L’implementation de la vision biologique sur machine est un problème majeur que la recherche actuelle a à peine effleuré la surface. Les organismes vivants sont capables de réaliser des tâches visuelles très complexes et de manière très efficace. La stéréovision fait partie de ces mécanismes complexes que les sci- entifiques tentent de reproduire à l’aide de caméras à haute résolution. Cette thèse aborde le problème de la stéréovision d’une manière neuromorphique par l’intermédiaire d’une nouvelle génération de capteurs de vision appelés ”rétines de silicium”. Ces rétines de silicium imitent les rétines biologiques en capturant l’information visuelle sous forme de flux asynchrones d’événements codant les changements de contraste avec une grande précision temporelle. Ces capteurs sont utilisés pour étudier l’importance de la précision et de la dynamiquetemporelledelascènedansleproblèmedemiseencorrespondance stéréo. Nous proposons une des premières méthodes de reconstruction 3D capable de produire des modèles 3D d’une manière totalement asynchrone, á partir de l’information visuelle. Cette approche, outre son originalité, permet également de préserver la dynamique native de la scène. Cette thèse montre que le temps en tant que medium d’information, joue un rôle primordial dans la stéréovision. Le temps peut compléter, compenser, voire remplacer l’information apportée habituellement par la luminance et la géométrie. Ce travail établit également les fondations solides des futures recherches en vision stéréo á haute vitesse et haute dynamique, basée sur les événements. Il ouvre également de nouvelles perspectives prometteuses pour la résolution de problèmes traditionels de vision artificielle grâce à l’apport du nouveau paradigme de la vision asynchrone. / Reproducing biological vision in a machine is a challenging problem for which scientists have just scratched the surface. Living organisms are able to per- form complex tasks in an awestruckly efficient manner. The stereovision is one of these complex mechanisms that computer scientists try to replicate with high resolution cameras. This thesis takes on the stereovision problem in a neuromorphic way by mean of a new generation of vision sensors also called ”silicon retinas”. These silicon retinas mimic biological retinas by cap- turing the visual information into the form of asynchronous stream of events that encode contrast change at high temporal precision. These sensors are used to study the importance of the precise timing and the scene temporal dynamics in solving the stereo correspondence problem. We propose one of the first 3D reconstruction methods which is able to produce 3Dmodelsinatrulyevent-basedandasynchronousmanner, fromevent-based visual information. Besides the novelty of proposing a truly temporal- based asynchronous event-driven approach of 3D reconstructions, this work is also able to preserve the native dynamic of the scene. Time as information medium is proven to have a critical role in stereovision. Time can supplement, compensate and even replace the usual luminance and spatial information. This work lays strong foundations for future research on high temporal and event-based dynamic stereo vision. It also opens new promisingperspectivesforsolvingtraditionalmachinevisionproblemsthanks to the use of the new asynchronous vision paradigm.

As estruturas oculares dos vertebrados apresentam diversas adaptações relacionadas aos hábitats e atividades das espécies. A infra-ordem Serpentes possui amplo número de espécies distribuídas em quase todas as regiões da Terra e seu sistema visual apresenta variações que apontam para adaptações ecológicas. O presente estudo teve por objetivo fazer uma análise comparativa do sistema visual de diferentes espécies de serpentes Caenophidia, das famílias Dipsadidae e Colubridae, centrada no potencial de visão de cores, na densidade e topografia celular da retina e na acuidade visual. Para tanto, foram identificados os genes de opsinas expressos nas retinas, e analisadas a densidade e distribuição dos diferentes tipos de fotorreceptores e das células da camada de células ganglionares (CCG). As serpentes obtidas junto ao Laboratório de Herpetologia do Instituto Butantan foram sacrificadas com dose letal do anestésico thiopental. Os olhos foram enucleados e as retinas dissecadas para estudos genéticos e morfológicos, com imunohistoquímica e coloração de Nissl. Para sequenciamento dos genes das opsinas SWS1, Rh1 e LWS, dois olhos de 17 espécies foram utilizados. A amplificação por PCR mostrou que os três genes são expressos nas retinas de todas as espécies analisadas; o pico de sensibilidade espectral (max) de cada opsina foi estimado a partir das sequências de aminoácidos. O max do fotopigmento SWS1 foi estimado em 360 nm (UV), para todas as espécies. O fotopigmento Rh1, apresentou três diferentes combinações de aminoácidos que geram picos de sensibilidade em 500 nm, 494 nm e 484 nm. Todas as espécies de serpentes diurnas apresentaram a combinação de aminoácidos que gerou o max 484 nm. O fotopigmento LWS apresentou 4 diferentes combinações de aminoácidos, com max variando entre 543 nm e 560 nm. Para os estudos morfológicos foram utilizadas 86 retinas de 20 diferentes espécies. Retinas íntegras foram marcadas com anticorpos específicos para quantificação e análise topográfica de fotorreceptores. A coloração de Nissl foi empregada em retinas planas para quantificação de células da CCG e cálculo da acuidade visual. As análises morfológicas em retinas de serpentes noturnas mostraram uma grande densidade média de fotorreceptores (82.042 ± 37.945 células/mm2), com predominância de bastonetes, enquanto espécies diurnas apresentaram baixa densidade média de fotorreceptores (11.290 ± 2.810 células/mm2) e ausência de bastonetes. Serpentes noturnas apresentaram densidade média mais baixa de células da CCG (7.653 ± 1.636 4 células/mm2) comparada às diurnas (9.575 ± 2.301 células/mm2). O poder de resolução espacial também foi maior em espécies diurnas (2,3 ± 0,7 cpg) do que nas noturnas (1,45 ± 0,4 cpg). A distribuição de fotorreceptores e células da CCG nas retinas mostrou a presença de area centralis em diferentes regiões das retinas de espécies noturnas, e faixa horizontal em retinas das espécies diurnas, com exceção da serpente aquática e diurna Helicops modestus, que apresentou area centralis. As diferenças de localização das areae centralis variaram de acordo com hábitat e características comportamentais das espécies. Serpentes fossoriais do gênero Atractus, por exemplo, apresentaram area centralis na região dorsal da retina, que favorece o campo de visão inferior e auxilia no comportamento de escavar. Os resultados obtidos neste abrangente estudo apontam para a complexidade das adaptações do sistema visual deste grupo de vertebrados. As variações do padrão de atividade (diurna ou noturna) e uso de hábitat parecem ser fatores de forte influência sobre as características do sistema visual, como a sensibilidade espectral dos pigmentos visuais, a densidade e distribuição de neurônios nas retinas e o poder de resolução espacial do olho / The structures of vertebrate eyes have many adaptations related to the habitats and activities of the species. The infra-order Serpentes has a large number of species distributed in almost all regions of the Earth and its visual system presents variations that point to ecological adaptations. This study aimed to compare the visual system of different species of Caenophidian snakes, from the Dipsadidae and Colubridae families. To do so, the opsin genes expressed in the retinas were identified and the density and distribution of the different types of photoreceptors and the cells of the ganglion cell layer (GCC) were analyzed. The snakes were colected from Butantan Institute and were sacrificed with a lethal dose of the anesthetic thiopental. The eyes were enucleated and the retinas dissected for genetic and morphological studies, using Nissl stainig technique and immunohistochemistry. For the sequencing the opsins genes SWS1, Rh1 and LWS, two eyes of 17 species were colected. PCR amplification showed that the three opsin genes are expressed in the retinas of all species analyzed; the maximum spectral sensitivity (max) of each opsin was estimated based on the amino acid sequences. The max of the SWS1 photopigment was estimated at 360 nm (UV), for all species. The photopigment Rh1 had three different combinations of amino acids that generate max at 500 nm, 494 nm and 484 nm. All diurnal species had the amino acid combination that generate the max at 484 nm. The photopigment LWS had 4 different combinations of amino acids with max ranging from 543 nm to 560 nm. For morphological studies, 86 retinas of 20 different species were analyzed. Wholemounted retinas were stained with specific antibodies for analysis of the photoreceptors density and topography. The Nissl stainig technique was used for quantification of GCL cells in flatmounted retinas and estimation of the spatial resolving power. Nocturnal snakes had retinas with higher photoreceptor densities (82,042 ± 37,945 cells/mm2), with predominance of rods, compared to diurnal species that had low photoreceptors density (11,290 ± 2,810 cells/mm2) and the absence of rods. On the other hand, diurnal snakes had higher density of GCL cells (9,575 ± 2,301 cells/mm2) and spatial resolving power (2.3 ± 0.7 cpd), compared to nocturnal (7,653 ± 1,636 cells/mm2 and 1.45 ± 0.4 cpg). The distribution of cells in the retinas had variations related to the circadian rhythm of the species, with the presence of area centralis in retinas of nocturnal species and horizontal streak in retinas of diurnal snakes, except for the diurnal and aquatic Helicops 6 modestus, that had an area centralis in the ventral retina. The location of the area centralis varies according the habitat and specific behavior of each species. The fossorial snake Atractus, for example, had an area in the dorsal retina, which improves the resolution of the inferior visual field and benefits the digging habit in this snake. The results of this comprehensive study point to the complexity of adaptations of the visual system of this group of vertebrates. The differences in the activity pattern (diurnal or nocturnal) and habitat seem to be of great influence on the characteristics of the visual system, such as the spectral sensitivity of the visual pigments, the density and distribution of neurons in the retina and the spatial resolving power of eye

L’angiogenèse est le processus biologique par lequel de nouveaux vaisseaux sanguins se forment à partir du réseau vasculaire pré-existant. Sa première étape, l’activation endothéliale, est caractérisée par la prolifération des cellules endothéliales, la sécrétion de facteurs pro-angiogéniques comme l’Angiopoïétine-2 (Ang-2) et la relocalisation de la nucléoline du noyau vers la surface cellulaire. Dans les vaisseaux matures, les cellules endothéliales sont quiescentes et l’endothélium est recouvert de péricytes. L’activation endothéliale induit un détachement des péricytes favorisant le remodelage du réseau vasculaire. L’objectif de cette thèse est d’étudier les mécanismes de l’activation endothéliale au cours de l’angiogenèse physiologique et d’évaluer les effets de son inhibition dans un contexte d’angiogenèse tumorale. Des études in vivo dans la rétine de souris et in vitro sur des cellules endothéliales humaines ont montré que le VEGF régule l’exocytose des Corps de Weibel et Palade (WPBs), des compartiments cytoplasmiques spécifiques des cellules endothéliales pouvant contenir de l’Ang-2. Ce travail suggère que l’exocytose des WPBs induite par le VEGF régule la sécrétion de l’Ang-2 par les cellules endothéliales activées et que l’Ang-2 sécrétée régule à son tour le recrutement des péricytes sur les vaisseaux. Le ciblage de la nucléoline dans un modèle de cancer du pancréas a inhibé l’activation endothéliale et cette inhibition a diminué la croissance et l’angiogenèse tumorales tout en favorisant le recrutement des péricytes et la normalisation des vaisseaux tumoraux. La normalisation vasculaire induite par l’inhibition de l’activation endothéliale via le ciblage de la nucléoline représente une stratégie prometteuse pour le traitement de pathologies associées à une dérégulation de l’angiogenèse comme les cancers ou les rétinopathies. / Angiogenesis is the biological process of new blood vessel formation from the pre-existing vascular network. Its first step, endothelial activation, is characterized by endothelial cell proliferation, the secretion of pro-angiogenic factors such as Angiopoietin-2 (Ang-2) and the relocation of nucleolin from the nucleus to the cell surface. In the mature vessels, endothelial cells are quiescent and the endothelium is covered by pericytes. Endothelial activation induces pericyte detachment which promotes the remodeling of the vascular network. The aim of this thesis is to study the mechanisms of endothelial activation during physiological angiogenesis and to evaluate the effects of its inhibition in a context of tumor angiogenesis. In vivo studies in mouse retina and in vitro studies on human endothelial cells showed that VEGF regulates the exocytosis of Weibel-Palade bodies (WPB), cytoplasmic compartments specific for endothelial cells that may contain Ang-2. This work suggests that the exocytosis of WPBs induced by VEGF regulates the secretion of Ang-2 by activated endothelial cells and that secreted Ang-2 regulates the recruitment of pericytes on the vessels. Nucleolin targeting in a pancreatic cancer model inhibited endothelial activation and this inhibition decreased tumor growth and angiogenesis while promoting recruitment of pericytes and normalization of tumor vessels. Vascular normalization induced by the inhibition of endothelial activation via nucleolin targeting may be a promising strategy for the treatment of pathologies associated with dysregulation of angiogenesis, such as cancers or retinopathies.