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Thesis (PhD (Biochemistry))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: The multiplication of cells proceeds through consecutive phases of growth and division (G1, S, G2 and M phases), in a process known as the cell cycle. The transition between these phases is regulated by so-called checkpoints, which are important to ensure proper functioning of the cell cycle. For instance, mutations leading to faulty regulation of the G1/S transition point are seen as one of the main causes of cancer. Traditionally, models for biological systems that show rich dynamic behavior, such as the cell cycle, are studied using dynamical systems analysis. However, using this analysis method one cannot quantify the extent of control of an individual process in the system. To understand system properties at the process level, one needs to employ methods such as metabolic control analysis (MCA). MCA was, however, developed for steady-state systems, and is thus limited to the analysis of such systems, unless the necessary extensions would be made to the framework. The central question of this thesis focuses on quantifying the control in mathematical models of the G1/S transition by the individual cell cycle processes. Since MCA was never applied to the cell cycle, several new methods needed to be added to the framework. The most important extension made it possible to follow and quantify, during a single cell cycle, the control properties of the individual system processes. Subsequently, these newly developed methods were used to determine the control by the individual processes of an important checkpoint in mammalian cells, the restriction point. The positioning of the restriction point in the cell cycle was distributed over numerous system processes, but the following processes carried most of the control: reactions involved in the interplay between retinoblastoma protein (Rb) and E2F transcription factor, reactions responsible for the synthesis of Delayed Response Genes and Cyclin D/Cdk4 in response to growth signals, the E2F dependent Cyclin E/Cdk2 synthesis reaction, as well as the reactions involved in p27 formation. In addition it was shown that these reactions exhibited their control on the restriction point via the Cyclin E/Cdk2/p27 complex. Any perturbation of the system leading to a change in the restriction point could be explained via its e ect on the Cyclin E/Cdk2/p27 complex, showing a causal relation between restriction point positioning and the concentration of the Cyclin E/Cdk2/p27 complex. Finally, we applied the new methods, with a modular approach, to compare a number of cell cycle models for Saccharomyces cerevisiae (budding yeast) and mammalian cells with respect to the existence of a mass checkpoint. Such a checkpoint ensures that cells would have a critical mass at the G1/S transition point. Indeed, in budding yeast, a correction mechanism was observed in the G1 phase, which stabilizes the size of cells at the G1/S transition point, irrespective of changes in the specific growth rate. This in contrast to the mammalian cell cycle models in which no such mass checkpoint could be observed in the G1 phase. In this thesis it is shown that by casting specific questions on the regulation and control of cell cycle transition points in the here extended framework of MCA, it is possible to derive consensus answers for subsets of mathematical models. / AFRIKAANSE OPSOMMING: Die selsiklus bestaan uit agtereenvolgende groei- en delingsiklusse wat tot selvermeerdering lei. Die siklus word gekenmerk deur onderskeie fases (G1, S, G2 en M) wat deur sogenaamde beheerpunte gereguleer word. Hierdie beheerpunte verseker dat selvermeerdering nie ongekontroleerd kan plaasvind nie en mutasies wat lei tot foutiewe regulering van die G1/S transisiepunt word as een van die hoofoorsake van kanker beskou. Die hoofdoel van hierdie studie was om die beheer wat selsiklusprosesse op die G1/S transisie uitoefen met behulp van wiskundige modelle te kwantifiseer. Omdat biologiese sisteme soos die selsiklus ryk dinamiese gedrag vertoon, word hulle tradisioneeldeur middel van dinamiese sisteemanalise bestudeer. Die analisemetode beskik egter nie oor die vermoë om die hoeveelheid beheer wat afsonderlike sisteemprosesse op 0n sisteemeienskap uitoefen te kwantifiseer nie. Om sisteemeienskappe op prosesvlak te verstaan moet metodes soos metaboliese kontrole analise (MKA) ingespan word. MKA was egter ontwikkel om sisteme in 0n bestendige toestand te analiseer en aangesien MKA nog nooit vantevore vir selsiklus analises gebruik was nie, moes nuwe MKA tegnieke gedurende die studie ontwikkel word. Die belangrikste van die metodes maak dit moontlik om beheer (soos uitgeoefen deur die onderskeie sisteemprosesse) oor 0n enkele selsiklus na te volg en te kwantifiseer. Die nuut-ontwikkelde metodes was vervolgens gebruik om te bepaal hoe een so 0n beheerpunt in soogdierselle - die restriksiepunt - deur die onderskeie sisteemprosesse beheer word. Die studie het aangedui dat die posisie van die restriksiepunt tydens die selsiklus deur ’n verskeidenheid sisteemprosesse beheer word. Die bevinding was dat vier prosesse beduidend meer beheer op die posisie van die restriksiepunt uitoefen: Reaksies wat betrekking het op die wisselwerking tussen retinoblastoma proteïen (Rb) en E2F transkripsiefaktor; reaksies verantwoordelik vir die sintese van vertraagde responsgene en Siklien D/Cdk4 in respons tot groeiseine; die E2F afhanklike Siklien E/Cdk2 sintesereaksie; sowel as die reaksies betrokke in p27 vorming. Daar was ook aangetoon dat hierdie reaksies hul beheer op die posisie van die restriksiepunt deur die Siklien E/Cdk2/p27 kompleks uitoefen, siende enige sisteemversteuringe (wat tot veranderinge in die restriksiepuntposisie aanleiding gee) deur veranderinge in die kompleks verklaar kon word - 0n observasie wat aandui dat daar 0n kousale verhouding is tussen die posisie van die restriksiepunt en die Siklien E/Cdk2/p27 kompleks. Die nuut-ontwikkelde metodes was verder gebruik om 0n verskeidenheid selsiklusmodelle van Saccharomyces cerevisiae (bakkersgis) en soogdierselle met 0n modulêre aanpak te vergelyk om te bepaal of daar 0n massa beheerpunt in beide soogdier- en bakkersgisselle bestaan. Daar word gepostuleer dat hierdie beheerpunt verseker dat selle 0n kritiese massa by die G1/S transisiepunt bereik. Die resultate van die studie dui daarop dat bakkersgis, anders as soogdierselle, oor so 0n korreksiemeganisme beskik. Die meganisme stabiliseer die grootte van selle in die G1 fase ondanks veranderinge in die groeitempo van die selle, sodat massa homeostaties by die G1/S transisiepunt gehandhaaf word. Die studie het getoon dat moeilike vrae met betrekking tot die selsiklus beantwoord kan word deur van wiskundige modelle gebruik te maak en die probleme in die nuut-ontwikkelde metaboliese kontrole analise raamwerk te giet.

O objetivo dessa pesquisa foi avaliar aspectos genéticos que relacionados à produção in vitro de embriões na raça Guzerá. O primeiro estudo focou na estimação de (co) variâncias genéticas e fenotípicas em características relacionadas a produção de embriões e na detecção de possível associação com a idade ao primeiro parto (AFC). Foi detectada baixa e média herdabilidade para características relacionadas à produção de oócitos e embriões. Houve fraca associação genética entre características ligadas a reprodução artificial e a idade ao primeiro parto. O segundo estudo avaliou tendências genéticas e de endogamia em uma população Guzerá no Brasil. Doadoras e embriões produzidos in vitro foram considerados como duas subpopulações de forma a realizar comparações acerca das diferenças de variação anual genética e do coeficiente de endogamia. A tendência anual do coeficiente de endogamia (F) foi superior para a população geral, sendo detectado efeito quadrático. No entanto, a média de F para a sub- população de embriões foi maior do que na população geral e das doadoras. Foi observado ganho genético anual superior para a idade ao primeiro parto e para a produção de leite (305 dias) entre embriões produzidos in vitro do que entre doadoras ou entre a população geral. O terceiro estudo examinou os efeitos do coeficiente de endogamia da doadora, do reprodutor (usado na fertilização in vitro) e dos embriões sobre resultados de produção in vitro de embriões na raça Guzerá. Foi detectado efeito da endogamia da doadora e dos embriões sobre as características estudadas. O quarto (e último) estudo foi elaborado para comparar a adequação de modelos mistos lineares e generalizados sob método de Máxima Verossimilhança Restrita (REML) e sua adequação a variáveis discretas. Quatro modelos hierárquicos assumindo diferentes distribuições para dados de contagem encontrados no banco. Inferência foi realizada com base em diagnósticos de resíduo e comparação de razões entre componentes de variância para os modelos em cada variável. Modelos Poisson superaram tanto o modelo linear (com e sem transformação da variável) quanto binomial negativo à qualidade do ajuste e capacidade preditiva, apesar de claras diferenças observadas na distribuição das variáveis. Entre os modelos testados, a pior qualidade de ajuste foi obtida para o modelo linear mediante transformação logarítmica (Log10 X +1) da variável resposta. / The objective of this research was to evaluate genetic aspects permeating in vitro embryo production in Guzerá cattle. The first study aimed for estimating genetic and phenotypic (co)variances among embryo production traits and detecting possible genetic association with the age at first calving (AFC). Low and medium heritabilities were detected for oocyte and embryo production traits. A weak genetic association between artificial reproduction traits and AFC was identified. The second study evaluated genetic and inbreeding trends in the Brazilian Guzerá population. Female donors and in vitro produced embryos were considered as two subpopulations in order to perform comparisons and infer over differences in inbreeding and genetic annual variations. Embryos\' subpopulation showed higher genetic gains for age at first calving and milk production than donors\' subpopulation and the general population. Higher annual mean inbreeding values were also detected for the embryos\' subpopulation. The third study examined the effects of donor, sire (used for in vitro fertilization) and embryos\' inbreeding coefficient over in vitro embryo production traits in Guzerá cattle. Donors\' and embryos\' inbreeding effects over the analyzed traits were detected. Fourth and final study was designed to compare the performance of Linear and Generalized Linear Mixed Models under Restricted Maximum Likelihood method when fitting discrete variables. Four hierarchical models assuming different distributions for the response variable were fit to the (count) data. Inference was performed upon residual diagnostics and comparison of variance component ratios between models within each trait. Poisson models outperformed both linear (with and without variable transformation) and negative binomial models for goodness of fit and predictive ability despite clear differences in each trait\'s distribution. Logarithmic transformation (Log10 X +1) showed lowest goodness of fit among all models tested.

<p>The MIUU mesoscale model was further developed, in order to include information on large-scale atmospheric fields from global or regional atmospheric climate- and weather-prediction models. For this purpose, a new lateral boundary condition was developed and implemented into the model. The new lateral boundary condition is a combination of two existing conditions, namely the flow relaxation scheme and the tendency modification scheme.</p><p>Tests indicated that an optimum lateral boundary configuration would be obtained with moderate to strong flow relaxation at higher levels, small flow relaxation at lower levels (within the atmospheric boundary layer), upstream advection at the outermost 4 grid points, and 6% horizontal grid stretching starting at a substantial distance from the lateral boundaries. The flow relaxation coefficients should be specified carefully, in order to minimize the reflection of all kinds of waves at the lateral boundaries.</p><p>The summer thermal low in the mean-sea-level pressure field over North America is traditionally analyzed over the northern end of the Gulf of California. The position of this low is influenced by the application of the so-called plateau correction in obtaining mean-sea-level pressure values from highly elevated stations in North America. A model study indicated that the low should be located approximately 450 km to the north and somewhat to the east of the above location. </p><p>A statistical comparison of model results from two mesoscale models against upper-air and surface measurements from several sites was carried out. Statistical methods, however, give only an insufficient picture of overall model performance. A comparison between predicted and measured tracer concentrations could be used to better evaluate the overall performance of different models.</p><p>Sound propagation in the atmosphere was predicted in a mountain valley using a mesoscale atmospheric model together with a sound propagation model. This suggests that forecasts of sound propagation should be possible in future.</p>

The MIUU mesoscale model was further developed, in order to include information on large-scale atmospheric fields from global or regional atmospheric climate- and weather-prediction models. For this purpose, a new lateral boundary condition was developed and implemented into the model. The new lateral boundary condition is a combination of two existing conditions, namely the flow relaxation scheme and the tendency modification scheme. Tests indicated that an optimum lateral boundary configuration would be obtained with moderate to strong flow relaxation at higher levels, small flow relaxation at lower levels (within the atmospheric boundary layer), upstream advection at the outermost 4 grid points, and 6% horizontal grid stretching starting at a substantial distance from the lateral boundaries. The flow relaxation coefficients should be specified carefully, in order to minimize the reflection of all kinds of waves at the lateral boundaries. The summer thermal low in the mean-sea-level pressure field over North America is traditionally analyzed over the northern end of the Gulf of California. The position of this low is influenced by the application of the so-called plateau correction in obtaining mean-sea-level pressure values from highly elevated stations in North America. A model study indicated that the low should be located approximately 450 km to the north and somewhat to the east of the above location. A statistical comparison of model results from two mesoscale models against upper-air and surface measurements from several sites was carried out. Statistical methods, however, give only an insufficient picture of overall model performance. A comparison between predicted and measured tracer concentrations could be used to better evaluate the overall performance of different models. Sound propagation in the atmosphere was predicted in a mountain valley using a mesoscale atmospheric model together with a sound propagation model. This suggests that forecasts of sound propagation should be possible in future.

This paper considers the problem of model uncertainty associated with variable selection and specification of the spatial weight matrix in spatial growth regression models in general and growth regression models based on the matrix exponential spatial specification in particular. A natural solution, supported by formal probabilistic reasoning, is the use of Bayesian model averaging which assigns probabilities on the model space and deals with model uncertainty by mixing over models, using the posterior model probabilities as weights. This paper proposes to adopt Bayesian information criterion model weights since they have computational advantages over fully Bayesian model weights. The approach is illustrated for both identifying model covariates and unveiling spatial structures present in pan-European growth data. (authors' abstract) / Series: Department of Economics Working Paper Series

There is a demand for decision support tools that can model the electricity markets and allows to forecast the hourly electricity price. Many different ap- proach such as artificial neural network or support vector regression are used in the literature. This thesis provides comparison of several different estima- tors under one settings using available data from Czech electricity market. The resulting comparison of over 5000 different estimators led to a selection of several best performing models. The role of historical weather data (temper- ature, dew point and humidity) is also assesed within the comparison and it was found that while the inclusion of weather data might lead to overfitting, it is beneficial under the right circumstances. The best performing approach was the Lasso regression estimated using modified Lars. 1

La température de l'eau joue un rôle majeur dans le cycle de vie des poissons. Dans un contexte de changement climatique global, le réchauffement peut avoir un impact fort sur la croissance, la fécondité et la survie. L'enjeu de cette thèse est la modélisation mathématique de l'influence de la température sur les traits d'histoire de vie d'une population de chabot (Cottus gobio) afin de faire de la prédiction à la fois au niveau individuel et populationnel. Les données expérimentales qui permettront de calibrer les modèles sont issues du bassin de la Drôme (France) et plus particulièrement du sous-bassin du Bez. Dans une première étape, il s'agit de développer un modèle de rétrocalcul qui peut être utilisé pour calculer les longueurs individuelles des chabots aux âges précédents à partir des données mesurées à la capture. Il s'agit, dans un deuxième temps, de développer un modèle de croissance dépendant de la température de l'eau qui sert à prédire la longueur moyenne des chabots à un âge donné. Enfin, il s'agit de passer de l'échelle de l'individu à celle de la population en prenant en compte tous les traits d'histoire de vie et leurs dépendances vis-à-vis de la température. Plus précisément, un modèle matriciel de type Leslie, à la fois dépendant du temps et de la température, structuré en classe d'âges est développé et utilisé pour prédire la dynamique de population sous différents scénario du réchauffement climatique / Water temperature plays a key role in the life cycle of fish. Therefore, increasing temperatures due to the expected climate change may have a strong impact on growth, fecundity and survival. The goal of this thesis is to model the impact of temperature on the life-history traits of a bullhead population (Cottus gobio) in order to make predictions both at individual and at population level. The models developed here are calibrated on experimental field data from a population living in the Bez River network (Drôme, France). First, a new back-calculation model is derived that can be used to compute individual fish body lengths at earlier ages from capture data. Next, a growth model is proposed that incorporates the water temperature and can be used to predict the mean length at a given age and temperature. Finally, the population is modelled as a whole by linking all life-history traits to temperature. For this purpose, a spatialised time- and temperature-dependent Leslie matrix model structured in age classes was used to predict the population dynamics under different temperature scenarios

O objetivo dessa pesquisa foi avaliar aspectos genéticos que relacionados à produção in vitro de embriões na raça Guzerá. O primeiro estudo focou na estimação de (co) variâncias genéticas e fenotípicas em características relacionadas a produção de embriões e na detecção de possível associação com a idade ao primeiro parto (AFC). Foi detectada baixa e média herdabilidade para características relacionadas à produção de oócitos e embriões. Houve fraca associação genética entre características ligadas a reprodução artificial e a idade ao primeiro parto. O segundo estudo avaliou tendências genéticas e de endogamia em uma população Guzerá no Brasil. Doadoras e embriões produzidos in vitro foram considerados como duas subpopulações de forma a realizar comparações acerca das diferenças de variação anual genética e do coeficiente de endogamia. A tendência anual do coeficiente de endogamia (F) foi superior para a população geral, sendo detectado efeito quadrático. No entanto, a média de F para a sub- população de embriões foi maior do que na população geral e das doadoras. Foi observado ganho genético anual superior para a idade ao primeiro parto e para a produção de leite (305 dias) entre embriões produzidos in vitro do que entre doadoras ou entre a população geral. O terceiro estudo examinou os efeitos do coeficiente de endogamia da doadora, do reprodutor (usado na fertilização in vitro) e dos embriões sobre resultados de produção in vitro de embriões na raça Guzerá. Foi detectado efeito da endogamia da doadora e dos embriões sobre as características estudadas. O quarto (e último) estudo foi elaborado para comparar a adequação de modelos mistos lineares e generalizados sob método de Máxima Verossimilhança Restrita (REML) e sua adequação a variáveis discretas. Quatro modelos hierárquicos assumindo diferentes distribuições para dados de contagem encontrados no banco. Inferência foi realizada com base em diagnósticos de resíduo e comparação de razões entre componentes de variância para os modelos em cada variável. Modelos Poisson superaram tanto o modelo linear (com e sem transformação da variável) quanto binomial negativo à qualidade do ajuste e capacidade preditiva, apesar de claras diferenças observadas na distribuição das variáveis. Entre os modelos testados, a pior qualidade de ajuste foi obtida para o modelo linear mediante transformação logarítmica (Log10 X +1) da variável resposta. / The objective of this research was to evaluate genetic aspects permeating in vitro embryo production in Guzerá cattle. The first study aimed for estimating genetic and phenotypic (co)variances among embryo production traits and detecting possible genetic association with the age at first calving (AFC). Low and medium heritabilities were detected for oocyte and embryo production traits. A weak genetic association between artificial reproduction traits and AFC was identified. The second study evaluated genetic and inbreeding trends in the Brazilian Guzerá population. Female donors and in vitro produced embryos were considered as two subpopulations in order to perform comparisons and infer over differences in inbreeding and genetic annual variations. Embryos\' subpopulation showed higher genetic gains for age at first calving and milk production than donors\' subpopulation and the general population. Higher annual mean inbreeding values were also detected for the embryos\' subpopulation. The third study examined the effects of donor, sire (used for in vitro fertilization) and embryos\' inbreeding coefficient over in vitro embryo production traits in Guzerá cattle. Donors\' and embryos\' inbreeding effects over the analyzed traits were detected. Fourth and final study was designed to compare the performance of Linear and Generalized Linear Mixed Models under Restricted Maximum Likelihood method when fitting discrete variables. Four hierarchical models assuming different distributions for the response variable were fit to the (count) data. Inference was performed upon residual diagnostics and comparison of variance component ratios between models within each trait. Poisson models outperformed both linear (with and without variable transformation) and negative binomial models for goodness of fit and predictive ability despite clear differences in each trait\'s distribution. Logarithmic transformation (Log10 X +1) showed lowest goodness of fit among all models tested.

Parmi les méthodes qui permettent de détecter des exoplanètes, la photométrie des transits est celle qui a connu le plus grand essor ces dernières années grâce à l’arrivée des télescopes spatiaux CoRoT (en 2006) puis Kepler (en 2009). Ces deux satellites ont permis de détecter des milliers de transits potentiellement planétaires. Étant donnés leur nombre et l’effort nécessaire à la confirmation de leur nature, il est essentiel d’effectuer, à partir des données photométriques, un classement efficace permettant d’identifier les transits les plus prometteurs et qui soit réalisable en un temps raisonnable. Pour ma thèse, j’ai développé un outil logiciel, rapide et automatisé, appelé BART (Bayesian Analysis for the Ranking of Transits) qui permet de réaliser un tel classement grâce une estimation de la probabilité que chaque transit soit de nature planétaire. Pour cela, mon outil s’appuie notamment sur le formalisme bayésien des probabilités et l’exploration de l’espace des paramètres libres par méthode de Monte Carlo avec des chaînes de Markov (mcmc).Une fois les exoplanètes détectées, l’étape suivante consiste à les caractériser. L’étude du système solaire nous a démontré, si cela était nécessaire, que l’information spectrale est un point clé pour comprendre la physique et l’histoire d’une planète. L’interférométrie annulante est une solution technologique très prometteuse qui pourrait permettre cela. Pour ma thèse, j’ai travaillé sur le banc optique Nulltimate afin d’étudier la faisabilité de certains objectifs technologiques liés à cette technique. Au-delà de la performance d’un taux d’extinction de 3,7.10^-5 en monochromatique et de 6,3.10^-4 en polychromatique dans l’infrarouge proche, ainsi qu’une stabilité de σN30 ms = 3,7.10^-5 estimée sur 1 heure, mon travail a permis d’assainir la situation en réalisant un budget d’erreur détaillé, une simulation en optique gaussienne de la transmission du banc et une refonte complète de l’informatique de commande. Tout cela m’a finalement permis d’identifier les faiblesses de Nulltimate. / From all exoplanet detection methods, transit photometry went through the quickest growth over the last few years thanks to the two space telescopes, CoRoT (in 2006) and Kepler (in 2009). These two satellites have identified thousands of potentially planetary transits. Given the number of detected transits and the effort required to demonstrate their natures, it is essential to perform, from photometric data only, a ranking allowing to efficiently identify the most promising transits within a reasonable period of time. For my thesis, I have developed a quick and automated software called bart (Bayesian Analysis for the Ranking of Transits) which realizes such a ranking thanks to the estimation of the probability regarding the planetary nature of each transit. For this purpose, I am relying on the Bayesian framework and free parameter space exploration with Markov Chain Monte Carlo (mcmc) methods.Once you have detected exoplanets, the following step is to characterise them. The study of the solar system demonstrated, if it was necessary, that the spectral information is a crucial clue for the understanding of the physics and history of a planet. Nulling interferometry is a promising solution which could make this possible. For my thesis, I worked on the optical bench Nulltimate in order to study the feasibility of certain technological requirements associated with this technique. Beyond the obtention of a nulling ratio of 3,7.10^-5 in monochromatic light and 6,3.10^-4 in polychromatic light in the near infrared, as well as a stability of σN30 ms = 3,7.10^-5 estimated on 1 hour, my work allowed to clarify the situation thanks to a detailed error budget, a simulation of the transmission based on Gaussian beam optics and a complete overhaul of the computer control system. All of this finally resulted in the identification of the weaknesses of Nulltimate.