Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

This paper explores the fit of a stochastic volatility model, in which the Box-Cox transformation of the squared volatility follows an autoregressive Gaussian distribution, to the continuously compounded daily returns of the Australian stock index. Estimation was difficult, and over-fitting likely, because more variables are present than data. We developed a revised model that held a couple of these variables fixed and then, further, a model which reduced the number of variables significantly by grouping trading days. A Metropolis-Hastings algorithm was used to simulate the joint density and derive estimated volatilities. Though autocorrelations were higher with a smaller Box-Cox transformation parameter, the fit of the distribution was much better.

Oxidative phosphorylation apparatus (OXPHOS) is responsible for production of majority of ATP in mammalian organisms. This process, occurring in the inner mitochondrial membrane, is partly regulated by nuclear-encoded subunits of cytochrome c oxidase (COX), the terminal enzyme of electron transport chain. Cox4 subunit, participating in OXPHOS regulation, is an early-assembly state subunit, which is necessary for incorporation of Cox2 catalytic subunit, thus for assembly of catalytically functional COX enzyme. Moreover, regulated expression of two isoforms (Cox4i1, Cox4i2) of Cox4 subunit is hypothesized to optimize respiratory chain function according to tissue oxygen supply. However, the functional impact of the isoform switch for mammalian tissues and cells is still only partly understood. In the present thesis, unique HEK293 cell line-based model with complete absence of subunit Cox4 (knock-out, KO) was prepared employing novel CRISPR CAS9-10A paired nickase technology and further characterized. Knock-out of both isoforms Cox4i1 and Cox4i2 (COX4i1/4i2 KO clones) showed general decrease of majority of Cox subunits resulting in total absence of fully assembled COX. Moreover, detected Complex I subunits as well as the content of assembled Complex I were decreased in COX4i1/4i2 KO clones. On the...

Resumo:As neoplasias testiculares caninas são achados ocasionais. São descritas como benignas, mas podem metastatizar ou mostrar características de malignidade com o avanço da idade do animal, o que torna necessário o melhor entendimento do comportamento destas neoplasias no cão. O objetivo deste estudo foi caracterizar a expressão imuno-histoquímica de Ki-67, COX-2, MMP-9 e p53 em neoplasias testiculares de 50 cães, verificar a relação entre o padrão histológico e raça, idade e posicionamento testicular e verificar a expressão imuno-histoquímica dos anticorpos avaliados nos diferentes tipos de neoplasia. A avaliação imuno-histoquímica das proteínas Ki-67, MMP-9 e p53 foi mais intensa nos seminomas, enquanto que os leydigocitomas exibiram maior marcação para COX-2. A avaliação histológica e imuno-histoquímica dos subtipos de seminomas em cães, particularmente o seminoma difuso, podem resultar em diferença significativa que permita a utilização destas proteínas como marcadores de prognóstico. As características histopatológicas em associação ao histórico dos animais e à expressão das proteínas estudadas podem contribuir para a caracterização do comportamento biológico nas neoplasias testiculares caninas / Abstract:testicular neoplasms are sporadic findings. They are described as benign, but they can metastasize or express malignant features with the animal ageing, which makes necessary the better understanding of theses neoplasms behavior in dogs. The aim of this study was to characterize the immunoexpression of Ki-67, COX-2, MMP-9 and p53 in testicular neoplasms of fifty dogs, to verify the relation among histological pattern of the neoplasms and breed, age and testicular localization; and also to verify the immunoexpression of these markers in different types of testicular tumours. Ki-67, MMP-9 and p53 immunostaining were more intense in seminomas, whereas COX-2 presented a more intense staining in Leydig cell tumors. The histological and immunohistochemical analyses of the subtypes of canine seminomas, especially the diffuse seminoma, may result in significant differences which would allow the use of these markers as prognostic factors. The histopathological features associated with the day-history of the animals and with these markers may contribute to the characterization of the biological behavior of canine testicular neoplasms / Orientador:Gisele Fabrino Machado / Banca:Felipe Augusto Ruiz Sueiro / Banca:Rosemary de Oliveira Vasconcelos / Mestre

This thesis focuses on two fundamental topics, specifically in medical statistics: the modelling of correlated survival datasets and the variable selection of the significant covariates and random effects. In particular, two types of survival data are considered: the classical survival datasets, where subjects are likely to experience only one type of event and the competing risks datasets, where subjects are likely to experience one of several types of event. In Chapter 2, among other topics, we highlight the importance of adding frailty terms on the proposed models in order to account for the association between the survival time and characteristics of subjects/groups. The main novelty of this thesis is to simultaneously select fixed effects and frailty terms through the proposed statistical models for each survival dataset. Chapter 3 covers the analysis of the classical survival dataset through the proposed Cox Proportional Hazard (PH) model. Utilizing a Cox PH frailty model, may increase the dimension of variable components and estimation of the unknown coefficients becomes very challenging. The method proposed for the analysis of classical survival datasets involves simultaneous variable selection on both fixed effects and frailty terms through penalty functions. The benefit of penalty functions is that they identify the non-significant parameters and set them to have a zero effect in the model. Hence, the idea is to 'doubly-penalize' the partial likelihood of the Cox PH frailty model; one penalty for each term. Estimation and selection implemented through Newton-Raphson algorithms, whereas closed iterative forms for the estimation and selection of fixed effects and prediction of frailty terms were obtained. For the selection of frailty terms, penalties imposed on their variances since frailties are random effects. Based on the same idea, we further extend the simultaneous variable selection in the competing risks datasets in Chapter 4, using extended cause-specific frailty models. Two different scenarios are considered for frailty terms; in the first case we consider that frailty terms vary among different types of events (similar to the fixed effects) whereas in the second case we consider shared frailties over all the types of events. Moreover, our 'individual penalization' approach allows for one covariate to be significant for some types of events, in contrast to the frequently used 'group-penalization' where a covariate is entirely removed when it is not significant over all the events. For both proposed methods, simulation studies were conduced and showed that the proposed procedure followed for each analysis works well in simultaneously selecting and estimating significant fixed effects and frailty terms. The proposed methods are also applied to real datasets analysis; Kidney catheter infections, Diabetes Type 2 and Breast Cancer datasets. Association of the survival times and unmeasured characteristics of the subjects was studied as well as a variable selection for fixed effects and frailties implemented successfully.

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Lung cancer is the most frequent fatal cancer in the United States. Following the notion in actuarial math analysis, we assume an exponential form for the baseline hazard function and combine Cox proportional hazard regression for the survival study of a group of lung cancer patients. The covariates in the hazard function are estimated by maximum likelihood estimation following the proportional hazards regression analysis. Although the proportional hazards model does not give an explicit baseline hazard function, the baseline hazard function can be estimated by fitting the data with a non-linear least square technique. The survival model is then examined by a neural network simulation. The neural network learns the survival pattern from available hospital data and gives survival prediction for random covariate combinations. The simulation results support the covariate estimation in the survival model.

The abuse of methylenedioxymethamphetamine (MDMA) during pregnancy is of concern. MDMA treatment of rats during a period of brain growth analogous to late human gestation leads to neurochemical and behavioral changes. MDMA from postnatal day (P)11–20 in rats produces reductions in serotonin and deficits in spatial and route-based navigation. In this experiment we examined the impact of MDMA from P11 to P20 (20 mg/kg twice daily, 8 h apart) on neuronal architecture. Golgi impregnated sections showed significant changes. In the nucleus accumbens, the dendrites were shorter with fewer spines, whereas in the dentate gyrus the dendritic length was decreased but with more spines, and for the entorhinal cortex, reductions in basilar and apical dendritic lengths in MDMA animals compared with saline animals were seen. The data show that neuronal cytoarchitectural changes are long-lasting following developmental MDMA exposure and are in regions consistent with the learning and memory deficits observed in such animals.

To increase diversity of enzymes and proteins, cells mix and match exonic and intronic regions retained in mature mRNAs by alternative splicing. An estimated 94% of all multi-exon genes express one or more alternatively spliced transcripts generating proteins with similar or modified functions. Cyclooxygenase is a signaling enzyme that catalyzes the rate-limiting step in the synthesis of diverse bioactive lipids termed prostaglandins. Prostaglandins are involved in myriad physiological and pathopysiological processes including vasoregulation, stomach mucosal maintenance, parturition, pain, fever, inflammation, neoplasia and angiogenesis and are inhibited by aspirin-like drugs known as NSAIDs. In 2002 an alternatively spliced, intron-1 retaining variant of COX-1 was cloned from canine brain tissue. This new variant, termed COX-3 or COX-1b, is an enzymatically active prostaglandin synthase expressed at relatively high levels in a tissue and cell type dependant manner in all species examined. In humans and most rodent species intron-1 is 94 and 98 nucleotides long respectively. Retention of the intron in these species introduces a frameshift and is predicted to result in translation of a very small 8-16kD protein with little similarity to either 72kD COX-1 or COX-2, calling into question the role of this variant. In this dissertation, I present my results from cloning and ectopically expressing a complete and accurate COX-3 cDNA from both rat and human. I confirmed that COX-3 mRNA encodes multiple large molecular weight cyclooxygenase-like proteins in the same reading frame as COX-1. Translation of these proteins relies on several recoding mechanisms including cap-independent translation initiation, alternative start site selection, and ribosomal frameshifting. Using siRNA and Western blotting I have identified some of these proteins in tissues and cells. Two COX-3 encoded proteins are active prostaglandin synthase enzymes with activities similar to COX-1 and represent novel targets of NSAIDs. Other COX-3 proteins have unknown function, but their size and cellular location suggest potential roles as diverse as cytosolic enzymes and nuclear factors.

While extensive research has been conducted on the causes of intimate partner violence in the community, very little is known about rates and predictors of domestic violence perpetrated by offenders who have recently been incarcerated. Some evidence suggests that formerly incarcerated individuals may be at an increased risk to perpetrate intimate partner violence during the transition from prison to the community (e.g., Hairston & Oliver 2006; Hilton, Harris, Popham, & Lang, 2010; Oliver & Hairston, 2008). The primary goal of this dissertation was to examine the extent to which former inmates engage in domestic violence during the transition from prison to the community. A second goal of this dissertation was to determine the independent and interactive effects of selected individual, situational, and social-structural factors on post-prison domestic violence. The current dissertation project involved a retrospective study of data collected from n = 1,137 formerly-incarcerated male offenders who were released from state prison between 2004 and 2009. Data regarding individual-level factors of borderline and antisocial personality characteristics and exposure to family-of-origin violence were extracted from institutional records. Additional individual-level demographic characteristics including offenders' age, ethnicity, education need, marital status, number of children, crime of conviction, length of incarceration, and participation in correctional rehabilitation programs extracted from institutional records were also considered. The situational-level factor of offenders' employment after prison release was also collected from institutional records; and the social-structural factor of neighborhood disadvantage was collected from information available in offenders' community supervision records and Census tract-level data. The outcome measure of post-prison domestic violence was gathered from local law enforcement records. Data were entered into statistical models to predict post-prison domestic violence. Main effects on post-prison domestic violence were examined for each of the individual-level demographic characteristics, borderline and antisocial personality features, exposure to family-of-origin violence, employment, and neighborhood disadvantage. Interactive effects on post-prison domestic violence were examined between borderline and antisocial personality characteristics, exposure to family-of-origin violence, employment, and neighborhood disadvantage. Significant predicted main effects on post-prison domestic violence included age, ethnicity, education need, number of children, violent criminal history, attendance of substance abuse treatment in prison, witnessing interparental violence as a child, and neighborhood disadvantage. Significant predicted interaction effects on post-prison domestic violence included the interaction between physical abuse as a child and neighborhood disadvantage. Implications for policies regarding post-prison supervision sentencing, housing, and the advancement of programming to prevent intimate partner violence during the transition from prison to the community are discussed. Contributions to the literature on intimate partner violence, environmental transition theory, and ecological theoretical frameworks are also addressed.