Instructive signals, whether external or internal, play critical roles in regulating the developmental potency or ability to self-renew of stem cells. External signals may range from secreted growth factors to extracellular matrix proteins found in the stem cell niche. Internal signals include activated signalling cascades and the eventual transcriptional mechanisms they initiate. In either fashion, stem cells are regulated in a complex temporal and context specific manner in order to maintain or maximise their unique characteristics. Previous experiments suggest that Wnt3a plays a role in maintaining the pluripotent state of mouse embryonic stem (mES) cells. However, in the absence of leukemia inhibitory factor (LIF), Wnt signalling is unable to maintain ES cells in the undifferentiated state. This implies that maintaining the pluripotent state of mES cells is not the primary function of canonical Wnt signalling. To further characterize the role of Wnt3a in pluripotency and lineage specification undifferentiated and differentiated mES cells were induced with Wnt3a. Wnt3a induced the formation of a metastable primitive endoderm state and upon subsequent differentiation, the induction of large quantities of visceral endoderm. Furthermore, we determined that the ability of Wnt3a to induce a metastable primitive endoderm state was mediated by the T-box transcription factor Tbx3. Our data demonstrates a novel role for Wnt3a in promoting the interconversion of undifferentiated mES cells into a pluripotent primitive endoderm state. Aging of skeletal muscle tissue is accompanied by fibrosis, atrophy and remodeling all of which negatively affect muscle performance. Whether this reduction in skeletal muscle competency is directly attributed to a resident adult stem cell population called satellite cells remains largely unknown. Here, we undertook an investigation into how age affects the transcriptional profile of satellite cells and their repopulating ability following transplantation. We determined that as satellite cells age, both their regenerative capacity and ability to colonize the satellite cell niche is reduced. Additionally, we identified satellite cell specific transcriptional profiles that differed with respect to age. Therefore, we conclude that intrinsic factors are an important determinant of satellite cell regenerative capacity during the aging process.

Instructive signals, whether external or internal, play critical roles in regulating the developmental potency or ability to self-renew of stem cells. External signals may range from secreted growth factors to extracellular matrix proteins found in the stem cell niche. Internal signals include activated signalling cascades and the eventual transcriptional mechanisms they initiate. In either fashion, stem cells are regulated in a complex temporal and context specific manner in order to maintain or maximise their unique characteristics. Previous experiments suggest that Wnt3a plays a role in maintaining the pluripotent state of mouse embryonic stem (mES) cells. However, in the absence of leukemia inhibitory factor (LIF), Wnt signalling is unable to maintain ES cells in the undifferentiated state. This implies that maintaining the pluripotent state of mES cells is not the primary function of canonical Wnt signalling. To further characterize the role of Wnt3a in pluripotency and lineage specification undifferentiated and differentiated mES cells were induced with Wnt3a. Wnt3a induced the formation of a metastable primitive endoderm state and upon subsequent differentiation, the induction of large quantities of visceral endoderm. Furthermore, we determined that the ability of Wnt3a to induce a metastable primitive endoderm state was mediated by the T-box transcription factor Tbx3. Our data demonstrates a novel role for Wnt3a in promoting the interconversion of undifferentiated mES cells into a pluripotent primitive endoderm state. Aging of skeletal muscle tissue is accompanied by fibrosis, atrophy and remodeling all of which negatively affect muscle performance. Whether this reduction in skeletal muscle competency is directly attributed to a resident adult stem cell population called satellite cells remains largely unknown. Here, we undertook an investigation into how age affects the transcriptional profile of satellite cells and their repopulating ability following transplantation. We determined that as satellite cells age, both their regenerative capacity and ability to colonize the satellite cell niche is reduced. Additionally, we identified satellite cell specific transcriptional profiles that differed with respect to age. Therefore, we conclude that intrinsic factors are an important determinant of satellite cell regenerative capacity during the aging process.

Metastable states are classically stable at zero temperature but can decay due to quantum tunneling. The rate of this process is exponentially small and it may be computed in Euclidean space in the Coleman-de Luccia formalism. The exponential suppression is determined by the Euclidean action computed on a trajectory with definite boundary conditions, known as Coleman-de Luccia instanton, or bounce. In some theories, the bounce may not exist or its on-shell action may be ill-defined or infinite, thus hindering the vacuum decay process. The issue of vacuum stability is, in fact, not just speculation: the Standard Model vacuum state is itself metastable. The Higgs field may tunnel outside its potential well, with catastrophic consequences for all observers. Luckily, the typical lifetime of such a state is predicted to be very long. Still, unknown high energy physics can change it by several orders of magnitude, and particle physics theories as well as cosmological models that predict large decay rates are ruled out thanks to the anthropic principle. Moreover, gravitational effects play an important role in this process, especially in the early Universe. It is thus important to examine in detail vacuum decay phenomena in gravitational settings and to keep the underlying field theory as general as possible. This thesis aims at exploring existence conditions for the Coleman-de Luccia instanton in gravitational settings. The first two chapters are dedicated to outlining the basic formalism and describing preexisting results about vacuum decay in cosmology. The Euclidean path integral approach for decay rate calculations, which was first discussed by Callan and Coleman, is introduced in Chapter 1. A quantum mechanical description of the problem is formulated and then extended to field theory. A detailed analysis of bounce calculations and their physical interpretation as bubbles of true vacuum follows. The Higgs field stability within the Standard Model is also addressed. Gravitational effects on the vacuum decay process are considered in Chapter 2, by focusing on the decay from Minkowski and de Sitter space, as they have important cosmological consequences respectively in the current Universe (due to the smallness of the cosmological constant) and at early times. The implications on Higgs decay are discussed in both settings. The last two chapters are dedicated to new results. Vacuum decay in field theories with a scalar field and quadratic gravity is investigated. An Einstein-Hilbert term, a non-minimal coupling, and a quadratic Ricci scalar are considered while keeping the scalar field potential general. The focus is on decay from Minkowski and de Sitter space, due to their importance in cosmology. Scalar fields with Einstein-Hilbert gravity are discussed in Chapter 3, by showing that the bounce at large Euclidean radii has an analytical form that is almost entirely independent of the potential, which is called the "asymptotic bounce". Bounds on the Hubble parameter in the de Sitter case are also explored, by giving an analytical explanation to numerical evidence present in the literature. These properties are used, in Chapter 4, to test for stabilization of the false vacuum state in quadratic gravity. Conclusions follow.

Pressurized metered-dose inhalers (pMDIs) are the most widely-prescribed inhaler devices for therapeutic aerosol delivery in the treatment of lung diseases. In spite of its undoubted therapeutic and commercial success, the propellant flow mechanics and aerosol formation by the pMDIs is poorly understood. The process involves a complex transient cavitating turbulent fluid that flashes into rapidly evaporating droplets, but details remain elusive, partly due to the difficulty of performing experiments at the small length scales and short time scales. The objective of the current work is the development of a numerical model to predict the internal flow conditions (pressure, temperature, velocity, void fraction, quality, etc.) and provide deeper insight into the atomization process and fluid mechanics involved in the twin-orifice of pMDIs. The main focus is propellant metastability, which has been identified by several past authors as a key element that is missing in accounts of pMDI performance. First the flashing propellant flow through single orifice systems (both long and short capillary tubes) was investigated using three different models : homogeneous equilibrium model (HEM), delayed equilibrium model (DEM) and improved delayed equilibrium model (IDEM). Both, the pure propellants and the propellant mixtures were used as working fluid. The numerical results were compared with the experimental data. For long capillary tubes the three models gave reasonable predictions, but the present results showed that DEM predicts the mass flow rate well for pure propellants and IDEM predicts the mass flow rate well for propellant mixtures. For short capillary tubes, the present results showed that DEM predicts the mass flow rate and pressure distribution along the short tube better compared to HEM and IDEM. The geometry of the twin-orifice system of a pMDI is complex and involves several singularities (sudden enlargements and sudden contractions). Various assumptions were made to evaluate their effect on the vaporisation process and to evaluate the flow variables after the shock at the exit of the spray orifice when the flow is choked. Also, three different propellant flow regimes were explored at the inlet of the valve orifice. A specific combination of assumptions, which offers good agreement with the experimental data was selected for further computations. Numerical investigations were carried out using delayed equilibrium model (DEM) with these new assumptions to validate the two-phase metastable flow through twin-orifice systems with continuous flows of various propellants studied previously by Fletcher (1975) and Clark (1991). A new correlation was developed for the coefficient in the relaxation equation. Along with this correlation a constant coefficient was used in the relaxation equation to model the metastability. Both the coefficients showed good agreement against the Fletcher's experimental data. The comparison with the Clark s experimental data showed that the new correlation coefficient predicted the mass flow rate well in compare to that of the constant coefficient, but over predicted the expansion chamber pressure. The DEM with both the coefficients for continuous discharge flows were applied to investigate the quasi-steady flashing flow inside the metered discharge flows at various time instants. The DEM results were compared with the Clark s metered discharge experimental data and the well established homogeneous equilibrium model (HEM). The comparison between the HEM and DEM with Clark s (1991) experimental data showed that the DEM predicted the mass flow well in compare to that of HEM. Moreover, both the models underpredicted the expansion chamber pressure and temperature. The findings of the present thesis have given a better understanding of the role played by the propellant metastability inside the twin-orifice system of pMDIs. Also, these have provided detailed knowledge of thermodynamic state, void fraction and critical velocity of the propellant at the spray orifice exit, which are essential step towards the development of improved atomisation models. Improved understanding of the fluid mechanics of pMDIs will contribute to the development of next-generation pMDI devices with higher treatment efficacy, capable of delivering a wider range of therapeutic agents including novel therapies based around.

With rapid technology scaling, flip-flops are becoming more susceptible to metastability due to tighter timing budgets and the more prominent effects of process, temperature, and voltage variation that can result in frequent setup and hold time violations. This thesis presents a detailed methodology and analysis on the design of metastable-hardened, high-performance, and low-power flip-flops. The design of metastable-hardened flip-flops is focused on optimizing the value of τ mainly due to its exponential relationship with the metastability window δ and the mean-time-between-failure (MTBF). Through small-signal modeling, τ is determined to be a function of the load capacitance and the transconductance in the cross-coupled inverter pair for a given flip-flop architecture. In most cases, the reduction of τ comes at the expense of increased delay and power. Hence, two new design metrics, the metastability-delay-product (MDP) and the metastability-power-delay-product (MPDP), are proposed to analyze the tradeoffs between delay, power and τ. Post-layout simulation results have shown that the proposed optimum MPDP design can reduce the metastability window δ by at least an order of magnitude depending on the value of the settling time and the flip-flop architecture. In this work, we have proposed two new flip-flop designs: the pre-discharge flip-flop (PDFF) and the sense-amplifier-transmission-gate (SATG) based flip-flop. Both flip-flop architectures facilitate the usage in both single and dual-supply systems as reduced clock-swing flip-flop and level-converting flip-flop. With a cross-coupled inverter in the master-stage that increases the overall transconductance and a small load transistor associated with the critical node, the architecture of both the PDFF and the SATG is very attractive for the design of metastable-hardened, high-performance, and low-power flip-flops. The amount of overhead in delay, power, and area is all less than 10% under the optimum MPDP design scheme when compared to the traditional optimum PDP design. In designing for metastable-hardened and soft-error tolerant flip-flops, the main methodology is to improve the metastability performance in the master-stage while applying the soft-error tolerant cell in the slave-stage for protection against soft-error. The proposed flip-flops, PDFF-SE and SATG-SE, both utilize a cross-coupled inverter on the critical path in the master-stage and generate the required differential signals to facilitate the usage of the Quatro soft-error tolerant cell in the slave-stage.

The simple exclusion process is formally defined as follows : each particle performs a simple random walk on a set of sites and interacts with other particles by never moving on occupied sites. Despite its simplicity, this process has properties that are found in many more complex statistical mechanics models. It is the combination of the simplicity of the process and the importance of the observed phenomena that make it one of the reference models in out of equilibrium statistical mechanics. In this thesis, I'm interested in the case of the totally asymmetric exclusion process (particles jump only to the right) on N to study its behavior according to the mechanism of particle creation : particles are created at site 0 with arate depending on the current configuration. Once this mechanism is no longer a Poisson process, the associated exclusion process does not admit a product invariant measure. As a consequence, classical computation methods with theinfinitesimal generator are rarely successful. So I used mainly the methods of coupling and second class particles.In the first part of the thesis, I'm interested in the model introduced by Grosskinsky for which I get the following result : if the maximum rate of creation and the initial density of particles are smaller than 12 and if the creation mechanism is of integrable range, there is no phase transition which means that there is only one invariant measure. In the second part of the thesis, my goal was to construct a process with finite and non-integrable range that has a phase transition. For this, I was inspired by methods developed for the process of specification of Bramson and Kalikow.

With rapid technology scaling, flip-flops are becoming more susceptible to metastability due to tighter timing budgets and the more prominent effects of process, temperature, and voltage variation that can result in frequent setup and hold time violations. This thesis presents a detailed methodology and analysis on the design of metastable-hardened, high-performance, and low-power flip-flops. The design of metastable-hardened flip-flops is focused on optimizing the value of τ mainly due to its exponential relationship with the metastability window δ and the mean-time-between-failure (MTBF). Through small-signal modeling, τ is determined to be a function of the load capacitance and the transconductance in the cross-coupled inverter pair for a given flip-flop architecture. In most cases, the reduction of τ comes at the expense of increased delay and power. Hence, two new design metrics, the metastability-delay-product (MDP) and the metastability-power-delay-product (MPDP), are proposed to analyze the tradeoffs between delay, power and τ. Post-layout simulation results have shown that the proposed optimum MPDP design can reduce the metastability window δ by at least an order of magnitude depending on the value of the settling time and the flip-flop architecture. In this work, we have proposed two new flip-flop designs: the pre-discharge flip-flop (PDFF) and the sense-amplifier-transmission-gate (SATG) based flip-flop. Both flip-flop architectures facilitate the usage in both single and dual-supply systems as reduced clock-swing flip-flop and level-converting flip-flop. With a cross-coupled inverter in the master-stage that increases the overall transconductance and a small load transistor associated with the critical node, the architecture of both the PDFF and the SATG is very attractive for the design of metastable-hardened, high-performance, and low-power flip-flops. The amount of overhead in delay, power, and area is all less than 10% under the optimum MPDP design scheme when compared to the traditional optimum PDP design. In designing for metastable-hardened and soft-error tolerant flip-flops, the main methodology is to improve the metastability performance in the master-stage while applying the soft-error tolerant cell in the slave-stage for protection against soft-error. The proposed flip-flops, PDFF-SE and SATG-SE, both utilize a cross-coupled inverter on the critical path in the master-stage and generate the required differential signals to facilitate the usage of the Quatro soft-error tolerant cell in the slave-stage.

Le processus d’exclusion simple est défini formellement de la façon suivante : chaque particule effectue une marche aléatoire sur un ensemble de sites et interagit avec les autres particules en ne se déplaçant jamais sur un site occupé.Malgré sa simplicité, ce processus présente des propriétés que l’on retrouve dans beaucoup de modèles de mécanique statistique plus complexes. C’est la conjonction de la simplicité du processus et de l’intérêt des phénomènes observés quien fait l’un des modèles de référence en mécanique statistique hors équilibre. Dans cette thèse, je me suis intéressé au cas du processus d’exclusion totalement asymétrique (les particules sautent uniquement vers la droite) sur Nafin d’étudier son comportement en fonction du mécanisme de création de particules: on crée des particules au site 0 avec un taux dépendant de la configurationactuelle. Dès que ce mécanisme n’est plus un processus de Poisson, le processusd’exclusion associé n’admet plus de mesure invariante sous forme de produitce qui fait que les méthodes classiques de calcul sur le générateur infinitésimaln’aboutissent que rarement. Je me suis donc appuyé principalement sur les méthodesde couplage et de particules de deuxième classe.Dans la première partie de la thèse, je me suis intéressé au modèle introduitpar Grosskinsky pour lequel j’ai obtenu les résultats suivants : si le taux maximumde création et la densité initiale de particules sont plus petits que 12 et sile mécanisme de création est à portée intégrable, il n’y a pas de transition dephase c’est-à-dire qu’il n’y a qu’une seule mesure invariante.Dans la deuxième partie de la thèse, je me suis intéressé au problème inversedont le but est de construire un processus à portée finie mais non-intégrableayant une transition de phase. Pour cela, je me suis inspiré des méthodes développéespour le processus des spécifications de Bramson et Kalikow. / The simple exclusion process is formally defined as follows : each particle performs a simple random walk on a set of sites and interacts with other particles by never moving on occupied sites. Despite its simplicity, this process has properties that are found in many more complex statistical mechanics models. It is the combination of the simplicity of the process and the importance of the observed phenomena that make it one of the reference models in out of equilibrium statistical mechanics. In this thesis, I’m interested in the case of the totally asymmetric exclusion process (particles jump only to the right) on N to study its behavior according to the mechanism of particle creation : particles are created at site 0 with arate depending on the current configuration. Once this mechanism is no longer a Poisson process, the associated exclusion process does not admit a product invariant measure. As a consequence, classical computation methods with theinfinitesimal generator are rarely successful. So I used mainly the methods of coupling and second class particles.In the first part of the thesis, I’m interested in the model introduced by Grosskinsky for which I get the following result : if the maximum rate of creation and the initial density of particles are smaller than 12 and if the creation mechanism is of integrable range, there is no phase transition which means that there is only one invariant measure. In the second part of the thesis, my goal was to construct a process with finite and non-integrable range that has a phase transition. For this, I was inspired by methods developed for the process of specification of Bramson and Kalikow.

Iron is often present in leach liquors produced in chemical and hydrometallurgical processes. It is known that voluminous iron precipitates with high impurity values are formed if the conditions during its formation are not controlled well. These products are also often difficult to treat in downstream processes. This study therefore focused on the determination of product quality parameters for the production of good quality iron precipitates from zinc-rich solutions. Special attention was given to the quality of metastable phases such as ferrihydrite and schwertmannite formed at elevated temperatures and in the pH range 1.5 to 3.5 in a continuous crystallizer. These phases are produced over a range of supersaturation levels with the best quality products formed at lower supersaturation. It was shown that most industrial processes are operated well above the metastability limit at relatively high supersaturation. However, stagewise precipitation of iron, even above the metastability limit, yielded better quality products. It was also shown that localized supersaturation levels could be controlled through changes in the micro and macromixing environments. The three-zone model approach was used to improve the quality of ferrihydrite and schwertmannite precipitates. Changes in the reactor design and the position of reagent feed points also impacted on the quality of the precipitates. Control over the localized supersaturation not only ensures the production of good quality nuclei, but also impacts on particle growth, which is required to make downstream processing of precipitates possible. In precipitation processes, growth mainly takes place through agglomeration as the rate of molecular growth is generally low. The final quality of iron precipitates is greatly influenced by the quality of the agglomerates formed during iron precipitation. A Hadamard matrix was used to indicate the relative importance of the most relevant operating parameters for the formation of good quality iron precipitates. / Thesis (PhD (Metallugical Engineering))--University of Pretoria, 2007. / Materials Science and Metallurgical Engineering / unrestricted

Les verres de chalcogénures sont développés en raison de leurs propriétés de transparences dans l'infrarouge. Il est par exemple possible de fabriquer des fibres optiques pour des fonctions capteurs fonctionnant dans le moyen infrarouge. L'objet de la présente thèse consiste à étudier le comportement métastable des verres de chalcogénures lorsqu'ils sont soumis à des contraintes particulières : thermiques, rayon γ, ajout d'élément déstabilisant. Des compositions dopées par des terres rares ont également étudiées pour développer des sources fonctionnant dans le moyen IR. / Chalcogenide glasses are developed because of their properties of transparency in the infrared. For example it is possible to manufacture optical fiber or planar wavguide for sensing in the mid-infrared. The purpose of this thesis is to study the metastable behavior of chalcogenide glasses when subjected to specific constraints: thermal behavior, γ ray irradiation, addition of destabilizing elements. Compositions doped with rare-earth have also been also studied in order to develop sources operating in the mid-infrared range.