II-independent manner. The buckling occurs between the front of the lamellipodium, where nascent adhesions are positioned in rows, and the base of the lamellipodium, where a vinculin-dependent clutch couples actin to previously positioned adhesions. As membrane tension decreases, protrusion resumes and buckling disappears, until the next cycle. We propose that the mechanical signal of membrane tension exerts upstream control in mechanotransduction by periodically compressing and relaxing the lamellipodium, leading to the positioning of adhesions at the leading edge of cells.
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