Endothelial-to-mesenchymal transition (EndMT) is a dynamic, biological process in which endothelial cells (ECs) suppress fundamental endothelial properties and adopt mesenchymal characteristics such as the loss of cell-cell contacts, an increase in migratory potential, and increased contractility. Although this trans-differentiation program is recognized as essential for development and vascular homeostasis there is rising evidence of its incidence in vascular pathological conditions, particularly atherosclerosis, venous disease, and varicose veins. Therapeutic targeting of EndMT appears promising but in-vitro EndMT studies face numerous hurdles including the lack of standardized experimental models and the dynamic nature of endothelial plasticity. This study aims to directly quantify the physical forces behind EndMT progression to identify a mechanophenotype. To address these challenges, we performed immunofluorescence imaging of endothelial and mesenchymal-specific markers, morphological analysis, and measured tractions and intercellular stresses of venous endothelial cells exposed to TGF-β1, a known EndMT inducer, at 24, 48, and 72 hours. Interestingly, our time-point analysis revealed a decrease in tractions and intercellular stresses and increase in cell area and eccentricity at 24 hours followed by a decrease in endothelial markers and increase in mesenchymal markers via immunofluorescence at 48 and 72 hours. Additionally, our results revealed EndMT to occur gradually, with most cells progressing to an intermediate phenotype, however, a subpopulation of cells progressed to a more complete mesenchymal phenotype and prompted us to investigate the mechanics at the single-cell level. Our single-cell results revealed TGF-β1 treated cells yielded a 1.65-fold increase in tractions compared to control cells. The mechanics-oriented focus of this study is unique and complimentary to standard biochemical and molecular strategies used to study EndMT, which can offer new perspectives for innovative therapeutic interventions for endothelial dysfunction and vascular disease.

Functionally graded structures have material properties that continuously vary in one or more directions. Examples include human teeth, seashells, bamboo stems and human organs, where the varying volume fraction of fibers and their orientations optimize functionality. Deformations of such structures typically involve bending, stretching, and shearing. An everyday example of shearing deformation is the twisting of wet fabrics to extract water. In this study, we analytically examine the large deformations of functionally graded Mooney-Rivlin circular cylinders, focusing on how radial grading of material moduli can be beneficially utilized. We investigate the finite deformations caused by pressures applied to the bounding surfaces and axial loads or twisting moments on the end faces. We also simulate residual stresses in a hollow cylinder either by inverting it inside out or by closing a longitudinal wedge opening parallel to the cylinder axis through axisymmetric deformation before other loads are applied. It is observed that the maximum shear stress in an initially stress-free Mooney-Rivlin cylinder can occur at an interior point. In the absence of axial forces on the end faces, the cylinder elongates when twisted, with the degree of elongation depending on the grading of the material moduli. These findings should aid numerical analysts in verifying their algorithms for simulating large deformations of rubber-like materials modeled by the Mooney-Rivlin relation. / Master of Science / Functionally graded materials (FGMs) are composites whose properties vary in one or more directions to exploit the functionality of the individual components. An example would be a sheet of material that is fully metallic on one side and fully ceramic on the other, with properties changing gradually through the thickness. The Mooney-Rivlin model is used to capture the stress-strain response of rubber-like materials. Therefore, functionally graded Mooney-Rivlin cylinders are rubber-like composite cylinders whose properties change throughout their thickness. Functionally graded cylinders have a wide array of applications, including in pressure vessels, vibration damping systems and tires. Therefore, having a thorough understanding of the stresses induced in these cylinders when subjected to loads is essential for safe and reliable designs. This research aims to investigate the effects of material inhomogeneity on the stresses induced in functionally graded cylinders subjected to torsion, radial expansion, eversion, and various combinations of these. Furthermore, realizing that stresses induced during the fabrication process cannot be easily quantified, we study a problem in which these induced stresses can be determined and analyze their effect on subsequent deformations of the cylinder when subjected to torsion and radial expansion. To achieve this aim, we use a member of Ericksen's third family of universal deformations, which mathematically describes torsion, inflation, and eversion, along with the Mooney-Rivlin model to determine the stress state resulting from deformation. The results show that for cylinders of the same geometry in the stress-free undeformed state subjected to identical surface tractions, material inhomogeneities greatly influence the stresses in the cylinder. It was also found that the magnitude of the normal and shear stresses, axial stretch, and the geometry of the cylinder after deformation depend on the type of deformation and functional grading. Additionally, the results indicate that the normal stresses induced in an initially stressed cylinder are much greater than those in a cylinder that is initially stress-free when subjected to the same boundary conditions.

The main objective of the study was to investigate and simulate skeletal muscleforce production during and after isometric contractions, active muscle lengtheningand active muscle shortening. The motivation behind this work was to improve thedominant model of muscle force generation based on the theories of Hill from 1938. Effects of residual force enhancement and force depression were observed after concentric and eccentric contractions, and also during stretch-shortening cycles. It wasshown that this force modification is not related to lengthening/shortening velocity, butinstead the steady-state force after non-isometric contractions can be well describedby an initial isometric force to which a modification is added. The modification isevaluated from the mechanical work performed by and on the muscle during lengthvariations. The time constants calculated for isometric force redevelopment appearedto be in certain relations with those for initial isometric force development, an observation which extended our basis for muscle modelling. A macroscopic muscular model consisting of a contractile element, and paralleland series elastic elements was supplemented with a history component and adoptedfor mouse soleus muscle experiments. The parameters from the experiment analysis, particularly the force modification after non-isometric contractions and the timeconstants, were reproduced by the simulations. In a step towards a general implementation, the history modification was introduced in the muscluloskeletal model ofOpenSim software, which was then used for simulations of full body movements. / QC 20120525

L’originalité du sujet de thèse, initié lors du stage de M2R consiste à mesurer les propriétés de mobilité des molécules d’adhérence de cellules mécaniquement contrôlées. Le contrôle des propriétés géométriques et mécaniques du substrat seront fixées grace a l'utilisation d'une lamelle de verre comprenant des motifs de matrice extracellulaire. Nous utiliserons plusieurs techniques de mesures de mobilités, permettant d'accèder à des échelles temporelles d'étude différentes ; La FCS permettant d'accèder au dynamique rapide ; Le FRAP pour accèder au dynamique lente. / The originality of the project, initiated during the M2 internship, consist to measure the mobility of adhesive molecules of cells mechanically controlled.This control will be fixed thanks to a coverslip with adhesive protein pattern. We will next use different technics of mobility measurement to have information about different time scale : FCS for fast dynamics, FRAP for slow dynamics.

Continental rifting is an important geodynamic process during which the Earth's outer-most rigid shell undergoes continuous stretching resulting in continental break-up and theformation of new oceanic basins. The East African Rift System, which has two continentalsegments comprising largely of the East African Rift (EAR) to the West and the easternmostsegment Madagascar, is the largest narrow rift on Earth. However, the driving mechanismsof continental rifting remain poorly understood due to a lack of numerical infrastructure tosimulate rifting, the lack of knowledge of the underlying mantle dynamics, and poor knowl-edge of mantle rheology. Here, we use state-of-art computational modeling of the upper660 km of the Earth to: 1) provide a better understanding of mantle flow patterns and themantle rheology beneath Madagascar, 2) to elucidate the main driving forces of observedpresent-day∼E-W opening in the EAR, and 3) to investigate the role of multiple plumesor a superplume in driving surface deformation in the EAR. In chapter 1, we simulate EdgeDriven convection (EDC), constrained by a lithospheric thickness model beneath Madagas-car. The mantle flow associated with the EDC is used to calculate induced olivine aggregates'Lattice Preferred Orientation (LPO), known as seismic anisotropy. The predicted LPO isthen used to calculate synthetic seismic anisotropy, which were compared with observationsacross the island. Through a series of comparisons, we found that asthenospheric flow result-ing from undulations in lithospheric thickness variations is the dominant source of the seismicanisotropy, but fossilized structures from an ancient shear zone may play a role in southern Madagascar. Our results suggest that the rheological conditions needed for the formationof seismic anisotropy, dislocation creep, dominates the upper asthenosphere beneath Mada-gascar and likely other continental regions. In chapter 2, we use a 3D numerical model ofthe lithosphere-asthenosphere system to simulate instantaneous lithospheric deformation inthe EAR and surroundings. We test the hypothesis that the∼E-W extension of the EAR isdriven by large scale forces arising from topography and internal density gradients, known aslithospheric buoyancy forces. We calculate surface deformation solely driven by lithosphericbuoyancy forces and compare them with surface velocity observations. The lithosphericbuoyancy forces are implemented by imposing observed topography at the model surfaceand lateral density variations in the crust and mantle down to a compensation depth of 100km. Our results indicate that the large-scale∼E-W extension across East Africa is driven bylithospheric buoyancy forces, but not along-rift surface motions in deforming zones. In chap-ter 3, we test the hypothesis that the anomalous northward rift-parallel deformation observedin the deforming zones of the EAR is driven by viscous coupling between the lithosphereand deep upwelling mantle material, known as a superplume, flowing northward. We testtwo end-member plume models including a multiple plumes model simulated using high res-olution shear wave tomography-derived thermal anomaly and a superplume model (Africansuperplume) simulated by imposing a northward mantle-wind on the multiple plumes model.Our results suggest that the horizontal tractions from northward mantle flow associated withthe African Superplume is needed to explain observations of rift-parallel surface motions indeforming zones from GNSS/GPS data and northward oriented seismic anisotropy beneaththe EAR. Overall, this work yields a better understanding of the geodynamics of Africa. / Doctor of Philosophy / Continental rifting is an important geodynamic process during which the Earth's outer-most rigid shell undergoes continuous stretching resulting in continental break-up and theformation of new oceanic basins. The East African Rift System, which has two continentalsegments comprising largely of the East African Rift (EAR) to the West and the easternmostsegment Madagascar, is the largest narrow rift on Earth. However, the driving mechanismsof continental rifting remain poorly understood due to a lack of numerical infrastructure tosimulate rifting, the lack of knowledge of the underlying mantle dynamics, and poor knowl-edge of mantle rheology. Here, we use state-of-art computational modeling of the upper660 km of the Earth to: 1) provide a better understanding of mantle flow patterns and themantle rheology beneath Madagascar, 2) to elucidate the main driving forces of observedpresent-day∼E-W opening in the EAR, and 3) to investigate the role of multiple plumesor a superplume in driving surface deformation in the EAR. In chapter 1, we simulate EdgeDriven convection (EDC), constrained by a lithospheric thickness model beneath Madagas-car. The mantle flow associated with the EDC is used to calculate induced olivine aggregates'Lattice Preferred Orientation (LPO), known as seismic anisotropy. The predicted LPO isthen used to calculate synthetic seismic anisotropy, which were compared with observationsacross the island. Through a series of comparisons, we found that asthenospheric flow result-ing from undulations in lithospheric thickness variations is the dominant source of the seismicanisotropy, but fossilized structures from an ancient shear zone may play a role in southern Madagascar. Our results suggest that the rheological conditions needed for the formationof seismic anisotropy, dislocation creep, dominates the upper asthenosphere beneath Mada-gascar and likely other continental regions. In chapter 2, we use a 3D numerical model ofthe lithosphere-asthenosphere system to simulate instantaneous lithospheric deformation inthe EAR and surroundings. We test the hypothesis that the∼E-W extension of the EAR isdriven by large scale forces arising from topography and internal density gradients, known aslithospheric buoyancy forces. We calculate surface deformation solely driven by lithosphericbuoyancy forces and compare them with surface velocity observations. The lithosphericbuoyancy forces are implemented by imposing observed topography at the model surfaceand lateral density variations in the crust and mantle down to a compensation depth of 100km. Our results indicate that the large-scale∼E-W extension across East Africa is driven bylithospheric buoyancy forces, but not along-rift surface motions in deforming zones. In chap-ter 3, we test the hypothesis that the anomalous northward rift-parallel deformation observedin the deforming zones of the EAR is driven by viscous coupling between the lithosphereand deep upwelling mantle material, known as a superplume, flowing northward. We testtwo end-member plume models including a multiple plumes model simulated using high res-olution shear wave tomography-derived thermal anomaly and a superplume model (Africansuperplume) simulated by imposing a northward mantle-wind on the multiple plumes model.Our results suggest that the horizontal tractions from northward mantle flow associated withthe African Superplume is needed to explain observations of rift-parallel surface motions indeforming zones from GNSS/GPS data and northward oriented seismic anisotropy beneaththe EAR. Overall, this work yields a better understanding of the geodynamics of Africa.