Mon travail de thèse a été principalement de comprendre comment les voies de signalisations contrôlent la différenciation et la morphogenèse de l'embryon de vertébré. Les communications entre cellules sont à la base du développement des métazoaires et de leurs évolutions et sont souvent impliquées dans les pathologies humaines. J'ai profité de la puissance des approches fonctionnelles chez le xenope pour essayer de comprendre comment les signaux BMP, FGF, Nodal et Notch sont intégrés dans le temps et l'espace afin de coordonnées différentes décisions cellulaires. Premièrement, nous avons montré que la voie Nodal est active avant la transition mid-blastuléene et permet l'induction du mesedoderme à travers l'auto régulation de l'expression de ces ligands Xnr5 et Xnr6 (Skirkanish et al. soumis à Development). Deuxièmement, j'ai montré que différent ligand de la voie Nodal contrôlent séquentiellement l'induction du mesendoderm et les mouvements de gastrulation (Luxardi et al., Development, 2010). Troisièmement, j'ai montré qu'un cinquième ligand de la voie Nodal, Xnr4, contrôle la régionalisation médio latérale de la plaque neurale ouverte et la neurogenèse. Quatrièmement, nous avons montré qu'une famille de microARN, nir449, contrôle la différenciation des cellules multi-ciliées à travers son action sur un ligand de la voie Notch, Delta-1 (Marcet et al. Nature Cell Biology, en révision). Enfin, j'ai découvert une nouvelle fonction des signaux BMP dans le control de la spécification des épithéliums muco cilié. / My PhD work generally addressed how signaling pathways control differentiation and morphogenesis in the vertebrate embryo. intercellular communication is the basis of metazoan development and evolution and is often involved in human pathologies. I take advantage of the power of functional approaches in the Xenopus embryo, to try and understand how BMP, FGF, Nodal and Notch signals are intragrated in time ans space to coordinate vatious cellular decisions. First, we showed that Nodal signaling is activated before the mid blastula transition and allow mesendoderm induction through the auro regulation of the expression of its ligands Xnr5 and Xnr6 (Skirkanish et al., submitted to development). Second, I have demonstrated that in a gastrulation movements (Luxardi et al., Development, 2010). Third, I have demonstrated that a fifth Nodal ligand, Xnr4, control medio-lateral patterning of the open neural plate and neurogenesis. Froth, we showed that a microRNA family, mir449, controls differenciation of multiciliated cells through the regulation of the Notch ligand Delta-1 (Marcet et al. Nature Cell Biology, in revision). Last, I have discovered a novel function of the BMP pathway in the control of cell type specification within the epidermal mucocialiary epithelium

By exploring how my/a tattooed body functions as becoming through the concept of bodies without organs (BwO), this work pushes the edges of qualitative inquiry. Following St. Pierre’s call to deconstruct the concepts on which qualitative research is built, this inquiry troubles the I/we of authorship and linear meaning making as it examines the tattooed body functioning as becoming a BwO. The nodal ethnography is a Deleuzo-Guattarian-based methodological inquiry in which interruptions and layers of narrative are used to create spaces for conversation between my multinodes. The tattoos on my semipermeable corporeal flesh tell multilayered stories that are constantly moving and shifting, and I (re)make meaning of these stories within, amongst, and between the nodes that constitute this disorganized body while approaching the limits of a BwO, always in progress, becoming. There is no beginning or end, only a middle, made up of lines that can be read in any order, as linearity does not live here. The Laminar Express iPhone/iPad photography application allowed for the layering of images, text, and color to rupture and even to distort the lines of ink on my body as a plane of representation adds yet another collaborative space to have dialogue(s); thus offering endless possibilities for the nodes of my ethnography to be (re)connected and (re)produced. My tattooed body evokes response from my multiselves as well as from others; ergo, I invite the reader to become a co-collaborator of this nodal ethnography, and to take lines of flight with/in this experimental space of what may appear when tattoos/images/multinodes/selves and storied lines of inked/textured text collide with Deleuzo-Guattarian theory in exploring my tattooed skin as becoming a BwO.

L’induction neurale est le processus au travers duquel les cellules ectodermiques de l’embryon deviennent neurales. De nombreuses études sur les mécanismes contrôlant ce processus on été réalisées mais du fait de sa complexité, de nombreuses questions restent sans réponse. Au cours de ce travail de thèse, je me suis intéressé à l’étude de l’induction neurale sous une perspective évolutive en étudiant ce processus chez le céphalocordé amphioxus, l’un des plus proches parents des vertébrés. J’ai pu mettre en évidence que, comme les vertébrés, l’amphioxus possède un organisateur. J’ai également confirmé une conservation du rôle des voies de signalisation BMP et FGF respectivement dans l’induction de l’épiderme et la régionalisation du tissu neural. Cependant, au contraire des vertébrés, le signal FGF ne semble pas être un acteur prépondérant de l’induction neurale. Au contraire, un rôle important de la voie de signalisation Activine/Nodal a été mis en évidence.Les résultats obtenus soutiennent d’une part la conservation de certains aspects de ce mécanisme chez tous les chordés, et suggèrent d’autre part l’implication de certains acteurs comme la voie Activine/Nodal jusque là inconnue chez les vertébrés. La position phylogénétique de l’amphioxus et la conservation globale de ce processus entre les céphalochordés et les vertébrés nous permettent de suggérer que l’ancêtre des chordés formait du tissue neurale au travers des mécanismes mis en évidence dans cet étude. Ces résultats nous permettent également de proposer de nouvelles études chez les vertébrés visant à établir un rôle putatif de la voie Activine/Nodal au cours de ce processus, rôle jusque la complètement inconnu. / Neural induction is the process through which embryonic ectodermal cells become neural. Many studies on the mechanisms controlling this process have been made, but because of its complexity, many questions remain unanswered. In this thesis, I have focused my interest on the study of neural induction in an evolutionary context studying this process in the cephalochordate amphioxus, one of the closest relatives of vertebrates. I have highlighted that amphioxus, as vertebrates, possesses an organizer. I have demonstrated a conservation of the role of BMP and FGF signals in the induction of the epidermis and the regionalization of neural tissue respectively. However, in contrast to vertebrates, FGF signal does not appear to be a major player in neural induction. Instead, an important role of Activin/Nodal signaling pathway has been demonstrated. These results support, first, the conservation of several aspects of this mechanism in all chordates, and second, they suggest the involvement of the Activin/Nodal signaling in this process, something previously unknown in vertebrates. The phylogenetic position of amphioxus and the overall conservation of this process between cephalochordates and vertebrates allow us to suggest that the ancestor of chordates formed its neural tissue through mechanisms highlighted in this study. These results also allow us to propose new studies in vertebrates for establishing a putative role of the Activin/Nodal signaling during this process, a role previously completely unknown.

Orientador: Marcos Tadeu de Oliveira Pimenta / Resumo: Para uma classe de equações quasilineares de Schrödinger, estabelecemos a existência de soluções positivas e nodais pelo método de Nehari. / Abstract: For a class of Schrödinger quasilinear equations, we established the existence of positive and nodal solutions by the Nehari method. / Mestre

<p>Organizations, like individuals, are expected to learn from their mistakes. Companies that successfully rely on past knowledge to inform programmatic decisions use knowledge management tools to capture and disseminate this information, often in the form of lessons learned databases. However, past mistakes continue to happen in the aerospace industry, including NASA. Although NASA has taken measures to stress the importance of lessons learned in organizational culture, relatively little work has been done to develop the user interface of their lessons learned database. Encouraging engineers to review lessons only goes so far when the interface itself is outdated and difficult to use. We propose that an interactive network tool is an effective way to disseminate lessons learned to novice systems engineers.</p><p><br></p><p>In this thesis, I begin by developing a model to represent spacecraft anomaly narratives and applying this model to the Jet Propulsion Laboratory’s publicly available lessons learned database. I then create an interactive network tool and populate it with the set of modeled lessons. Then, I design an experiment to determine how novice engineers use two different knowledge management tools—the interactive network and the NASA database. I use transcripts of users’ thought processes, verbalized to me during the experiment, to create a mental model of how users with access to knowledge management tools respond to engineering scenarios. From the mental model, I identify the functional strengths and weakness of both the interactive network and the NASA database. Finally, I discuss the results of the experiment and recommend future improvements to the interactive network tool.</p><p><br></p><p>We found that the interactive network was a better resource for users to make connections between topics, and that the NASA database was a better resource for users to search for specific information. Using the interactive network over the NASA database correlated with an increase in performance for the majority of the experiment, but data we collected do not provide enough evidence for us to conclude that the interactive network is a better dissemination tool than the NASA database in all scenarios. We found that receiving lessons learned from either of the tools takes time because each tool’s functionality elicits new tasks from the user. Finally, we found that the top performers in the experiment used each of the tool’s strongest features.</p><div><br></div><p></p>

Nodal semimetals host either degenerate points (Dirac/Weyl points) or lines whose band topology in Brillouin zone can be classified either as trivial (normal nodal semimetals) or non trivial (topological nodal semimetals). This thesis investigates the electronic structure of two different categories of topological nodal semimetals probed by angleresolved photoemission spectroscopy (ARPES): The first material is Indium Bismuth (InBi). InBi is a semimetal with simple tetragonal structure with P4/nmm space group. This space group is predicted to host protected nodal lines along the perpendicular momentum direction at the high symmetry lines of the Brillouin zone boundary even under strong spin-orbit coupling (SOC) situation. As a semimetal with two heavy elements, InBi is a suitable candidate to test the prediction. The investigation by ARPES demonstrates not only that InBi hosts the nodal line in the presence of strong SOC, it also shows the signature of type-II Dirac crossing along the perpendicular momentum direction from the center of Brillouin zone. However, as the nodal line observed is trivial in nature, there is no exotic drumhead surface states observed in this material. This finding demonstrates that Dirac crossings can be protected in a non-symmorphic space group. The second material is NbIrTe₄ which is a semimetal that breaks inversion symmetry predicted to host only four Weyl points. This simplest configuration is confirmed by the measurement from the top and bottom surface of NbIrTe₄ showing only a pair of Fermi arcs each. Furthermore, it is found that the Fermi arc connectivity on the bottom surface experiences re-wiring as it evolves from Weyl points energy to the ARPES Fermi energy level. This change is attributed to the hybridisation between the surface and the bulk states as their projection lie within the vicinity of each other. The finding in this work demonstrates that although Fermi arcs are guaranteed in Weyl semimetals, their shape and connectivity are not protected and may be altered accordingly.

Humans display a 90% population level bias towards right-handedness, implying the vast majority of people have a left-hemisphere dominant for motor control. Although handedness presents a weak, but very consistent heritability across the literature (estimated to be approximately 25%), to date few genetic loci associated with this complex trait have been identified and replicated in subsequent studies. One such gene which has been found to be associated with handedness and subsequently replicated is PCSK6, most recently through a quantitative GWAS (P < 0.5*10−8, Brandler et al. (2013)). Interestingly, PCSK6 is known to activate Nodal, a morphogen involved in a highly conserved bilaterian pathway known to regulate left-right body axis determination. Here I present the first molecular characterisation of a handedness-associated region by conducting a detailed functional analysis of the PCSK6 locus, combining genetic analysis, in silico prediction and molecular assays to investigate how common genetic variants influence handedness-related phenotypes. Specifically, I defined the associated locus to be 12.7 kb in size, spanning a predicted 1.8 kb bidirectional promoter which controls the expression of both an antisense long non-coding RNA (lncRNA), and a novel short PCSK6 isoform. A series of luciferase-expressing constructs were generated to characterise the promoter, identifying a minimal sequence capable of driving transcription in a sense strand direction. I have demonstrated experimentally that one of the top associated markers in previous GWA studies, rs11855145, directly creates/disrupts a suspected transcription factor bind site in the vicinity of this bidirectional promoter. Further functional studies of the genetic variation within PCSK6 may help explain the molecular regulatory mechanisms affecting gene expression. This project provides a model for assays to study other GWAS-nominated candidate genes, and in particular for establishing the role of noncoding variants. The findings from this study support the role of common variants in influencing complex phenotypes, such as handedness.

Cette thèse est divisée en deux parties. Dans la première partie, nous introduisons une nouvelle condition, appelée additivité torique, sur une famille de variétés abéliennes qui dégénèrent en un schéma semi-abelien au-dessus d’un diviseur à croisements normaux. La condition ne dépend que du module de Tate T l A(K sep ) de la fibre générique. Nous montrons que l’additivité torique est une condition suffisante pour l’existence d’un modèle de Néron, si la base est un schéma de caractéristique nulle. Dans le cas de la jacobienne d’une courbe lisse à réduction semi-stable, on obtient le même résultat sans aucune hypothèse sur la caractéristique de base; et nous montrons que l’additivité torique est aussi nécessaire pour l’existence d’un modèle de Néron, si la base est un schéma de caractéristique nulle. Dans la deuxième partie, on considère le cas d’une famille de courbes nodales sur un anneau de valuation discrète. On donne une condition combinatoire sur le graphe dual de la fibre spéciale, appelée semi-factorialité, qui équivaut au fait que tous les faisceaux inversibles sur la fibre générique s’étendent en des faisceaux inversibles sur l’espace total de la courbe. Il est démontré par la suite que cette condition est automatiquement satisfaite après un éclatement centré aux points fermés non-réguliers de la famille de courbes. On applique le résultat ci-dessus pour généraliser un théorème de Raynaud sur le modèle de Néron des jacobiennes de courbes lisses, au cas des courbes nodales. / This thesis is subdivided in two parts. In the first part, we introduce a new condition, called toric-additivity, on a family of abelian varieties degenerating to a semi-abelian scheme over a normal crossing divisor. The condition depends only on the Tate module TlA(Ksep) of the generic fibre, for a prime l invertible on the base. We show that toric-additivity is a sufficient condition for the existence of a Néron model if the base is a Q-scheme. In the case of the jacobian of a smooth curve with semi-stable reduction, we obtain the same result without assumptions on the base characteristic; and we show that toric-additivity is also necessary for the existence of a Néron model, when the base is a Q-scheme. In the second part, we consider the case of a family of nodal curves over a discrete valuation ring, having split singularities. We say that such a family is semi factorial if every line bundle on the generic fibre extends to a line bundle on the total space. We give a necessary and sufficient condition for semi- factoriality, in terms of combinatorics of the dual graph of the special fibre. In particular, we show that performing one blow-up with center the non regular closed points yields a semi-factorial model of the generic fibre. As an application, we extend the result of Raynaud relating Néron models of smooth curves and Picard functors of their regular models to the case of nodal curves having a semi-factorial model.

Congenital heart disease (CHD) is the major cause of death in the first year of life, the estimated incidence being 0.5-5% of live births; therefore it is important to understand the genetic causes underlying the complex process of heart formation to help prophylaxis, diagnosis and treatment of affected patients. CHD is the commonest phenotype associated with left-right (LR) disorders. LR asymmetry is determined during embryonic development. The three major body axes ? antero-posterior, dorso-ventral and left-right ? are patterned at gastrulation. LR asymmetry is established shortly after the two other major axes are patterned. The process of LR determination can be sub-divided into four integrated steps: 1. breaking of molecular symmetry in the gastrulation organizer; 2. transfer or relay of this asymmetric information to the lateral plate mesoderm (LPM), from which most internal organs will be formed; 3. reinforcement and propagation of asymmetric cues throughout the LPM and 4. conversion of asymmetric molecular information into proper organ morphogenesis. The goal of this work is to investigate mechanisms involved at two specific points in the laterality pathway: the initial generation/maintenance of asymmetric gene expression in the LPM and the morphogenetic translation of these early events into correct heart formation in the mouse. My emphasis has been on the characterization of laterality targeted cells via careful analysis of Pitx2c expression using a Pitx2c-lacZ reporter transgene, the role of BMP signalling, via Smad1, in generation/maintenance of early asymmetric signalling in the LPM, and the later involvement of both Smad1 and Pitx2 in cardiac morphogenesis through analyses of knockout mice.

La conception de systèmes énergétiques innovants et la caractérisation du confort des occupants requièrent de d'être capable d'estimer les détails des écoulements et des transferts de chaleur au sein des zones des bâtiments. Les méthodes de modélisation permettant d'estimer ces détails, telles que les méthodes zonales et CFD, sont difficilement applicables à l'étude d'un bâtiment dans son ensemble et sur de longues périodes de temps. Notre étude consiste à proposer une plate-forme de simulation permettant dans un premier temps de traiter la plupart des zones du bâtiment et de son enveloppe à l'aide de l'approche nodale qui considère chacune des zones comme un volume parfaitement uniforme. Chaque zone est alors caractérisée par un seul noeud de calcul où sont déterminées les variables d'états (température, pression, concentration, etc.). Ensuite, il s'agit d'étudier les détails au sein d'un nombre limité de zones et d'estimer l'impact de ces détails sur le comportement global du bâtiment. Ainsi, nous proposons différentes méthodes de couplage entre d'une part la méthode nodale et d'autre part, les méthodes zonales et CFD. Après avoir présenté les différentes méthodes de modélisation retenues pour la détermination des transferts de masse et de chaleur dans les bâtiments, nous tentons de montrer l'intérêt d'utiliser l'une plutôt qu'une autre en fonction, des spécificités de chacune des zones, et de l'étude à effectuer. Ensuite, nous exposons la plate-forme de simulation développée, permettant de mettre en oeuvre aussi bien les approches nodales et zonales, que les différentes procédures de couplage dépendant du type d'association de modèles. Enfin, différentes applications viennent confirmer les capacités offertes par la plate-forme, pour moduler le niveau de finesse des modèles utilisés pour représenter chacune des zones d'un bâtiment, mais aussi pour proposer de nouvelles orientations de recherche. En effet, la dernière application présente une approche de couplage entre les approches zonale et CFD, dans laquelle la première tire la connaissance de la structure de l'écoulement de la seconde. L'outil développé apporte de nombreuses possibilités d'applications, aussi bien pour la caractérisation du bâtiment lui-même que de son intégration dans son environnement immédiat.