Couverture)Les rétrovirus sont des virus enveloppés à ARN simple brin omniprésents dans le monde animal et sources de nombreuses pathologies. Les rétrovirus de vertébrés comprennent sept genres dont les gamma et deltarétrovirus qui sont l’objet de ces travaux. Les rétrovirus dits endogènes (ERV), par opposition à leurs homologues infectieux exogènes, sont présents dans les cellules germinales et font partie intégrante du patrimoine génétique, avec transmission mendélienne. Au cours de l'évolution, les ERV ont fait l'objet de mutations, rendant défectives la plupart des copies dans les génomes de vertébrés, avec quelques exceptions notoires. De fait, certaines copies maintiennent de larges cadres de lecture suite à une pression de sélection positive.Rétrovirus exogènes et ERV partagent une organisation génétique similaire. Leurs glycoprotéines d’enveloppe (Env), dont une des propriétés est de lier un récepteur cellulaire, comprennent une composante de surface (SU) associée à une partie transmembranaire (TM). La SU des Env γ et -rétrovirales porte un module RBD (Receptor-Binding Domain) qui lie un récepteur appartenant à la famille SLC (Solute Carriers) des transporteurs de nutriments. Les SLC présents à la surface cellulaire conditionnent le métabolisme des cellules. Afin de pallier l'absence d'anticorps fiables reconnaissant les parties extracellulaires (exofaciales) des SLC, le laboratoire a dérivé des RBD solubles comme ligands des SLC, permettant de suivre leur expression à la surface cellulaire et ainsi, évaluer le métabolisme cellulaire.Parmi les ERV, certaines env partiellement ou entièrement conservées jouent un rôle physiologique essentiel dans les organismes qui les portent. Une hypothèse de mon laboratoire d’accueil est l’existence de RBD endogènes de mammifères capables de moduler le métabolisme cellulaire de leurs hôtes. Dans ce contexte, mes travaux sont articulés autour de deux axes : (i) identifier et produire de nouveaux RBD dérivés des ERV et (ii) identifier de nouveaux transporteurs de type SLC reconnus par des RBD issus de rétrovirus exogènes et ERV de mammifères. Nous avons identifié et caractérisé deux nouveaux RBD humains endogènes (HERV-41 et HERV-89), entrés et conservés chez les primates de l’Ancien Monde il y a environ 35 millions d’années. Nous avons caractérisé leurs séquences PBS (Primer Binding Site), amorces putatives de la réplication rétrovirale, comme étant complémentaires de l’ARNtLeu ou ARNtArg pour HERV-89, et de l'ARNtGlu pour HERV-41. Les séquences env les plus proches dans le génome humain présentent respectivement 38% et 69% d'identité, indiquant l'appartenance de HERV-89 à deux nouvelles familles d'Env. Nous avons pu produire le RBD soluble de HERV-89, montrer que son récepteur est distinct de l'Env HERV ayant la séquence la plus homologue, et étudier sa distribution tissulaire. Le RBD HERV-89 lie un récepteur sur de nombreuses cellules souches et lignées cellulaires établies et nous avons montré par immunohistochimie que le récepteur est exprimé de manière différentielle dans les tissus humains sains et tumoraux. Parallèlement, nous avons dérivé une banque d'expression de 170 SLC que nous avons utilisée pour le criblage à haut-débit de récepteurs des Env gamma et deltarétrovirales. Cette banque nous a permis d'identifier le récepteur, longtemps recherché, de l’Env du virus de la leucémie bovine (BLV). De plus, en utilisant la transfection d'une banque d’expression d’ADNc dans des cellules de hamster, nous avons aussi identifié le récepteur du virus endogène félin ERV-DC14/FeLV-D comme étant le transporteur de cuivre et de cisplatine CTR1/SLC31A1.L’identification du récepteur de BLV pourrait notamment aider dans la lutte contre la transmission du virus et les pathologies associées qui affectent environ 5% du bétail infecté. De plus, les BLV-RBD et DC14-RBD constituent respectivement de nouveaux marqueurs et modulateurs potentiels du métabolisme, dont celui du cuivre / Retroviruses are enveloped, single-stranded RNA viruses, that are omnipresent in animals and the causal agents of a large array of pathologies. Vertebrate retroviruses are divided into seven genera, including the γ and -retroviral groups, which we study particularly. Endogenous retroviruses (ERV), as opposed to exogenous infectious viruses, are present in germline cells and as such are bona fide components of the host genome, with Mendelian transmission. Most ERV have been inactivated by purifying mutations during evolution, although a few copies have been subjected to positive selection pressure with conserved open reading frames (ORFs).Exogenous viruses and ERV that belong to gamma and deltaretroviruses share similar genetic organization and their envelope glycoproteins (Env) comprises a transmembrane (TM) and a surface (SU) component, which binds a specific receptor on the host cell membrane. The SU contains a receptor-binding domain (RBD), responsible for receptor recognition, while TM engages membrane fusion and harbors an immunosuppressive domain. Noticeably, some ERVs have maintained entire or partial ORFs in env, which have been shown, in certain cases, to have essential physiological functions.Another common feature of gamma and deltaretroviral Env is the nature of their receptors, which, when identified, all belong to the solute carrier family of nutrient transporters (SLCs). The laboratory derived soluble RBDs from complete Env that can bind cognate receptors and be used to monitor SLC receptor expression at the cell surface. This important property of RBDs overcomes the notorious lack of reliable anti-SLC exofacial antibodies and provides a new way to evaluate, or even modulate, cell metabolism.Our laboratory postulates that some endogenous RBD-coding genes have been positively selected in their hosts for properties linked to binding SLCs and modulating host cell metabolism. In this context, the aim of my work was to: (i) search for new natural endogenous RBDs and (ii) characterize SLC transporters recognized by RBDs derived from ERVs or exogenous infectious mammalian retroviruses.Here, we describe the identification of two novel human endogenous RBDs (HERV-41 and HERV-89), which each harbor a significant ORF. We estimated that both RBDs have been introduced into Old World primate genomes 35 MYA ago, after the separation with New World monkeys. HERV-89 and HERV-41 are included within retroviral elements that comprise potential primer binding sites (PBS) complementary to tRNALeu or tRNAArg, for HERV-89, and tRNAGlu, for HERV-41. The envs of HERV-89 and HERV-41 do not share more than 38% and 69% amino acid identity with the closest known HERVs, respectively, which indicates that they belong to two new Env families. We derived a soluble HERV-89 RBD and monitored its receptor cell and tissue distribution. Using the ligand by flow cytometry, we observed that a HERV-89 receptor is expressed in a large panel of established cell lines and stem cells. Immunohistochemistry on 94 healthy and tumor human tissue samples showed that HERV-89 receptor is largely distributed, with distinct expression patterns in healthy and tumor tissues. In parallel, we derived a 170 gene-containing SLC expression library for high throughput screening of SLC/ligand interactions. Using this partial human SLC library, we identified the long-sought receptor for bovine leukemia virus (BLV). Moreover, transfection of a cDNA library expression into hamster cells, led us to identify CTR1/SLC31A1, the copper and cisplatin transporter, as the receptor for the feline ERV-DC14/FeLV-D.As a ligand for the BLV receptor, BLV-RBD may be used to help controlling BLV transmission and prevent associated pathologies that affect 5% of infected cattle. Also, BLV-RBD and DC14-RBD can now be used as metabolic markers and modulators of their SLC cognate receptors, including copper metabolism, in the case of DC14-RBD.

Membrane proteins constitute approximately 30% of all genes in the human genome and two large families of membrane proteins are G protein-coupled receptors (GPCRs) and Solute Carriers (SLCs) with about 800 and 380 human genes, respectively. In Papers I, II and IV, we report 16 novel human Adhesion GPCRs found by searches in NCBI and Celera databases. In Paper I, we report eight novel human GPCRs, and six in Paper II. We identified two new human Adhesion GPCRs and 17 mouse orthologs in Paper IV. Phylogenetic analysis demonstrates that the 16 novel human genes are additional members of the Adhesion GPCR family and can be divided into eight phylogenetic groups. EST expression charts for the entire repertoire of Adhesions in human and mouse were established, showing widespread distribution in both central and peripheral tissues. Different domains were found in their N-terminus, some, such as pentraxin in GPR112, indicates that they take part in immunological processes. In Paper III, we discovered seven new human Rhodopsin GPCRs. In Paper V, we present the identification of two new human genes, termed SLC6A17 and SLC6A18 from the Solute Carriers family 6 (SLC6). We also identified the corresponding orthologs and additional genes from the mouse and rat genomes. We analysed, in total, 430 unique SLC6 proteins from 10 animal, one plant, two fungi and 196 bacterial genomes. In Paper VI, we provide the first systematic analysis of the evolutionary history of the different SLC families in Eukaryotes. In all, we analysed 2403 sequences in eight species and we delineate the evolutionary history of each of the 46 SLC families.

Em um mundo de intensa competição global, a lógica da colaboração se tornou uma parte essencial da estratégia de negócios. Os relacionamentos entre empresas no mercado internacional, através da colaboração entre firmas parceiras, passam a ser considerados como a chave para o sucesso das metas empresariais das organizações. Aquelas empresas que estabelecerem e cultivarem os benefícios mútuos advindos das parcerias internacionais poderão esperar um desempenho competitivo superior. Nesse contexto, o objetivo central deste estudo é examinar os elementos estimuladores e inibidores do relacionamento entre empresas do setor metal-mecânico automotivo do Rio Grande do Sul/Brasil e da Argentina. Para tanto, a fim de se verificar a presença de tais elementos nas relações de troca no ambiente do Mercosul, a partir de uma abordagem exploratória, empregou-se o método de estudo de casos. Foram investigados três casos de relacionamento entre empresas estabelecidas no Rio Grande do Sul e suas respectivas firmas parceiras no mercado argentino. Foi utilizado o critério de duração de, no mínimo, dois anos de transações de troca entre as partes envolvidas. A presente investigação ocorreu entre os meses de outubro de 1997 e abril de 1998. O estudo apresenta resultados individuais quanto às características de cada relacionamento investigado e uma análise comparada no que diz respeito às motivações e aos aspectos inibidores identificados nas relações de troca estudadas. Por fim, são apresentadas implicações do estudo, que poderiam ser aprofundadas em novas pesquisas na área de relacionamentos nos mercados internacionais, bem como as limitações do referido trabalho.

Em um mundo de intensa competição global, a lógica da colaboração se tornou uma parte essencial da estratégia de negócios. Os relacionamentos entre empresas no mercado internacional, através da colaboração entre firmas parceiras, passam a ser considerados como a chave para o sucesso das metas empresariais das organizações. Aquelas empresas que estabelecerem e cultivarem os benefícios mútuos advindos das parcerias internacionais poderão esperar um desempenho competitivo superior. Nesse contexto, o objetivo central deste estudo é examinar os elementos estimuladores e inibidores do relacionamento entre empresas do setor metal-mecânico automotivo do Rio Grande do Sul/Brasil e da Argentina. Para tanto, a fim de se verificar a presença de tais elementos nas relações de troca no ambiente do Mercosul, a partir de uma abordagem exploratória, empregou-se o método de estudo de casos. Foram investigados três casos de relacionamento entre empresas estabelecidas no Rio Grande do Sul e suas respectivas firmas parceiras no mercado argentino. Foi utilizado o critério de duração de, no mínimo, dois anos de transações de troca entre as partes envolvidas. A presente investigação ocorreu entre os meses de outubro de 1997 e abril de 1998. O estudo apresenta resultados individuais quanto às características de cada relacionamento investigado e uma análise comparada no que diz respeito às motivações e aos aspectos inibidores identificados nas relações de troca estudadas. Por fim, são apresentadas implicações do estudo, que poderiam ser aprofundadas em novas pesquisas na área de relacionamentos nos mercados internacionais, bem como as limitações do referido trabalho.

Em um mundo de intensa competição global, a lógica da colaboração se tornou uma parte essencial da estratégia de negócios. Os relacionamentos entre empresas no mercado internacional, através da colaboração entre firmas parceiras, passam a ser considerados como a chave para o sucesso das metas empresariais das organizações. Aquelas empresas que estabelecerem e cultivarem os benefícios mútuos advindos das parcerias internacionais poderão esperar um desempenho competitivo superior. Nesse contexto, o objetivo central deste estudo é examinar os elementos estimuladores e inibidores do relacionamento entre empresas do setor metal-mecânico automotivo do Rio Grande do Sul/Brasil e da Argentina. Para tanto, a fim de se verificar a presença de tais elementos nas relações de troca no ambiente do Mercosul, a partir de uma abordagem exploratória, empregou-se o método de estudo de casos. Foram investigados três casos de relacionamento entre empresas estabelecidas no Rio Grande do Sul e suas respectivas firmas parceiras no mercado argentino. Foi utilizado o critério de duração de, no mínimo, dois anos de transações de troca entre as partes envolvidas. A presente investigação ocorreu entre os meses de outubro de 1997 e abril de 1998. O estudo apresenta resultados individuais quanto às características de cada relacionamento investigado e uma análise comparada no que diz respeito às motivações e aos aspectos inibidores identificados nas relações de troca estudadas. Por fim, são apresentadas implicações do estudo, que poderiam ser aprofundadas em novas pesquisas na área de relacionamentos nos mercados internacionais, bem como as limitações do referido trabalho.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18219号 / 薬博第809号 / 新制||薬||238(附属図書館) / 31077 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 松原 和夫, 教授 橋田 充, 教授 髙倉 喜信 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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Thousands of students drop out of high school every day in the United States and the repercussions affect more than just the individual. Research on smaller learning communities (SLC) reveals increased student achievement, as well as improved teacher perception of student engagement. Student attendance, grade point average, and standardized test scores have been seen to improve within the SLC. In addition, graduation rates for students enrolled in a SLC have revealed increases, but this research focuses on the SLC as an intervention for any student. The current research targets at-risk students in an educational climate of sparse resources, and an increasing need for clever use of capital. The current research fills this gap by evaluating a SLC developed for and populated solely with students identified as at-risk by collecting data from students enrolled in a SLC and comparing them to a population of similar at-risk students not enrolled in the SLC. A Chi-square analysis was conducted comparing graduation rates, a 1-factor analysis of variance compared state test scores, and a 2-factor mixed analysis of variance was conducted to compare GPA, attendance, and discipline between and within the 2 groups. The alpha level was adjusted per the Bonferroni method to correct for multiple data points on the same sample and resulting in a sample size of 106. Findings from this research found a one year SLC intervention made a difference in school attendance, and revealed an overall trend of difference between SLC and control at-risk students in all other areas. These findings contribute to positive social change understanding a one year SLC intervention is capable of improving attendance as well as producing an overall positive trend for at-risk high school students in the areas of graduation, standardized assessment, discipline, and standardized assessments.

In recent years many companies have investigated the use of hybrid technology due to the potential of increasing the driveline’s efficiency and thus reducing fuel consumption. Previous studies show that hydraulic hybrid technology can be favourable to use in construction machinery such as wheel loaders, which often operate in repetitive drive cycles and have high transient power demands. Parallel as well as Series hybrid configurations are both found suitable for wheel loader applications as the hybrid configurations can decrease the dependency on the torque converter. This project has investigated a novel hydraulic hybrid concept which utilizes the wheel loaders auxiliary pump as a supplement to enable both Series and Parallel hybrid operation. Impact of accumulator sizes has also been investigated, for which smaller accumulator sizes resembles a hydrostatic transmission. The hybrid concept has been evaluated by developing a wheel loader simulation model and a control system based on a rule-based energy management strategy. Simulation results indicate improved energy efficiency of up to 18.80 % for the Combined hybrid. Moreover, the accumulator sizes prove to have less impact on the energy efficiency. A hybrid system with decreased accumulator sizes shows improved energy efficiency of up to 16.40 %.

Cette thèse s’intéresse à la commande et l’observation d’une classe de systèmes linéaires à commutations (SLC). La classe considérée regroupe les systèmes pouvant être représentés par un modèle Hamiltonien à ports. Récemment, plusieurs travaux ont utilisé la théorie des systèmes dynamiques hybrides pour traiter les problèmes de stabilité, de commandabilité et d’observabilité des systèmes linéaires à commutations. Cependant, certains verrous scientifiques demeurent et nécessitent d’être levés tels que la synthèse d’observateurs pour des SLC présentant des modes de fonctionnement inobservables ou la commande hybride de systèmes possédant un nombre réduit d’entrées de commutations et un nombre élevé de variables d’état à contrôler. Dans ce travail, nous nous intéressons à la synthèse d’observateurs s’appuyant sur la modélisation moyenne et la modélisation hybride de SLC ayant une topologie Hamiltonienne à ports particulière. Ce formalisme possède les outils nécessaires pour établir des preuves de stabilité des erreurs d’observation. Dans un premier temps, nous proposons un observateur non linéaire reposant sur le modèle moyen de la classe des SLC considérée. Ensuite, nous traitons le problème de synthèse d’un observateur hybride où nous proposons un observateur commuté prenant en compte les modes de fonctionnement inobservables. Le problème de la commande des SLC est abordé par la suite. Au départ, la théorie de Lyapunov est utilisée pour proposer deux lois de commandes : La première est synthétisée à partir du modèle moyen et la deuxième exploite le modèle hybride. Une commande optimale hybride est élaborée en utilisant le principe du maximum de Pontryagin et une approche utilisant la recherche d’arcs singuliers. Finalement, une commande prédictive hybride est établie à partir d’un modèle discrétisé du système. Des résultats de simulation et une mise en œuvre expérimentale sur un convertisseur DC-DC SEPIC sont donnés pour montrer l’efficacité des méthodes proposées. L’étude d’un tel circuit est motivée par sa topologie particulière qui contient à la fois un mode de fonctionnement observable et un mode de fonctionnement inobservable. En outre, il possède une seule entrée de commutations et quatre variables d’état ce qui lui vaut la réputation être difficile à commander. / This thesis is dedicated to the control and the observation of a class of switched linear systems (SLS). This class contains the systems that can be represented by a port-Hamiltonian model. A lot of works have been studied SLS for several years using an average modeling approach. Recently, various works have shown that hybrid system theory allows to cope with stabilization, controllability, and observability problems of switched linear systems. However, several problems are still open and need more development such as the design of hybrid observers for SLS that have unobservable modes or the control of systems with reduced number of switching inputs and numerous variable states to control. In this work, we are interested in the design of state observers for a particular class of SLS using both the average and the hybrid port-Hamiltonian models. This formalism has the necessary tools to study and establish the stability of the observation errors. At the beginning, a nonlinear observer based on the average modeling is proposed. Next, a hybrid observer is designed for switched linear systems. This observer takes into account the unobservable operating modes of the system. The second point of our work concerns the design of control laws for the considered class of SLS. At first, two Lyapunov-based control laws have been established using either an average model or a hybrid model of the system. A hybrid optimal control based on the maximum principle of Pontryagin and the computation of singular arcs has been also proposed. Finally, a hybrid predictive control based on a discrete model of the system is synthesized. Simulation results and an experimental implementation on a SEPIC converter are given to show the efficiency of the proposed methods. Our motivation to study such a converter is mainly due to its particular topology that includes observable and unobservable subsystems. It is also known to be difficult to be controlled because only one switching input is used to control four state variables.