1 Abstract Liver fibrosis is a condition described by extensive accumulation of scar tissue in the liver. With further progression, it leads to cirrhosis or even to hepatocellular carcinoma. Liver fibrosis accompanies every chronic liver disease and its prevalence in adult European population is estimated to be around 4%. During my dissertation work, I studied the function of three members of Metzincin family of metalloproteinases - ADAM17, ADAM10 and MMP-19, in liver fibrosis and liver regeneration using mouse genetic models. ADAM17 and ADAM10 are important regulators of signalling pathways which are involved in immune response as well as differentiation. Both proteases are able to cleave ectodomains of their substrates from cell membrane, affecting bioavailability of ligands and functionality of receptors. Several of their substrates are involved in liver pathologies. MMP-19 on the other hand, is a metalloprotease mainly involved in extracellular matrix cleavage, important process in fibrosis development, as well as resolution of fibrosis. Our results demonstrate that ablation of ADAM10 results in increased susceptibility to liver fibrosis in mice, both spontaneous and toxin induced. ADAM10 deficiency affected biliary epithelium, as we detected higher markers of biliary damage in serum of ADAM10 deficient...

Background: Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive. Methods: With the goal to investigate the molecular basis of MET amplification (MET amp ) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET amp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo. Results: We find that cancer cells driven by MET amp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In MET amp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit MET amp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors. Conclusions: Our results demonstrate that MET amp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring MET amp , a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.

Cette thèse s’intéresse à la croissance épitaxiale à basse température (~200°C) des couches minces de silicium par dépôt chimique en phase vapeur assisté par plasma (PECVD), pour des applications aux cellules solaires. L’objectif de départ était de mieux comprendre cette croissance épitaxiale, en utilisant la microscopie électronique en transmission (MET) comme principal outil expérimental. D’abord, nous avons étudié les premiers stades de cette croissance épitaxiale en chimie SiF4/H2/Ar, en menant une série de dépôts courts – quelques dizaines jusqu’à quelques centaines de secondes – sur différents types de substrats. Nous avons établi une corrélation entre les images MET de coupes et de vues planes et les mesures d’ellipsométrie in-situ. Nous avons discuté les mécanismes de croissance en nous basant sur l’hypothèse de la croissance traditionnelle à base d’atomes, radicaux et ions et l’hypothèse (relativement nouvelle) reposant sur la fonte des nanoparticules générées par le plasma au moment de l’impact avec le substrat. De plus, pour comprendre comment l’épitaxie par PECVD à basse température se maintient, nous avons étudié comment elle se brise ou se perd. Pour cela, des expériences de perte d’épitaxie ont été visées en augmentant soit la puissance de la source RF, soit le flux d’hydrogène, toujours pour une chimie SiF4/H2/Ar. Dans les deux cas, le mécanisme de brisure d’épitaxie fait intervenir des macles et des fautes d’empilement qui interrompent la configuration épitaxiale ; ceci est accompagné par une rugosification de surface. Grâce à cette nouvelle compréhension de la brisure d’épitaxie, nous proposons quelques moyens pour maintenir l’épitaxie pour de plus grandes épaisseurs. En outre, nous avons observé une fascinante quasi-symétrie cinq dans les diagrammes de diffraction pour ces couches et aussi pour d’autres élaborées par un plasma de chimie SiH4/H2/HMDSO/B2H6/Ar. Nous avons attribué une telle symétrie à une brisure d’épitaxie par l’intermédiaire d’un maclage multiple. Nous avons développé une méthode d’analyse quantitative qui permet de discriminer les positions de maclage de celles du microcristal aléatoire dans les diagrammes de diffraction et d’estimer le nombre des opérations de maclage. Nous avons aussi discuté quelques raisons probables pour l’incidence du maclage et du maclage multiple sous forme de symétrie cinq. Finalement, une importante réalisation pour le monde de la MET, durant ce travail doctoral, a été l’optimisation de la préparation traditionnelle d’échantillon (polissage par tripode). Nous l’avons transformée d’une méthode longue et ennuyeuse en une méthode rapide qui devient compétitive par rapport à la technique du FIB relativement chère. / This thesis focuses on low temperature (LT, ~200°C) epitaxial growth of silicon thin films by plasma enhanced chemical vapor deposition (PECVD) for solar cell applications. Our starting goal was to acquire a better understanding of epitaxial growth, by using transmission electron microscopy (TEM) as the main experimental tool. First, we investigated the initial stages of epitaxial growth using SiF4/H2/Ar chemistry by performing a series of short depositions – from few tens to few hundred of seconds – on different types of substrates. We made a correlation between cross-sectional and plan-view TEM images and in-situ ellipsometry measurements. We discussed the growth mechanisms under the hypotheses of the traditional growth mediated by atoms, radicals and ions and the relatively new approach based on the melting of plasma generated nanoparticles upon impact with the substrate. Additionally, in order to understand how epitaxy by LT-PECVD is sustained, we studied how it is lost or how it breaks down. For that, experiments of intentional breakdown of epitaxy were performed by either increasing the RF power or the hydrogen flow rate using the same SiF4/H2/Ar chemistry. In both cases, the breakdown mechanism was based on the development of twins and stacking faults thus disrupting epitaxial configuration; this was accommodated with surface roughening. Thanks to this new understanding of epitaxy breakdown, we can propose some ways to sustain epitaxy for higher thicknesses. Moreover, we fascinatingly observed a quasi-fivefold symmetry in the diffraction patterns for these layers and for layers deposited using SiH4/H2/HMDSO/B2H6/Ar plasma chemistry as well. We attributed such symmetry to the breakdown of epitaxy through multiple twinning. We developed a quantitative analysis method to discriminate twin positions from random microcrystalline ones in the diffraction patterns and to estimate the number of twin operations. We also discussed some probable reasons for the occurrence of twinning and multiple twinning in a fivefold symmetry fashion. Finally, one important achievement to the TEM world is the optimization, during this doctoral work, of the traditional TEM sample preparation (tripod polishing), transforming it from a long and boring method to a fast method that is competitive with the relatively expensive focus ion beam (FIB) technique.

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Brake materials represent an important source of air pollution, especially in urban areas, where they can contribute to approx. 21 % of the traffic-related particulate matter emission. For this reason, the design of new brake materials with low emissions is a topical issue. In addition to low emissions, the design of new friction materials has to ensure excellent performance with stable coefficients of friction and low wear rate. Due to the several requirements that these materials need to fulfill, their development and testing are complex and intercorrelated. Good performance and low emission strongly depend on the mechanisms acting at the disc-pad interfaces. In this thesis, a brake dynamometer testing protocol is developed to better understand the relationships of the braking parameters with the brake performance and emission behavior, correlating them with the surface characteristics. The surface characteristics were investigated with a-posteriori analysis, in terms of extension of the contact area, degree of compaction of the wear particles and relevant composition. The work is focused on the bedding process and the influence of the braking parameters on the frictional, wear and emission behaviors. Regarding the bedding process, run-in, transition stage and steady states were identified as concerns the frictional, wear and emission behaviors. The frictional behavior gets stabilized by the extension of the secondary plateaus, whereas the wear and emission behaviors are stabilized as their degree of compaction increases. The influence of pressure and velocity under mild sliding conditions were studied for a low-met and NAO material, the two most common types of friction materials. The low-met material featured a more stable and higher friction coefficient and lower wear and emissions than the NAO material. The wear behavior is strongly affected by pressure for the NAO material, and for the low-met material, velocity is very influential. Emissions follow a cube relationship with velocity for both materials. The significant differences in the observed behaviors are explained in terms of the different features of the surfaces. The NAO material featured a smooth and uniform surface, with higher coverage than the low-met material, on which steel fibers play important adhesive and abrasive actions. From tests under mild sliding conditions of several friction materials sliding against cast-iron discs, a linear relationship is found between the specific wear rate and the emission factor. This relationship identifies a wear rate below 2.5 10-14 m2/N complying with the Euro 7 limitation of 3 mg/km/vehicle after 2034. Among the friction materials sliding against cast iron discs, the NAO material and only one friction material displayed an emission factor below the limit of 3 mg/km/vehicle. In addition, the emission factor of low-met material sliding against a cermet-coated disc was lower than this limit. These observations confirm that the NAO materials and coated discs are effective systems to mitigate emissions, whereas further efforts are required to improve the emission behavior of low-met materials. Interestingly, the low-met materials with a reduced presence of secondary plateaus featured higher wear and emissions. Regarding the brake performance, under severe sliding conditions, the NAO material displayed worse frictional and wear behaviors than the reference low-met material. For high-pressure ranges, the effect of pressure is to cause a monotonic decrease in the friction coefficient. The effect of temperature on the friction coefficient causes an increase in the friction coefficient when the tribo-oxidative processes are contained up to 300 °C. For combinations of high velocity and temperature, the tribo-oxidative processes are high enough to form a thick glaze layer on the surfaces. The glaze layers were correlated to a lubricating effect, or fade effect, at disc temperatures above 400 °C, especially when their extension covered the steel fibers. The cermet-coated disc displayed the same fade behavior at high velocity-temperature values, although at low velocities and high temperatures, friction instability was observed and related to larger but fewer patches originating to a significant extent from material transfer from the disc. The friction instability in the coated disc was ascribed to the different tribo-oxidative behavior in the formation of ‘glazes’ due to the low source of iron in the disc material.

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Dans la perspective de prédire les transformations chimico-minéralogiques possibles d'une bentonite placée en conditions de stockage profond de déchets radioactifs, plusieurs séries d'expériences ont été réalisées utilisant la bentonite MX80 en présence d'une solution chlorurée sodi-calcique, en absence ou en présence de fer (magnétite + hématite ou fer métal + magnétite), à 80 et 300 °C et pour des durées de 1 jour à 9 mois. Les produits de réactions ont fait l'objet de caractérisations multi-échelles et multi-techniques : diffraction des rayons X, microscope électronique à balayage et en transmission (imagerie haute résolution, EDS et EELS), microsonde électronique, spectroscopie Mössbauer et analyse ICP AES et ICP MS des solutions. Le code de calcul EQ3/6 a été utilisé pour simuler les expériences réalisées. Une nouvelle méthode ponctuelle de détermination de la valence du fer dans les argiles au MET par spectroscopie de perte d'énergie des électrons (EELS) a été développée.