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Le récepteur 5-HT6 de la sérotonine, un des derniers récepteurs de la sérotonine à avoir été découvert, est une des cibles les plus prometteuses pour traiter les déficits cognitifs de la schizophrénie et de la maladie d’Alzheimer. Les antagonistes 5-HT6 exercent des effets pro-cognitifs dans de nombreux paradigmes expérimentaux de cognition chez les rongeurs et plusieurs d’entre eux sont en développement clinique (phase III) dans la schizophrénie et la maladie d’Alzheimer. Exclusivement exprimé dans le système nerveux central, le récepteur 5-HT6 est présent dès les phases précoces du développement neural et est impliqué dans différents processus neuro-développementaux. Plusieurs études ont ainsi démontré que le récepteur jouait un rôle clé dans la migration des neurones (interneurones et neurones pyramidaux) du cortex cérébral (Riccio et al. Mol Psychiatry 14(3):280-90, 2009 ; Transl Psychiatry 11;1:e47, 2011 ; Jacobshagen et al. Development in revision). Grâce à un crible interactomique, notre équipe a récemment identifié un réseau de protéines recrutées par le domaine carboxy-terminal du récepteur, comprenant la cyclin-dependent kinase (Cdk)5 et certains de ses substrats et connues pour leur implication dans la migration neuronale, la pousse neuritique et la synaptogénèse. Nous avons également démontré que le récepteur stimulait la pousse neuritique de façon agoniste-indépendante par un mécanisme impliquant la phosphorylation du récepteur par Cdk5 et l’activation de la Rho GTPase Cdc42 (Duhr et al. Nature Chem. Biol., en révision). Cette étude a mis pour la première fois en évidence une activation constitutive d’un récepteur couplé aux protéines G dépendant de sa phosphorylation par une kinase associée. Des études préliminaires réalisées par l’équipe indiquent également que l’activation du récepteur 5-HT6 induit une diminution du nombre d’épines dendritiques et une modification de leur morphologie dans des cultures primaires de neurones d’hippocampe. Le projet de thèse aura pour objectif la caractérisation des mécanismes moléculaires impliqués dans cet effet. Une attention particulière sera portée sur le rôle de Cdk5 et de son substrat WAVE1, une protéine induisant la formation des épines dendritiques grâce à sa capacité à activer le complexe Arp2/3 (également identifié dans l’interactome du récepteur 5-HT6) et à promouvoir la polymérisation de l’actine. La phosphorylation de WAVE1 par Cdk5 inhibant son activité et la formation des épines, ce mécanisme pourrait être à l’origine de la diminution du nombre d’épines induite par le récepteur 5-HT6. Ces études seront réalisées in vitro, sur des cultures primaires de neurones d’hippocampe et in vivo, en utilisant un modèle (en cours de génération) de souris knock-in exprimant le récepteur 5-HT6 fusionné à une étiquette GFP. Grâce à ce modèle, un crible interactomique sera également réalisé afin d’identifier de nouveaux partenaires du récepteur potentiellement impliqués dans la différentiation neuronale dans un contexte tissulaire authentique. Ce projet sera réalisé à l’Institut de Génomique Fonctionnelle (IGF) au sein de l’équipe « Neuroprotéomique et signalisation des maladies neurologiques et psychiatriques » sous la co-direction de Philippe Marin et Séverine Chaumont-Dubel. Il permettra de caractériser de nouveaux substrats cellulaires potentiellement impliqués dans les déficits cognitifs de la schizophrénie de plus en plus considérée comme une pathologie du développement et d’identifier de nouvelles cibles pour le traitement précoce de ces déficits particulièrement invalidants et insuffisamment pris en en charge par l’arsenal antipsychotique existant. / The serotonin 5-HT6 receptor, one of the most recently cloned serotonin receptors, is a promising target for the treatment of cognitive deficits of both schizophrenia and Alzheimer’s disease. 5-HT6 receptor blockade by antagonists exerts pro-cognitive effects in a wide range of models of cognitive impairment in rodents and some of them are in phase III of clinical trials in schizophrenia and Alzheimer’s disease. The 5-HT6 receptor is exclusively expressed in the central nervous system, where it is detected at early phases of brain development. Studies have shown that 5-HT6 receptors have a key influence upon migration of both pyramidal neurons and interneurons of the cerebral cortex (Riccio et al. Mol Psychiatry 14(3):280-90, 2009 ; Transl Psychiatry 11;1:e47, 2011; Jacobshagen et al. Development, in revision). Using a proteomic strategy, our team recently identified a network of proteins interacting with the carboxy-terminal domain of the receptor. These include Cyclin-dependent kinase (Cdk)5 and some of its substrates, which are known to control neuro-developmental processes such as neuronal migration, neurite growth and dendritic spine morphogenesis. We have also demonstrated that the expression of the 5-HT6 receptor elicits neurite growth in an agonist-independent manner through a mechanism involving receptor phosphorylation at a serine residue by associated Cdk5 and engagement of the Rho GTPase Cdc42 (Duhr et al. Nature Chem. Biol., in revision). These studies show for the first time a constitutive activation of a G protein-coupled receptor mediated by its phosphorylation by an associated protein kinase. Preliminary experiments performed by the team also revealed that 5-HT6 receptors activation decreases the number of dendritic spines and modify spine morphology in hippocampal neurons in primary culture. This thesis project aims at characterizing the signalling mechanisms underlying the control of dendritic spine morphogenesis by the 5-HT6 receptors. Particular attention will be paid to Cdk5 and its substrate WAVE1, a protein known to induce neurite growth via the activation of the Arp2/3 complex (also identified in the 5-HT6 receptor interactome), which promotes actin polymerization. As phosphorylation of WAVE1 by Cdk5 inhibits its activity, we hypothesize that Cdk5-elicited phosphorylation of WAVE1 in the receptor-associated complex might underlies its control of spine morphogenesis. This project will combine in vitro studies performed on primary cultured hippocampal neurons and in vivo studies using transgenic mice expressing GFP tagged 5-HT6 receptors (this mouse line is currently being generated). We will also take advantage of this model to perform a novel interactomics screen to identify in an authentic tissue context novel receptor partners potentially involved in dendritic spine formation. This project should reveal novel cellular targets for the alleviation of the currently untreated and strongly debilitating cognitive deficits of schizophrenia, which are thought to result from abnormalities of brain development. It will be realized at the Institute of Functional Genomics in the “Neuroproteomics and signaling of neurodegenerative and psychiatric disorders” team under the supervision of Philippe Marin and Séverine Chaumont-Dubel.

O planejamento da produção é uma atividade que avalia decisões para um melhor uso dos recursos disponíveis, visando satisfazer aos objetivos produtivos da empresa ao longo de um horizonte de planejamento. Este trabalho enfoca o problema de dimensionamento de lotes com restrições de capacidade (PDLC), que é uma das tarefas centrais envolvidas no planejamento da produção. O PDLC visa determinar o tamanho dos lotes a serem produzidos em períodos de tempo de um horizonte de planejamento. Os PDLC estudados neste trabalho contemplam duas características importantes: a presença de múltiplos itens e a existência de tempos de preparação para as máquinas. Além disso, são consideradas restrições de capacidade e situações onde o atraso para atender a demanda é permitido (backlogging). Alguns dos modelos estudados permitem que a preparação do ambiente de produção para um dado item possa ser mantida de um período para o seguinte, o que propiciaria a economia de até uma preparação a cada período. Esta característica é chamada de preservação de preparação (carry-over). Também existem situações onde a preparação de uma máquina começa em um período e termina no período seguinte. Na literatura, esta característica é chamada de set-up crossover. Este trabalho tem três metas centrais: a) avaliar diferentes configurações do software comercial ILOG CPLEX 11 para a solução dos PDLC estudados; b) estudar a influência na solução dos PDLC quando se acrescenta a possibilidade de atraso na demanda, de preservação de preparação e de set-up crossover; c) aplicar local branching para resolver os problemas estudados. Para resolver as instâncias propostas, foram utilizados o software comercial ILOG CPLEX 11 e um programa em C++ que foi desenvolvido neste trabalho. Foram utilizados exemplos encontrados na literatura para avaliar as propostas, e bons resultados foram obtidos / The production planning is an activity that evaluates the decision for a better use of the available resources, in order to satisfy the productive objectives of the company over a planning horizon. This work focuses on the capacitated lot-sizing problem (CLSP), which is one of the central tasks involved in production planning. The CLSP means to determine the size of the lots to be produced in time periods of a planning horizon. The CLSP studied in this work contemplate two complicating characteristics: the presence of multiple items and the existence of set-up times for the machines. Besides that, capacity constraints and situations where backlog of the demand is allowed are also considered (backlogging). Some of the studied models allow the set-up of the production environment for a given item to be carried over to the next period, which could result in economy of a set-up in each period (carry-over). There are situations where the set-up of a machine starts in one period and crosses over to the next period (set-up crossover). This work has three main goals: a) evaluate different configurations of the commercial software ILOG CPLEX 11 to solve the different kinds of CLSP studied; b) study the influence of the solution of the CLSP when you consider the possibility of backlogging, set-up carry-over and set-up crossover; c) apply local branching to solve the studied problems. To solve the proposed instances, we used the commercial solver ILOG CPLEX 11 and the program in C++ developed in this work. The examples used to test both programs are found in the literature, and good results were obtained

O planejamento da produção é uma atividade que avalia decisões para um melhor uso dos recursos disponíveis, visando satisfazer aos objetivos produtivos da empresa ao longo de um horizonte de planejamento. Este trabalho enfoca o problema de dimensionamento de lotes com restrições de capacidade (PDLC), que é uma das tarefas centrais envolvidas no planejamento da produção. O PDLC visa determinar o tamanho dos lotes a serem produzidos em períodos de tempo de um horizonte de planejamento. Os PDLC estudados neste trabalho contemplam duas características importantes: a presença de múltiplos itens e a existência de tempos de preparação para as máquinas. Além disso, são consideradas restrições de capacidade e situações onde o atraso para atender a demanda é permitido (backlogging). Alguns dos modelos estudados permitem que a preparação do ambiente de produção para um dado item possa ser mantida de um período para o seguinte, o que propiciaria a economia de até uma preparação a cada período. Esta característica é chamada de preservação de preparação (carry-over). Também existem situações onde a preparação de uma máquina começa em um período e termina no período seguinte. Na literatura, esta característica é chamada de set-up crossover. Este trabalho tem três metas centrais: a) avaliar diferentes configurações do software comercial ILOG CPLEX 11 para a solução dos PDLC estudados; b) estudar a influência na solução dos PDLC quando se acrescenta a possibilidade de atraso na demanda, de preservação de preparação e de set-up crossover; c) aplicar local branching para resolver os problemas estudados. Para resolver as instâncias propostas, foram utilizados o software comercial ILOG CPLEX 11 e um programa em C++ que foi desenvolvido neste trabalho. Foram utilizados exemplos encontrados na literatura para avaliar as propostas, e bons resultados foram obtidos / The production planning is an activity that evaluates the decision for a better use of the available resources, in order to satisfy the productive objectives of the company over a planning horizon. This work focuses on the capacitated lot-sizing problem (CLSP), which is one of the central tasks involved in production planning. The CLSP means to determine the size of the lots to be produced in time periods of a planning horizon. The CLSP studied in this work contemplate two complicating characteristics: the presence of multiple items and the existence of set-up times for the machines. Besides that, capacity constraints and situations where backlog of the demand is allowed are also considered (backlogging). Some of the studied models allow the set-up of the production environment for a given item to be carried over to the next period, which could result in economy of a set-up in each period (carry-over). There are situations where the set-up of a machine starts in one period and crosses over to the next period (set-up crossover). This work has three main goals: a) evaluate different configurations of the commercial software ILOG CPLEX 11 to solve the different kinds of CLSP studied; b) study the influence of the solution of the CLSP when you consider the possibility of backlogging, set-up carry-over and set-up crossover; c) apply local branching to solve the studied problems. To solve the proposed instances, we used the commercial solver ILOG CPLEX 11 and the program in C++ developed in this work. The examples used to test both programs are found in the literature, and good results were obtained

The classical ethyl methanesulfonate (EMS) tomato mutant bushy root (brt) was studied using a homozygous near isogenic line (brtNIL) in the Micro-Tom (MT) genetic background. The mutation has a pleiotropic phenotype comprising slow seedling development, which may be a consequence of a maternally-inherited small seed phenotype, and a more compact, smaller but not bushier, root phenotype. The number of lateral roots, total root length and taproot size are all smaller in brtNIL than the WT. The BRT locus was mapped to a 137 kbp region containing 9 candidate genes on chr 12; an InDel in the promoter region of Solyc12g014590 – containing two highly conserved pirin domains (Pirin_C and Pirin), was detected. Different expression patterns were confirmed by transcriptomic results, supporting Solyc12g014590 as the gene responsible for the brt phenotype. A naturally occurring recessive mutant named bifuricate (bif) shows an increase in inflorescence (truss) branching in comparison to the wild type (WT) control line, LAM183. In addition, the number of flowers per truss was 235% higher in bif plants than WT. Low temperature is known to increase truss branching, and so a four day low temperature treatment was applied and it was demonstrated that flowering increased significantly more in bif than in LAM183. The BIF locus was mapped to a 2.01 Mbp interval of chromosome 12 containing 53 genes. All coding region polymorphisms in the interval were surveyed, and two genes Solyc12g019420 (a BTB/TAZ transcription factor) and Solyc12g019460 (a MAP kinase) contained one stop codon predicted to disrupt gene function; both genes are excellent candidates for inflorescence branching control based on literature evidence. A newly developed introgression browser was used to demonstrate that the origin of the bif mutant haplotype is Solanum galapagense.

Many real life problems can be formulated as constraint satisfaction problems <i>(CSPs)</i>. Backtracking search algorithms are usually employed to solve <i>CSPs</i> and in backtracking search the choice of branching strategies can be critical since they specify how a search algorithm can instantiate a variable and how a problem can be reduced into subproblems; that is, they define a search tree. In spite of the apparent importance of the branching strategy, there have been only a few empirical studies about different branching strategies and they all have been tested exclusively for numerical constraints. In this thesis, we employ the three most commonly used branching strategies in solving finite domain <i>CSPs</i>. These branching strategies are described as follows: first, a branching strategy with strong commitment assigns its variables in the early stage of the search as in k-Way branching; second, 2-Way branching guides a search by branching one side with assigning a variable and the other with eliminating the assigned value; third, the domain splitting strategy, based on the least commitment principle, branches by dividing a variable's domain rather than by assigning a single value to a variable. In our experiments, we compared the efficiency of different branching strategies in terms of their execution times and the number of choice points in solving finite domain <i>CSPs</i>. Interestingly, our experiments provide evidence that the choice of branching strategy for finite domain problems does not matter much in most cases--provided we are using an effective variable ordering heuristic--as domain splitting and 2-Way branching end up simulating k-Way branching. However, for an optimization problem with large domain size, the branching strategy with the least commitment principle can be more efficient than the other strategies. This empirical study will hopefully interest other practitioners to take different branching schemes into consideration in designing heuristics.

Finding the maximum size of a matching in an undirected graph and finding the maximum size of branching in a directed graph can be formulated as matrix rank problems. The Tutte matrix, introduced by Tutte as a representation of an undirected graph, has rank equal to the maximum number of vertices covered by a matching in the associated graph. The branching matrix, a representation of a directed graph, has rank equal to the maximum number of vertices covered by a branching in the associated graph. A mixed graph has both undirected and directed edges, and the matching forest problem for mixed graphs, introduced by Giles, is a generalization of the matching problem and the branching problem. A mixed graph can be represented by the matching forest matrix, and the rank of the matching forest matrix is related to the size of a matching forest in the associated mixed graph. The Tutte matrix and the branching matrix have indeterminate entries, and we describe algorithms that evaluate the indeterminates as rationals in such a way that the rank of the evaluated matrix is equal to the rank of the indeterminate matrix. Matroids in the context of graphs are discussed, and matroid formulations for the matching, branching, and matching forest problems are given.

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Thesis advisor: Jeffery A. Byers / This dissertation focuses on the development of iron-based polymerization catalysts for use in the production of high commodity polymers, polyethylene and poly(lactic acid). Chapter one establishes the current landscape of the plastic market and outlines the advantages to developing iron-based catalysts. Chapter two then explores the use of bis(pyridinylimino)isoindolate-ligated iron complexes as a family of ethylene polymerization catalysts possessing distinctive mechanistic behavior. Chapter three moves to focus on the polymerization of stereoregular poly(lactic acid) from an achiral bis(imino)pyridine-ligated iron precatalyst. The mechanism for the desymmetrization of the catalyst is further detailed, and new avenues for enhancing the behavior of the reaction are discussed. Chapter four details the development of conditions for the rapid chain transfer polymerization of lactide and cyclohexene oxide, offering another tool by which value and complexity may be added to polymerization reactions carried out by this family of bis(imino)pyridine-ligated iron complexes. Finally, chapter five leverages the known redox-switchable features of bis(imino)pyridine-ligated iron complexes to develop reaction conditions for the controlled branching of poly(lactic acid) in a one-pot polymerization reaction. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Le débourrement des bourgeons axillaires conditionne la ramification, donc l’établissement de l’architecture chez les végétaux. L’azote est impliqué dans la croissance des jeunes organes tels que les axes secondaires (axes II) issus du débourrement des bourgeons. Plusieurs études ont démontré que la concentration en acides aminés augmente dans la sève au cours de la reprise de croissance printanière, dont le débourrement des bourgeons est une étape importante. L’identité et l’origine des acides aminés impliqués dans le débourrement et les premières phases d’allongement des axes II n’ont pourtant pas encore été clairement établies. Ce travail a pour objectif de comprendre, chez Rosa hybrida, les phénomènes nutritionnels sous-jacents à l’apparition de différents phénotypes de ramification. Pour ce faire, nous avons fait varier la concentration et les périodes d’apport de nitrate dans la solution nutritive au cours de la croissance, avant et après l’initiation du débourrement par décapitation. Nous avons montré in planta que la concentration d’asparagine augmente dans la sève et dans l’ensemble des tissus pendant l’allongement des axes II et provient tout d’abord majoritairement des réserves puis, après la décapitation, en quantité de plus en plus importante de l’absorption courante. Cet acide aminé est le seul capable, en présence de sucres, d’initier une croissance efficace des axes II in vitro, notamment en contribuant à placer le statut des régulateurs de croissance dans un contexte favorable au débourrement. Une approche par RNAseq a mis en évidence 848 séquences potentiellement impliquées dans le débourrement en réponse au nitrate. Parmi elles, le couple Asparaginase / Asparagine synthétase s’exprime respectivement durant la phase de dormance ou le débourrement, ce qui renforce l’importante de l’asparagine dans ce phénomène. Ces deux échelles d’approche ont permis de compléter le modèle intégratif du débourrement en intégrant la nutrition des nouveaux organes. / Axillary bud outgrowth is an essential process of plant branching to set-up its architecture. Nitrogen is implicated in the development of young organs such as secondary axes (axes II) resulting from bud outgrowth. Several studies have previously shown that amino acid concentration increase in the xylem sap during spring regrowth whom bud outgrowth is an essential step. The exact nature of the amino acids implicated in the bud outgrowth and initial axe II elongation have not yet been determinated. The present work aims to understand in Rosa hybrida the nutrition processes implicated in the set-up of different branching phenotypes. To achieve this goal, we brought different nitrate concentrations to the plant before and after bud outgrowth initation by apex removing. We showed in planta that asparagine concentration increases in the sap and in the tissues during axes II growth, initialy originating from internal stores and, after decapitation, increasingly coming from current uptake. This amino acid is the sole able to evoke in vitro an efficient elongation of axes II in the presence of sugar throught the establishment of growth regulators metabolism status that is favorable to the outgrowth process. Transcriptome study using RNAseq features 848 sequences that are potentially implicated in bud outgrowth in response to nitrate. Among them, the expression of Asparaginase takes place during dormancy while, in contrast, Asparagine synthase gene is active during bud outgrowth, highlighting the importance of asparagine in this phenomenon. These approaches conducted at two different scales contribute to append with nitrogen nutrition the integrated model of bud outgrowth.