The mechanisms that control growth processes in biology tissues have attracted continuous research interest despite their complexity. With the emergence of big data experimental approaches there is an urgent need to develop statistical and computational models to fit the experimental data and that can be used to make predictions to guide future research. In this work we apply statistical methods on growth process of different biological tissues, focusing on development of neuron dendrites and tumor cells. We first examine the neuron cell growth process, which has implications in neural tissue regenerations, by using a computational model with uniform branching probability and a maximum overall length constraint. One crucial outcome is that we can relate the parameter fits from our model to real data from our experimental collaborators, in order to examine the usefulness of our model under different biological conditions. Our methods can now directly compare branching probabilities of different experimental conditions and provide confidence intervals for these population-level measures. In addition, we have obtained analytical results that show that the underlying probability distribution for this process follows a geometrical progression increase at nearby distances and an approximately geometrical series decrease for far away regions, which can be used to estimate the spatial location of the maximum of the probability distribution. This result is important, since we would expect maximum number of dendrites in this region; this estimate is related to the probability of success for finding a neural target at that distance during a blind search. We then examined tumor growth processes which have similar evolutional evolution in the sense that they have an initial rapid growth that eventually becomes limited by the resource constraint. For the tumor cells evolution, we found an exponential growth model best describes the experimental data, based on the accuracy and robustness of models. Furthermore, we incorporated this growth rate model into logistic regression models that predict the growth rate of each patient with biomarkers; this formulation can be very useful for clinical trials. Overall, this study aimed to assess the molecular and clinic pathological determinants of breast cancer (BC) growth rate in vivo.

L'arthrose (OA) est une maladie articulaire dégénérative, classée comme la forme la plus fréquente au monde. Elle est caractérisée par la dégénérescence du cartilage articulaire, l’inflammation de la membrane synoviale, et le remodelage de l’os sous-chondral. Ces changements structurels et fonctionnels sont dues à de nombreux facteurs. Les cytokines, les prostaglandines (PG), et les espèces réactives de l'oxygène sont les principaux médiateurs impliqués dans la pathophysiologie de l'OA. L'interleukine-1β (IL-1β) est une cytokine pro-inflammatoire majeure qui joue un rôle crucial dans l'OA. L'IL-1β induit l'expression de la cyclooxygénase-2 (COX-2), la microsomale prostaglandine E synthase-1 (mPGES-1), la synthase inductible de l'oxyde nitrique (iNOS), ainsi que leurs produits la prostaglandine E2 (PGE2) et l'oxyde nitrique (NO). Ce sont des médiateurs essentiels de la réponse inflammatoire au cours de l'OA qui contribuent aux mécanismes des douleurs, de gonflement, et de destruction des tissus articulaires. Les modifications épigénétiques jouent un rôle très important dans la régulation de l’expression de ces gènes pro-inflammatoires. Parmi ces modifications, la méthylation/ déméthylation des histones joue un rôle critique dans la régulation des gènes. La méthylation/ déméthylation des histones est médiée par deux types d'enzymes: les histones méthyltransférases (HMT) et les histones déméthylases (HDM) qui favorisent l’activation et/ou la répression de la transcription. Il est donc nécessaire de comprendre les mécanismes moléculaires qui contrôlent l’expression des gènes de la COX-2, la mPGES-1, et l’iNOS. L'objectif de cette étude est de déterminer si la méthylation/déméthylation des histones contribute à la régulation de l’expression des gènes COX-2, mPGES-1, et iNOS dans des chondrocytes OA humains induits par l'IL-1β. Nous avons montré que la méthylation de la lysine K4 de l'histone H3 (H3K4) par SET-1A contribue à l’activation des gènes COX-2 et iNOS dans les chondrocytes humains OA induite par l'IL-1β. Nous avons également montré que la lysine K9 de l’histone H3 (H3K9) est déméthylée par LSD1, et que cette déméthylation contribue à l’expression de la mPGES-1 induite par IL-1β dans les chondrocytes humains OA. Nous avons aussi trouvé que les niveaux d'expression des enzymes SET-1A et LSD1 sont élevés au niveau du cartilage OA. Nos résultats montrent, pour la première fois, l'implication de la méthylation/ déméthylation des histones dans la régulation de l’expression des gènes COX-2, mPGES-1, et iNOS. Ces données suggèrent que ces mécanismes pourraient être une cible potentielle pour une intervention pharmacologique dans le traitement de la physiopathologie de l'OA. / Osteoarthritis (OA) is a disabling disease classified as the most common form of arthritis worldwide. It is characterized by cartilage degeneration, synovium inflammation, and subchondral bone remodeling resulting in a loss of joint function. These structural and functional changes are due to numerous factors. Cytokines, prostaglandins (PG), and reactive oxygen species are the major mediators implicated in the pathophysiology of OA. Interleukin-1 (IL-1) is a major pro-inflammatory cytokine that plays a crucial role in OA. IL-1 induces the expression of Cyclo-oxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), inducible nitric oxide synthase (iNOS), as well as their products prostaglandin E2 (PGE2) and nitric oxide (NO). These are critical mediators of the inflammatory response during OA causing pain, swelling, and joint tissue destruction. The activation of these pro-inflammatory genes results from different changes at the level of chromatin known as epigenetic modifications. Epigenetic modifications such as DNA methylation and histone modifications play a crucial role in gene expression. Among these modifications, histone methylation/demethylation is the most critical one. Histone methylation/demethylation is mediated by two types of enzymes: histone methyltransferases (HMT) and histone demethylases (HDM) which can either activate or repress transcription. It is therefore necessary to understand the molecular mechanisms which underlie the regulation of COX-2, mPGES-1, and iNOS expression. The objective of this study is to investigate whether histone methylation/demethylation can modulate COX-2, mPGES-1, and iNOS expression in IL-1 induced OA human chondrocytes. We demonstrated that histone H3 lysine K4 (H3K4) methylation by SET-1A contributes to IL-1-induced COX-2 and iNOS expression in human OA Chondrocytes. We showed also that LSD1-mediated demethylation of histone H3 lysine 9 (H3K9) contributes to IL-1β-induced mPGES-1 expression in human OA chondrocytes. We found that levels of SET-1A and LSD1 expression are elevated in OA cartilage as compared with normal cartilage. Our data demonstrates, for the first time, the implication of histone methylation/demethylation in COX-2, mPGES-1, and iNOS regulation suggesting that these mechanisms could be a potential target for pharmacological intervention in the treatment of the pathophysiology of OA.

Connaître le sexe d’un oiseau est important pour divers domaines notamment pour les vétérinaires, les écologistes ainsi que pour les éleveurs d’oiseaux qui veulent former des couples qui serviront à la reproduction. Plusieurs espèces d’oiseaux, juvéniles et adultes, n’ont pas de dimorphisme sexuel. L’utilisation de l’ADN est une façon rapide de déterminer le sexe à partir d’un échantillon de sang, de muscle, de plumes ou de fèces. Par contre, la méthode devrait être validée pour chaque espèce et idéalement, standardisée. Le premier objectif de cette étude est de développer une méthode de sexage par séquençage des oiseaux à partir des séquences du gène CHD, en utilisant les oiseaux de proie et les perroquets vus en clinique au Québec. Un deuxième objectif est de faire l’identification de l’espèce à sexer, à partir du gène mitochondrial COX-1 et aussi à partir des séquences CHD-Z et CHD-W, utilisés pour le sexage. Un troisième objectif est d’évaluer les séquences sorties (CHD-Z, CHD-W et COX-1) en vue d’une étude phylogénique. Une extraction d’ADN a été effectuée chez 27 espèces de perroquets, 34 espèces d’oiseaux de proie, une corneille (Corvus brachyrhynchos) et un poulet (Gallus gallus). Une amplification par PCR a été exécutée pour les exons partiels 23 et 24 du gène CHD. Le séquençage de cet amplicon permettait de savoir s’il s’agissait d’un mâle (séquence simple CHD-Z) ou d’une femelle (séquences CHD-Z et CHD-W qui se chevauchent). Afin d’avoir des séquences CHD-W distinctes, un sous-clonage a été fait chez les femelles de chaque espèce. De cette manière, les séquences partielles du gène CHD, Z et W, ont été trouvées pour les espèces échantillonnées. Une étude phylogénique a été effectuée avec les séquences de COX-1, CHD-Z et CHD-W grâce au site « Clustal-Omega ». La méthode de sexage des oiseaux par séquençage du gène CHD est standard et efficace. Le gène COX-1 permet une meilleure identification des espèces parentes et le gène CHD-Z est le plus utile pour étudier la phylogénie profonde. / Knowing the sex of a bird is important for many disciplines, notably for veterinary, ecological and evolutionary studies, not to mention for bird breeders who need to form pairs for reproduction. For many species of birds, juveniles and adults do not display a sexual dimorphism. The use of DNA, derived from a sample of blood, muscle, feathers or feces, is a rapid method to determine a bird’s sex. However, this method must be validated for each species, and ideally, standardised. The first objective of this work was to develop a method of sexing birds by sequencing portions of their CHD gene, for birds of prey and parrots seen in veterinary clinics in Quebec. A second objective was to identify the species being sexed, first of all using the mitochondrial gene COX-1, and second of all using the CHD-Z and CHD-W sequences used for sexing. The third objective of these studies was to evaluate the sequences obtained (CHD-Z, CHD-W and COX-1) for performing phylogenetic studies. DNA was extracted from 27 species of parrots, 34 species of birds of prey, from one species of crow (Corvus brachyrhynchos) and from the chicken (Gallus gallus). A PCR amplification was performed for partial exons 23 and 24 of the CHD gene. Sequencing this amplicon resulted in simple CHD-Z sequences for a male and overlapping CHD-Z and CHD-W sequences for a female, allowing sexing of the bird. In order to obtain distinct CHD-W sequences, a sub-cloning was performed for females of each species. In this fashion, partial sequences of the CHD gene, both -Z and –W, were generated for the species studied. A phylogenetic study was performed using COX-1, CHD-Z and CHD-W sequences and the site “Clustal-Omega”. The method of sexing birds by sequencing was found to be standard and efficient. The COX-1 gene permitted a better resolution of closely related species, while the CHD-Z gene was the most useful for estimating deep phylogenetic relationships.

Title: Models of Marked Point Processes Author: Ivan Héda Department: Department of Probability and Mathematical Statistics Supervisor: doc. RNDr. Zbyněk Pawlas, Ph.D. Abstract: In the first part of the thesis, we present necessary theoretical basics as well as the definition of functional characteristics used for examination of marked point patterns. Second part is dedicated to review some known marking strategies. The core of the thesis lays in the study of intensity-marked point processes. General formula for the characteristics is proven for this marking strategy and general class of the models with analytically computable characteristics is introduced. This class generalizes some known models. Theoretical results are used for real data analysis in the last part of the thesis. Keywords: marked point process, marked log-Gaussian Cox process, intensity-marked point process 1

The subject of this thesis are selected interest rate models and valuation of interest rate derivatives, especially interest rate options. Time-homogeneous one-factor short rate models, Vasicek and Cox-Ingersoll-Ross, and time-inhomogeneous short rate model, Hull{White, are treated. Heath-Jarrow-Morton framework is introduced as an alternative to short rate models, evolving the entire term structure of interest rates. The short rate models are shown to be special cases of models within the framework. The models are derived using the risk-neutral pricing methodology.

[pt] Esta dissertação tem como objetivo propor uma abordagem pouco utilizada na área financeira para prever cancelamentos em planos de previdência privada. Métodos e modelos provenientes da análise de sobrevivência foram utilizados para prever o cancelamento, além de estimar o risco associado de o cliente cancelar. Os modelos propostos, modelo de regressão paramétrico e modelo de riscos proporcionais de Cox, foram estimados utilizando-se uma base de dados de clientes acompanhados durante um período de 6 anos e meio de uma seguradora nacional. Os modelos mostraram-se equivalentes, tendo capacidade de generalização de 58 por cento. / [en] This paper aims to propose an approach rarely used in finance to predict cancellations in private pension plans. Methods and models from survival analysiswere used to predict the cancellation and estimate the risk associated with the cliente cancellation. The proposed models, regression model and parametric proportional hazards model of Cox, were estimated using a database of customers followed for a period of 6 and a half years of a national insurer. The models showed equivalence and generalizability of 58 per cent.

Survival analysis is an effective tool for conservation studies, since it measure the risk of an event that is important for the survival of populations and preservation of biodiversity. In this thesis three different models for survival analysis are used to estimate the age at breeding between two genetically different populations of brown trout. These populations are an evolutionary enigma, since they apparently coexist in direct competition with each other, which according to ecological theory should not happen. Thus it is of interest if differences between them can be identified. The data consists of brown trouts and has been collected over 20 years. The models are the Cox Proportional Hazards model, the Complementary Log-Log Link model and the Log Logistic Accelerated Failure-Time model. The Cox model were estimated in three different ways due to the nonproportional hazards in the estimates of time to breeding, which gave different interpretations of the same model. All of the models agree that the population B breed at younger ages than the population A, which suggests that the two populations have different reproductive strategies.

Submitted by PPG Economia do desenvolvimento (economia-pg@pucrs.br) on 2017-12-19T18:30:22Z No. of bitstreams: 1 CARLOS_HERNAN_RODAS_CESPEDES_TES.pdf: 1347334 bytes, checksum: 034f22126306c06c90f7f135fc0970f5 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-12-26T16:25:24Z (GMT) No. of bitstreams: 1 CARLOS_HERNAN_RODAS_CESPEDES_TES.pdf: 1347334 bytes, checksum: 034f22126306c06c90f7f135fc0970f5 (MD5) / Made available in DSpace on 2017-12-26T16:31:46Z (GMT). No. of bitstreams: 1 CARLOS_HERNAN_RODAS_CESPEDES_TES.pdf: 1347334 bytes, checksum: 034f22126306c06c90f7f135fc0970f5 (MD5) Previous issue date: 2017-12-01 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / (Ensaio I) This study investigates the demographics of companies at Rio Grande do Sul State from 2006 to 2013. First, the birth, mortality and turnover of companies are quantified, as well as their survival over time. Then, these demographic events are analyzed by size, economic activity, and geographic location. For this purpose, an identified database is used, which allows the longitudinal monitoring of all formal companies existing in Rio Grande do Sul over the period under study. (Ensaio II) This paper proposes an empirical research on the survival of the companies of Rio Grande do Sul State for the period 2007-2013. The Kaplan-Meier procedure is applied to obtain the functions of survival of the companies, according to the geographic location, the economic activity and the size. Then, the Cox procedure is applied, in order to determine the effect of the size of the companies on the survival time. The results obtained show that survival is relatively higher: in the companies with the largest number of employed persons; in the manufacturing industry and financial activities; and located in the Northeast region of Rio Grande do Sul state. (Ensaio III) The objective of this paper is to analyze the birth of companies in the counties of Rio Grande do Sul State between 2007 and 2013. For this, exploratory analysis of spatial data and the panel data regression are used. The results indicated the existence of spatial autocorrelation of the birth of companies and the formation of some clusters of the counties with high births of companies. The spatial auto regression (SAR) model evidenced the spillover effect of the birth of companies and made it possible to measure the direct and indirect impacts of the independent variables on the birth of companies. / (Ensaio I) Este estudo investiga a demografia de empresas do Rio Grande do Sul no per?odo de 2006 a 2013. Primeiro ? quantificado o nascimento, a mortalidade e a rotatividade de empresas, al?m da sobreviv?ncia delas ao longo do tempo. Depois, esses eventos demogr?ficos s?o analisados segundo o tamanho, o setor e a localiza??o geogr?fica das empresas. Para tanto, utiliza-se uma base de dados identificada, que possibilita o acompanhamento longitudinal de todas as empresas formais existentes no Rio Grande do Sul ao longo do per?odo em estudo. (Ensaio II) Este trabalho prop?e uma pesquisa emp?rica sobre a sobreviv?ncia das empresas do Rio Grande do Sul para o per?odo 2007-2013. ? aplicado o procedimento de Kaplan-Meier para obter as fun??es de sobreviv?ncia das empresas, conforme o local, a atividade econ?mica e o tamanho. Da mesma forma, aplica-se o procedimento de Cox, com a finalidade de determinar o efeito do tamanho das empresas sobre o tempo de sobreviv?ncia. Os resultados obtidos mostram que a sobreviv?ncia ? relativamente maior: nas empresas com maior numero de pessoas ocupadas; no setor da ind?stria de transforma??o e atividades financeiras; e localizadas na regi?o Nordeste do Rio Grande do Sul. (Ensaio III) O objetivo deste ensaio ? analisar o nascimento de empresas nos munic?pios do Rio Grande do Sul no per?odo entre 2007 e 2013. Para isso, utilizam-se procedimentos da an?lise explorat?ria de dados espaciais e regress?o em painel espacial. Os resultados indicaram a exist?ncia de autocorrela??o espacial do nascimento de empresas e a forma??o de alguns clusters de munic?pios com altos nascimentos de empresas. O modelo de autorregress?o espacial (SAR) evidenciou o efeito transbordamento do nascimento de empresas e possibilitou a mensura??o dos impactos diretos e indiretos das vari?veis independentes sobre o nascimento de empresas.

Nous montrons pour la première fois qu’en plus de la MAPK ERK1/2, l’endothéline-1 (ET-1) via les récepteurs ETA et ETB active une autre MAP kinase : la p38 uniquement dans les cellules de léiomyomes utérins de rate (ELT3) mais pas dans les cellules myométriales saines. Dans les cellules ELT3, l’analyse des voies de signalisation montre que malgré les similitudes observées entre les modes d’activation des voies p38 et ERK1/2 par ET-1, celles-ci sont activées de façon indépendante l’une de l’autre. En plus, la forskoline active p38 (mais pas ERK1/2), par contre l’activation de p38 par ET-1 n’implique pas une production d’AMPc. Par ailleurs ERK1/2 et p38 coactivées par ET-1 coopèrent pour augmenter l’expression de COX2 et la production des prostaglandines E2 (PGE2) pour favoriser l’effet antiapoptotique de ET-1. De plus p38 activée par ET-1 contribue à la prolifération des léiomyomes. Nos résultats élucident les mécanismes par lesquels ET-1 contribue à la croissance des léiomyomes. / We demonstrated for the first time, that in addition to the MAPK ERK1/2, Endothelin-1 (ET-1) through ETA and ETB receptors activated another MAP kinase: p38 only in uterine leiomyoma cells (ELT3) but not in normal myometrial cells. In ELT3 cells, analysis of signaling pathways showed that, despite the similarities between the mechanisms involved in the activation of p38 and ERK1/2 pathways by ET-1, these kinases are activated independently one of another. In addition, forskolin (a cAMP inducer), activated p38 (but not ERK1/2), whereas the activation of p38 by ET-1 did not involve production cAMP. Moreover the coactivated ERK1/2 and p38 pathways by ET-1 cooperated to increase expression of COX2 and prostaglandin E2 (PGE2) production. This PGE2 like ET-1 exerted an antiapoptotic effect in ELT3 cells. Furthermore, p38 activated by ET-1 contributes to the proliferation of ELT3 leiomyoma cells. Our data highlight the mechanisms by which ET-1 could promote uterine leiomyoma growth.

Nesta tese são desenvolvidos três estudos sobre o risco associado aos acidentes de trânsito, com o objetivo de avaliar como a população o percebe, e o valor que estaria disposta a pagar para reduzi-lo. As análises foram feitas com duas diferentes metodologias econométricas e dois diferentes conjuntos de dados da população de Porto Alegre. O primeiro estudo procurou avaliar que fatores de risco contribuem para aumentar a gravidade dos acidentes de trânsito, utilizando dados de acidentes de trânsito ocorridos na cidade de Porto Alegre no período 2000-2008, através de modelos logit ordenados generalizados. Os resultados indicam que a maioria das vítimas feridas em acidentes de trânsito são condutores jovens, do sexo masculino e que estavam em motocicletas ou cujo acidente foi um choque contra obstáculos. Contudo, as vítimas fatais têm maior probabilidade de morte são os pedestres, com mais de 60 anos de idade. Os acidentes com maior gravidade ocorrem em maior proporção a noite ou finais de semana, em locais mais afastados do centro da cidade, o que sugere comportamento associado à alta velocidade e uso de substâncias psicoativas como álcool. Para os demais estudos utilizaram-se dados de um survey feito com a população de Porto Alegre em 2009. O segundo estudo avalia como as características sócio-demográficas, a experiência no trânsito e a informação recebida, afetam a percepção do risco e o comportamento no trânsito. Os resultados indicam que os indivíduos que tem risco maior de morte no trânsito subestimam seu próprio risco e vice-versa; e que os mais jovens têm maior percepção deste risco, assim como os que tiveram experiência de acidente de trânsito ou passam mais tempo expostos a ele. O risco do consumo de bebidas alcoólicas associado ao trânsito, no entanto é percebido maior pelos idosos, mulheres, não bebedores ou quem não tem comportamento de risco, assim como pelos que têm mais informação do risco. Da mesma maneira, o comportamento de risco no trânsito associado ao consumo de álcool está negativamente relacionado a percepção deste risco e a idade. O terceiro estudo estimou a disposição a pagar ( ) dos entrevistados pela redução no seu próprio risco de sofrer lesões em um acidente de trânsito e o valor de uma vida estatística ( ), utilizando modelos lineares e não-lineares ajustados através de uma transformação Box-Cox. Os resultados indicam que a esta relacionada de forma decrescente com a idade e com a não utilização de dispositivos de segurança, mas aumenta com a renda, o tempo de exposição ao trânsito, a experiência com acidentes, para as mulheres e para os que têm dependentes. O valor médio eliciado da para reduzir a zero o risco das lesões mais graves, que resultam em morte, implicou em de cerca de R$ 13,4 milhões (US$7,3 milhões) - valor menor, porém comparável ao encontrado para países desenvolvidos e em estudo para o Brasil. / This thesis develops three studies on the risk associated with traffic accidents, in order to assess how people perceive it and the value they would be willing to pay to reduce it. The analysis was made with two different econometric methods and two different sets of data from Porto Alegre's population. The first study to assess at risk factors that contribute to increased severity of accidents, using data obtained from traffic accidents in the city of Porto Alegre between the years 2000 and 2008, and applying the generalized ordered logit. The results indicate that most of the victims injured in accidents are young drivers, males, motorcyclists and whose crash was a “collision with obstacles”. However, fatal victims have a different profile: they are pedestrians, over 60 years old. The most serious accidents occur in greater proportions at nights or weekends, at locations further away from the city center, which suggests behavior associated with high speed driving and the use of psychoactive substances, such as alcohol. The other two studies used data from a survey done with the population of Porto Alegre in 2009. The second study evaluates how socio-demographic characteristics, traffic experience and the information received about the risks of driving under the influence of alcohol, affect risk perception and behavior in the traffic. The results indicate that individuals who have greater risk of dying in traffic, underestimate their own risk and vice versa; and that young people as well as those who have been in an accident or those who spend a lot of time in traffic, have a greater perception of their risk. On the other hand, the risk of alcohol consumption associated with traffic, is perceived better by older people, women, non-drinkers, people without risky behavior, and those who are more aware of the risks of driving under the influence of alcohol. Similarly, risky behavior in traffic, related to alcohol consumption, is inversely proportional to perception of risk and to age. The third study estimated the respondents' willingness to pay ( ) for the reduction in their risk of suffering injuries in a traffic accident, as well as the value of a statistical life ( ), using linear and nonlinear models adjusted by the Box-Cox transformation. The results indicate that the decreases with age and with not using safety devices, but increases with income, exposure to traffic, and the accidents experience, for women and for those who have dependents. The average value elicited by to reduce to zero the risk of severe injuries that result in death, implied a of about R$13.4 million (US$ 7.3 million) - lower, but still a comparable value to that found in developed countries, and studied in Brazil.