<p>Interleukin-15 (IL-15) is a cytokine that promotes maintenance and activation of cytotoxic immune cells. Therapeutic IL-15 stimulates these cells to fight cancer and chronic infections, such as Human Immunodeficiency Virus (HIV). Animal models of HIV have demonstrated that IL-15 agonists can suppress the virus, but this was transient and was not observed in all cohorts. We developed a mechanistic mathematical model of IL-15 therapy of HIV to explain these differences in efficacy and to explore solutions. First, the model was applied to evaluate mitigating factors, including immune regulation, viral escape, and drug tolerance, using Akaike Information Criterion.  We found that immune regulatory mechanisms could explain the viral rebound observed with continued IL-15 therapy. Next, the model was expanded to allow it to simultaneously explain both the transient viral suppression noted above and the lack of viral suppression observed in another animal cohort.  In this cohort, the model suggested that higher pre-treatment viral load came with higher activation of immune cells and a balancing regulatory inhibition of cytotoxicity. Finally, we conducted stability analysis at a range of IL-15 therapeutic strengths. While there was an ideal IL-15 strength, monotherapy could not maintain viral levels below what would clinically be considered to be safely controlled. Stable viral control in the model required the combination of IL-15 with blockade of key regulatory pathways. Immune therapy of complex diseases will likely require combinations of medicines that boost the immune response at multiple key points. Mathematical models like this can expedite development of these treatments.</p>

Le présent mémoire vise à démontrer que le projet des Cinq Grandes Odes de Paul Claudel et de l'Ode au Saint-Laurent de Gatien Lapointe est de retrouver, grâce à la parole poétique, une conscience mythique du monde, telle que définie par le philosophe Georges Gusdorf. Ces deux œuvres partagent en effet cette dimension fondamentale : enraciner l'être et la parole au cœur d'une expérience cosmogonique du langage et du réel. Nous expliquerons de manière plus générale ce qui fonde la spécificité de la parole poétique et en quoi elle rend possible l'expression de la conscience mythique. Cette réflexion préliminaire alimentera notre lecture de l'Ode au Saint-Laurent et des Cinq Grandes Odes. Nous tenterons de saisir les enjeux d'une poésie qui, chez Claudel comme chez Lapointe, puise la source de sa connaissance et son mouvement créateur au sein d'un imaginaire mythique.

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Largely based on material recorded during an internationally sponsored inter-university research tour through the Sesotho speaking area of southern Africa in August 2000, this thesis explores the state of the Basotho oral poetry, the dithoko `praise poems', the difela `mine workers' chants' and the diboko `family odes' at the beginning of the 21st century. Unlike the classical dithoko which were inspired by the wars or the battles in which the Basotho fought as well as cannibalism, those composed at the beginning of the 21st century are inspired by socio-economic and political situations of the poets. Lack of wars has resulted in the poets turning the praising to their chiefs and themselves. Changing socio-economic conditions inspired the difela compositions. The diboko though still a living tradition among the rural Basotho are not adhered to by some who are affected by modernism. Performance of the three oral genres has shifted from the natural settings such as the battlefield, working parties, traditional courts, assemblies, etc., to organized annual festivals such as Morija Arts & Cultural Festival which constitute the Basotho's `popular culture'. The subject-matter and themes of the dithoko have shifted from warfare to traditional chiefs, current heroic deeds of the poets, current political situations and religion. The difela are characterized by inclusion of new subject-matter. The diboko still play an important function as carriers of the names of the ancestors, the tribal idiosyncrasy of the clan and the history associated with the clan's establishment. The three Basotho oral genres demonstrate an emergence of a new phenomenon whereby one genre penetrates another, a phenomenon which may be called `migration of texts'. The last chapter explores the insights emanating from the entire research, and discusses suggestions on what should be done to ensure that the Basotho oral genres are maintained and improved. The video footage of the poets recorded at various places of the Free State and Lesotho have contributed to the success of the research. The thesis serves as a contribution to the Basotho's dynamic oral poetry on which scholars will hopefully do further research in the near future. / African Languages / D. Litt et Phil. (African Languages)

Ansätze der mathematischen Modellierung ermöglichen die Analyse der dynamischen Eigenschaften biologischer Systeme und den Einfluß spezifischer Funktionen. Das Ziel dieser Arbeit ist es verschiedene Aspekte der Interaktionen zwischen Wirt und Krankheitserregern zu analysieren. In Kapitel 3 diskutiere ich ein Modell der zellulären Antwort auf Hitzeschockstress im Pilz Candida albicans. Das Modell in Form von gewöhnlichen Differentialgleichungen erörtert mehrere Aspekte des Systems, wie z.B. die erworbene Thermotoleranz und eine perfekte Anpassung an die Beanspruchung durch die Temperaturwechsel. Im Rahmen der Interaktionen zwischen Wirt und Krankheitserreger ist die Studie relevant, da die Entwicklung von Fieber eine primäre Antwort des Organismus auf eine Pilzinvasion ist. Die Dynamik von C. albicans Virulenzfaktoren, wie z.B. der Übergang vom Hefe- zum Hyphenstadium, und die Abwehrmechanismen des Wirts bestimmen den Zustand des Pilzes, d.h. ob er als Kommensale oder Krankheitserreger vorkommt. Mit Hilfe einer agenten-basierten Modellierungstechnik, in Kapitel 4, untersuche ich die Auswirkungen potenzieller medikamentöser Behandlungen von Pilzpopulationen und ihre Effektivität. In Kapitel 5 analysiere ich die Dynamik der C. albicans Hefe- und Hyphenpopulationen unter der Annahme, das zwischen den Individuen beider Populationen paarweise Wechselwirkungen bestehen, die zusätzlich von Fresszellen und Ernährungsbedingungen beeinflusst werden. Das erste Modell basiert auf den Prinzipien der Spieltheorie. Aus dieser Studie lässt sich die Hypothese aufstellen, dass sich im Verlauf der Infektion die evolutionäre Spieldynamik von der Snowdrift Spieldynamik in Richtung Gefangendilemma verschiebt. Im zweiten Modell untersuche ich die Umschaltraten zwischen Hefen und Hyphen. Das Modell zeigt, dass in Pilzpopulationen die Ausprägung verschiedener Phänotypen der Grund für die erhöhte Überlebensfähigkeit der Population sein könnte. / Mathematical modeling approaches facilitate the analysis of dynamic properties of mechanisms triggering specific functions of biological systems. Through this work I aim to shed light on various aspects of host-pathogen interactions. In Chapter 3, I discuss a model of heat shock stress response activated in the fungus Candida albicans. The model in form of ordinary differential equations reveals several features of the system, such as acquired thermotolerance and a perfect molecular adaptation to the thermal insult. The study is relevant in the context of host-pathogen interactions since development of fever is a primary host response to fungal invasion. The dynamics of C. albicans virulence factors, e.g., yeast to hypha transition, and defense mechanisms of the host determine the state of the fungi, i.e. whether to act as a commensal or as a foe. Through application of an agent-based modeling technique, in Chapter 4, I investigate effects of potential drug treatments on fungal populations and their effectivity in the fungal clearance. In Chapter 5, I analyze the dynamics of candida yeast and hyphal populations assuming pairwise interactions influenced by phagocytic cells and nutritional conditions. The first model is based on game theory principles. From the study it can be hypothesized that during the course of infection the evolutionary game dynamics shift from Snowdrift game dynamics toward Prisoners’ dilemma. In the second model, I examine switching rates between yeast and hypha. The model reveals that phenotypic variations may occur in order to increase the fitness of the population.

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By the help of several examples the interactive work with the ClassPad330 is considered. The student can solve difficult exercises of practical applications step by step using the symbolic calculation and the graphic possibilities of the calculator. Sometimes several fields of mathematics are combined to solve a problem. Let us consider the ClassPad330 (with the actual operating system OS 03.03) and discuss on some new exercises in analysis, e.g. solving a linear differential equation by the help of the Laplace transformation and using the inverse Laplace transformation or considering the Fourier transformation in discrete time (the Fast Fourier Transformation FFT and the inverse FFT). We use the FFT- and IFFT-function to study periodic signals, if we only have a sequence generated by sampling the time signal. We know several ways to get a solution. The techniques for studying practical applications fall into the following three categories: analytic, graphic and numeric. We can use the Classpad software in the handheld or in the PC (ClassPad emulator version of the handheld).

La tendance actuelle dans le domaine des télécommunications mène à des systèmes capables de fonctionner selon plusieurs standards, et donc plusieurs fréquences porteuses. La synthèse de la fréquence porteuse est un élément clef, dont les propriétés reposent essentiellement sur les performances de l’oscillateur employé. Pour assurer le fonctionnement de systèmes compatibles avec plusieurs standards de télécommunication, la solution conventionnelle consiste à intégrer plusieurs oscillateurs locaux. Cette solution est coûteuse, d’autant plus que, malgré le fait que les technologies actuelles atteignent des niveaux d’intégration très importants, la surface occupée par des oscillateurs traditionnels de type LC ne peut pas être diminuée, alors que le coût de fabrication au millimètre carré devient de plus en plus élevé. Il serait donc très intéressant de remplacer les oscillateurs LC, ce qui nous amène à rechercher des solutions alternatives parmi de nouvelles technologies. L’oscillateur spintronique (STO) est un nouveau dispositif issu des études sur les couches minces magnétiques. Il apparait comme un candidat potentiel de remplacement des oscillateurs LC du fait de sa grande accordabilité en fréquence et de son faible encombrement. Toutefois des mesures effectuées sur les STOs ont montré que la performance en puissance et en bruit de phase d’un oscillateur seul ne permet pas de remplir les spécifications pour des applications de télécommunication. Nous proposons de remplir ces spécifications en couplant un nombre d’oscillateurs spintroniques important. Dans ce cadre se posent plusieurs questions qui concernent les procédures de modélisation, d’analyse et de synthèse des systèmes interconnectés. Les procédures de modélisation incluent la démarche de recherche de modèles à complexité croissante qui décrivent les propriétés entrée-sortie d’un oscillateur spintronique, ainsi que la démarche de généralisation des modèles des oscillateurs dans le cadre du réseau. Les procédures d’analyse cherchent à vérifier la stabilité et évaluer la performance des systèmes interconnectés. Les procédures de synthèse permettent de concevoir des interconnexions sophistiquées pour les oscillateurs afin d’assurer toutes les spécifications du cahier des charges. Dans ce document, nous établissons tout d’abord le problème de la synthèse de fréquence par couplage avec un cahier des charges formalisé en termes de gabarits fréquentiels sur des densités spectrales de puissance. Le cahier des charges posé amène la nécessité de modéliser l’oscillateur spintronique pour pouvoir simuler et analyser son comportement. Ici, nous proposons une modélisation originale selon des degrés de complexité croissante. Ensuite, nous discutons de la structure de la commande de l’ensemble des oscillateurs afin de remplir les spécifications du cahier des charges. La structure de commande proposée nécessite de développer une méthode de conception des interconnexions du réseau d’après les critères de performance. Dans les deux derniers chapitres, nous proposons deux méthodes fréquentielles de synthèse originales pour résoudre le problème de synthèse de fréquence par couplage. La première méthode de synthèse permet de prendre en compte un critère mathématique du cahier des charges, qui correspond à un gabarit fréquentiel à respecter, et permet d’obtenir une matrice d’interconnexion des sous-systèmes, telle que le module de la réponse fréquentielle du réseau approxime le gabarit imposé par le cahier des charges. La deuxième méthode de synthèse permet de prendre en compte plusieurs gabarits fréquentiels à la fois. La solution obtenue est une matrice d’interconnexion des sous-systèmes, qui résout le problème de la synthèse de fréquence par couplage d’oscillateurs spintroniques. / The current trends in telecommunication are leading to systems that are compatible with multiple standards and consequently multiple carrier frequencies. The frequency synthesis is a key element influenced by the local oscillator performance. In order to ensure the system compatibility with multiple telecommunication standards, the conventional solution consists in using one local oscillator for each standard. This solution is expensive, even more, since the cost per squared millimetre is increasing, while the silicon area occupied by the traditional LC-tank oscillators cannot be reduced in spite of the fact that technology is going to higher integration levels. Thus, it should be interesting to find a substitution to the LC-tank oscillators which leads to research for alternative solutions among new technologies. The spin torque oscillator (STO) is a new device issued from the ferromagnetic thin-film research. Due to its frequency accord ability and its capability to occupy relatively small volume, it appears as a potential candidate for the LC-tank oscillator replacement. However, a set of measurements prove that these devices exhibit poor power and phase noise performance, making them unable to fulfill the technical specification of the radiofrequency applications. We propose to reach these specifications by coupling of a large number of spin torque oscillators. In this scope, numerous questions appear regarding the procedures of modelling, analysis and synthesis of the complex interconnected systems. The modelling procedures are dedicated to the increasing complexity models that describe the input-output behaviour of a spin torque oscillator and its behaviour within the interconnected network. The analysis procedures are targeted to verify the stability and to evaluate the performance level of the interconnected systems. The synthesis procedures allow to design the interconnection law for spin torque oscillators in order to fulfill the technical requirements. In this document, the frequency synthesis problem by spin torque oscillator coupling with technical specification description in terms of power spectral densities is established. The formulated specifications introduce the problem of the oscillator modelling in order to perform a simulation and an analysis of the oscillator behaviour. Here, we propose an original model using several conventional models with increasing complexity. An original oscillator network model that describes qualitative properties of the oscillator synchronisation is introduced. Afterwards, the control law architecture for an oscillator set is established in order to accomplish the technical requirement specifications. The suggested control architecture needs to be developed with quantitative systematic and efficient design method for the network interconnection taking into account the formulated performance criteria. In the last two chapters we propose two original frequency domain design methods allowing the resolution of our frequency synthesis problem. The first design method allows to consider explicitly a performance criterium corresponding toa desired frequency constraint. The method allows to obtain a suitable sub-system interconnection matrix that fits the frequency specification constraint. The second design method allows to find an interconnection matrix and to take into account simultaneously several frequency specification constraints. The interconnection matrix obtained with the proposed method solves the problem of frequency synthesis by coupling of spin torque oscillators.

In this thesis, I investigate dynamic and computational properties of prokaryotic signalling architectures commonly known as the Two Component Signalling networks and phosphorelays. The aim of this study is to understand the information processing capabilities of different prokaryotic signalling architectures by examining the dynamics they exhibit. I present original investigations into the dynamics of different phosphorelay architectures and identify network architectures that include a commonly found four step phosphorelay architecture with a capacity for tuning its steady state output to implement different signal-response behaviours viz. sigmoidal and hyperbolic response. Biologically, this tuning can be implemented through physiological processes like regulating total protein concentrations (e.g. via transcriptional regulation or feedback), altering reaction rate constants through binding of auxiliary proteins on relay components, or by regulating bi-functional activity in relays which are mediated by bifunctional histidine kinases. This study explores the importance of different biochemical arrangements of signalling networks and their corresponding response dynamics. Following investigations into the significance of various biochemical reactions and topological variants of a four step relay architecture, I explore the effects of having different types of proteins in signalling networks. I show how multi-domain proteins in a phosphorelay architecture with multiple phosphotransfer steps occurring on the same protein can exhibit multistability through a combination of double negative and positive feedback loops. I derive a minimal multistable (core) architecture and show how component sharing amongst networks containing this multistable core can implement computational logic (like AND, OR and ADDER functions) that allows cells to integrate multiple inputs and compute an appropriate response. I examine the genomic distribution of single and multi domain kinases and annotate their partner response regulator proteins across prokaryotic genomes to find the biological significance of dynamics that these networks embed and the processes they regulate in a cell. I extract data from a prokaryotic two component protein database and take a sequence based functional annotation approach to identify the process, function and localisation of different response regulators as signalling partners in these networks. In summary, work presented in this thesis explores the dynamic and computational properties of different prokaryotic signalling networks and uses them to draw an insight into the biological significance of multidomain sensor kinases in living cells. The thesis concludes with a discussion on how this understanding of the dynamic and computational properties of prokaryotic signalling networks can be used to design synthetic circuits involving different proteins comprising two component and phosphorelay architectures.