The successful regeneration of muscle tissue is dependent upon the infiltration of phagocytic CD14++CD16- monocytes that support the proliferation and differentiation of myogenic precursor cells. Physiologically, the magnitude of the cellular response following resistance exercise is dictated by the level of receptor expression on the plasma membrane of the monocyte, as well as the secretion of their cognate ligands from tissue resident cells. However, it remains unclear whether the innate pro-inflammatory immune response varies with different resistance training protocols, and how it may impact recovery and the muscle remodeling process. Therefore, the purpose of this investigation was to examine temporal changes in the expression of chemotactic and adhesion receptors following an acute bout of high-volume, moderate-intensity (VOL) versus high-intensity, low-volume (HVY) lower-body resistance exercise in experienced, resistance trained men. Changes in receptor expression were assessed in conjunction with plasma concentrations of MCP-1, TNF?, and cortisol. Ten resistance-trained men (90.1 ± 11.3 kg; 176.0 ± 4.9 cm; 24.7 ± 3.4 yrs; 14.1 ± 6.1% body fat) performed each resistance exercise protocol in a random, counterbalanced order. Blood samples were obtained at baseline (BL), immediately (IP), 30 minutes (30P), 1 hour (1H), 2 hours (2H), and 5 hours (5H) post-exercise. Analysis of target receptor expression on CD14++CD16- monocytes was completed at BL, IP, 1H, 2H and 5H time points via flow cytometric analysis. Plasma concentrations of myoglobin, and LDH AUC were significantly greater following HVY compared to VOL (p = 0.003 and p = 0.010 respectively). Changes in plasma TNF?, MCP-1, and expression of CCR2, CD11b, and GCR on CD14++CD16- monocytes were similar following HVY and VOL. When collapsed across groups, TNF? was significantly increased at IP, 30P, 1H and 2H post-exercise (p = 0.001 – 0.004), while MCP-1 was significantly elevated at all post-exercise time points (p = 0.002 – 0.033). CCR2 expression was significantly lower at IP, 1H, 2H and 5H post-exercise (p = 0.020 – 0.040). In contrast, CD11b receptor expression was significantly greater at 1H relative to BL (p = 0.001), while GCR expression was not significantly different from baseline at any time point. As expected, plasma cortisol concentrations were significantly higher following VOL compared to HVY (p = 0.001), although this did not appear to be related to changes in receptor expression. Plasma testosterone concentrations and TNFr1 receptor expression did not appear to be affected by resistance exercise. Our results do not support a role for cortisol in the modulation of CCR2 receptors in vivo, while the degree of muscle damage does not appear to influence plasma concentrations of TNF?, or MCP-1. It is therefore likely that both HVY and VOL protocols constitute an exercise stimulus that is sufficient enough to promote a robust pro-inflammatory response, which is similar in timing and magnitude.

La dérégulation du compartiment de cellules B est une conséquence importante de l’infection par le virus de l’immunodéficience humaine (VIH-1). On observe notamment une diminution des nombres de lymphocytes B sanguins ainsi qu’une variation des fréquences relatives des différentes populations de lymphocytes B chez les individus infectés par rapport aux contrôles sains. Notre laboratoire a précédemment démontré l’implication des cellules dendritiques dans la dérégulation des lymphocytes B via la roduction excessive de BLyS/BAFF, un stimulateur des cellules B. De plus, lors l’études menées chez la souris transgénique présentant une maladie semblable au SIDA, et chez la souris BLyS/BAFF transgénique, l’infection au VIH-1 fut associée à une expansion de la zone marginale (MZ) de la rate. De façon intéressante, nous observons chez les contrôleurs élites une diminution de la population B ‘mature’ de la MZ. Il s’agit du seul changement important chez les contrôleurs élites et reflète possiblement un recrutement de ces cellules vers la périphérie ainsi qu’une implication dans des mécanismes de contrôle de l’infection. Pour tenter d’expliquer et de mieux comprendre ces variations dans les fréquences des populations B, nous avons analysé les axes chimiotactiques CXCL13-CXCR5, CXCL12-CXCR4/CXCR7, CCL20-CCR6 et CCL25-CCR9. L’étude longitudinale de cohortes de patients avec différents types de progression clinique ou de contrôle de l’infection démontre une modulation des niveaux plasmatiques de la majorité des chimiokines analysées chez les progresseurs rapides et classiques. Au contraire, les contrôleurs élites conservent des niveaux normaux de chimiokines, démontrant leur capacité à maintenir l’homéostasie. La migration des populations de cellules B semble être modulée selon la progression ou le contrôle de l’infection. Les contrôleurs élites présentent une diminution de la population B ‘mature’ de la MZ et une augmentation de la fréquence d’expression du récepteur CXCR7 associé à la MZ chez la souris, suggérant un rôle important des cellules de la MZ dans le contrôle de l’infection au VIH-1. De façon générale, les résultats dans cette étude viennent enrichir nos connaissances du compartiment de cellules B dans le contexte de l’infection au VIH-1 et pourront contribuer à élaborer des stratégies préventives et thérapeutiques contre ce virus. / Deregulation of the B-cell compartment is an important consequence of human immunodeficiency virus (HIV-1) infection. We observe a decrease in blood B lymphocyte numbers accompanied by variations in the relative frequency of B cell populations in infected individuals when compared to healthy controls. Our lab has previously exposed the implication of dendritic cells in B-cell deregulation via excessive production of B lymphocyte stimulator (BLyS/BAFF). Additionally, the study of BLYS/BAFF-transgenic mice as well as mice exhibiting an AIDS-like disease revealed an expansion of the marginal zone (MZ) of the spleen. Interestingly, we found reduced relative frequencies of mature MZ-like B cells in the blood of elite controllers while rapid and classic HIV progressors had increased ‘precursor’ MZ-like cells. This variation in elite controllers is the only one observed for all population analyzed and could be the reflection of active recruitment of these cells to the periphery to help control infection. To try and understand these variations in B-cell frequencies we have analyzed the Btropic chemotaxis axes CXCL13-CXCR5, CXCL12-CXCR4/CXCR7, CCL20-CCR6 and CCL24-CCR9. The longitudinal study of patients with varying degrees of disease progression and control shows a modulation of the levels of most chemokines in the blood of rapid and classic progessors. Meanwhile, elite controllers maintain normal levels of these chemokines, demonstrating their ability to preserve homeostasis. Our results suggest that the type of disease progression impacts B-cell migration, resulting in modified B-cell population frequencies. The decrease in mature MZ-like B-cells and the increased frequency of cells expressing CXCR7, a receptor associated to the MZ in mice, in elite controllers suggest an important role for the MZ in controlling HIV-1 infection. Overall, our results provide more information about the B-cell compartment in the context of HIV-1 infection and can contribute to the elaboration of preventive and therapeutic strategies for HIV-1.

In this thesis, a number of mathematical models of haptotactic cell migration are developed. The modelling of haptotaxis is presented in two distinct parts - the first comprises an investigation of haptotaxis in pre-necrotic avascular tumours, while the second consists of the modelling of adhesion-mediated haptotactic cell migration within tissue, with particular attention paid to the biological appropriateness of the description of cell-extracellular matrix adhesion. A model is developed that describes the effects of passive and haptotactic migration on the cellular dynamics and growth of pre-necrotic avascular tumours. The model includes a description of the extracellular matrix and its effect on cell migration. Questions are posed as to which cell types act as a source of the extracellular matrix, and the model is used to simulate the possible effects of different matrix sources. Simulations in one-dimensional and spherically symmetric geometry are presented, displaying familiar results such as three-phase tumour growth and tumours comprising a rim of proliferating cells surrounding a non-proliferating region. Novel effects are also described such as cell population splitting and tumour shrinkage due to haptotaxis and appropriate extracellular matrix construction. The avascular tumour model is then extended to describe the internalisation of labelled cells and inert microspheres within multicell tumour spheroids. A novel model of adhesion-receptor mediated haptotactic cell migration is presented and specific applications of the model to tumour invasion processes are discussed. This model includes a more biologically realistic description of cell adhesion than has been considered in previous models of cell population haptotaxis. Through assumptions of fast kinetics, the model is simplified with the identification of relationships between the simplified model and previous models of haptotaxis. Further simpli.cations to the model are made and travelling wave solutions of the original model are then investigated. It is noted that the generic numerical solution routine NAG D03PCF is not always appropriate for the solution of the model, and can produce oscillatory and inaccurate solutions. For this reason, a control volume numerical solver with .ux limiting is developed to provide a better method of solving the cell migration models.

Thesis (Ph. D.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).

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.

Cette thèse vise à étudier certains modèles biologiques dans le réseau neuronal et dans la chimiotaxie avec la méthode d’analyse spectrale. Afin de traiter les principaux problèmes, tels que l’existence et l’unicité des solutions et des états stationnaires ainsi que les comportements asymptotiques, le modèle linéaire ou linéarisé associé est considéré par l’aspect du spectre et des semi-groupes dans les espaces appropriés, puis la stabilité de modèle non linéaire suit. Plus précisément, nous commençons par une équation de courses-et-chutes linéaire dans la dimension d≥1 pour établir l’existence d’un état stationnaire unique, positif et normalisé et la stabilité exponentielle asymptotique dans l’espace L¹ pondéré basé sur la théorie de Kerin-Rutman avec quelques estimations du moment de la théorie cinétique. Ensuite, nous considérons le modèle du temps écoulé sous les hypothèses générales sur le taux de tir et nous prouvons l’unicité de l’état stationnaire et sa stabilité exponentielle non linéaire en cas sans ou avec délai au régime de connectivité faible de la théorie de l’analyse spectrale pour les semi-groupes. Enfin, nous étudions le modèle sous une hypothèse de régularité plus faible sur le taux de tir et l’existence de la solution ainsi que la même stabilité exponentielle sont généralement établies n’importe la prise en compte du délai ou non, au régime de connectivité faible ou forte. / This thesis is aimed to study some biological models in neuronal network and chemotaxis with the spectral analysis method. In order to deal with the main concerning problems, such as the existence and uniqueness of the solutions and steady states as well as the asymptotic behaviors, the associated linear or linearized model is considered from the aspect of spectrum and semigroups in appropriate spaces then the nonlinear stability follows. More precisely, we start with a linear runs-and-tumbles equation in dimension d≥1 to establish the existence of a unique positive and normalized steady state and the exponential asymptotic stability in weighted L¹ space based on the Krein-Rutman theory together with some moment estimates from kinetic theory. Then, we consider time elapsed model under general assumptions on the firing rate and prove the uniqueness of the steady state and its nonlinear exponential stability in case without or with delay in the weak connectivity regime from the spectral analysis theory for semigroups. Finally, we study the model under weaker regularity assumption on the firing rate and the existence of the solution as well as the same exponential stability are established generally no matter taking delay into account or not and no matter in weak or strong connectivity regime.

Indiana University-Purdue University Indianapolis (IUPUI) / More than 300 million people world-wide suffer from breathlessness, wheezing, chest tightness, and coughing characteristic of chronic bronchial asthma, the global incidence of which is on the rise. Allergen-sensitization and challenge elicits pulmonary expression of chemoattractants that promote a chronic eosinophil-rich infiltrate. Eosinophils are increasingly recognized as important myeloid effectors in chronic inflammation characteristic of asthma, although few eosinophil molecular signaling pathways have successfully been targeted in asthma therapy. p21 activated kinases (PAKs), members of the Ste-20 family of serine/threonine kinases, act as molecular switches in cytoskeletal-dependent processes involved in cellular motility. We hypothesized that PAK1 modulated eosinophil infiltration in an allergic airway disease (AAD) murine model. In this model, Pak1 deficient mice developed reduced inflammatory AAD responses in vivo with notable decreases in eosinophil infiltration in the lungs and broncho-alveolar lavage fluids (BALF). To test the importance of PAK1 in hematopoietic cells in AAD we used complementary bone marrow transplant experiments that demonstrated decreased eosinophil inflammation in hosts transplanted with Pak1 deficient bone marrow. In in vitro studies, we show that eotaxin-signaling through PAK1 facilitated eotaxin-mediated eosinophil migration. Ablating PAK1 expression by genetic deletion in hematopoietic progenitors or siRNA treatment in derived human eosinophils impaired eotaxin-mediated eosinophil migration, while ectopic PAK1 expression promoted this migration. Together these data suggest a key role for PAK1 in the development of atopic eosinophil inflammation and eotaxin-mediated eosinophil migration.

Dans cette thèse, nous étudions l'ensemble des solutions d'équations aux dérivées partielles résultant de modèles d'astrophysique et de biologie. Nous répondons aux questions de l'existence, mais aussi nous essayons de décrire le comportement de certaines familles de solutions lorsque les paramètres varient. Tout d'abord, nous étudions deux problèmes issus de l'astrophysique, pour lesquels nous montrons l'existence d'ensembles particuliers de solutions dépendant d'un paramètre à l'aide de la méthode de réduction de Lyapunov-Schmidt. Ensuite un argument de perturbation et le théorème du Point xe de Banach réduisent le problème original à un problème de dimension finie, et qui peut être résolu, habituellement, par des techniques variationnelles. Le reste de la thèse est consacré à l'étude du modèle Keller-Segel, qui décrit le mouvement d'amibes unicellulaires. Dans sa version plus simple, le modèle de Keller-Segel est un système parabolique-elliptique qui partage avec certains modèles gravitationnels la propriété que l'interaction est calculée au moyen d'une équation de Poisson / Newton attractive. Une différence majeure réside dans le fait que le modèle est défini dans un espace bidimensionnel, qui est expérimentalement consistant, tandis que les modèles de gravitationnels sont ordinairement posés en trois dimensions. Pour ce problème, les questions de l'existence sont bien connues, mais le comportement des solutions au cours de l'évolution dans le temps est encore un domaine actif de recherche. Ici nous étendre les propriétés déjà connues dans des régimes particuliers à un intervalle plus large du paramètre de masse, et nous donnons une estimation précise de la vitesse de convergence de la solution vers un profil donné quand le temps tend vers l'infini. Ce résultat est obtenu à l'aide de divers outils tels que des techniques de symétrisation et des inégalités fonctionnelles optimales. Les derniers chapitres traitent de résultats numériques et de calculs formels liés au modèle Keller-Segel / In this thesis we study the set of solutions of partial differential equations arising from models in astrophysics and biology. We answer the questions of existence but also we try to describe the behavior of some families of solutions when parameters vary. First we study two problems concerned with astrophysics, where we show the existence of particular sets of solutions depending on a parameter using the Lyapunov-Schmidt reduction method. Afterwards a perturbation argument and Banach's Fixed Point Theorem reduce the original problem to a finite-dimensional one, which can be solved, usually, by variational techniques. The rest of the thesis is de-voted to the study of the Keller-Segel model, which describes the motion of unicellular amoebae. In its simpler version, the Keller-Segel model is a parabolic-elliptic system which shares with some gravitational models the property that interaction is computed through an attractive Poisson / Newton equation. A major difference is the fact that it is set in a two-dimensional setting, which experimentally makes sense, while gravitational models are ordinarily three-dimensional. For this problem the existence issues are well known, but the behaviour of the solutions during the time evolution is still an active area of research. Here we extend properties already known in particular regimes to a broader range of the mass parameter, and we give a precise estimate of the convergence rate of the solution to a known profile as time goes to infinity. This result is achieved using various tools such as symmetrization techniques and optimal functional inequalities. The last chapters deal with numerical results and formal computations related to the Keller-Segel model