VictorJuiz/thesis huggingface dataset:
The Effects of Ethanol and Nicotine on Hepatic and Brain CYP2 Family Enzymes in African Green Monkeys

Cytochromes P450 (CYPs) metabolize a vast array of xenobiotics, including many drugs and toxins. Induction or downregulation of the CYPs can have important consequences such as changes in drug efficacy and altered susceptibility to toxicity. Our study investigated the independent and combined effects of ethanol and nicotine on hepatic and/or brain levels of CYP2E1, CYP2B6 and CYP2A6 in African green monkeys. Monkeys were randomized into four groups (N = 10/group): an ethanol-only group, a nicotine-only group, an ethanol + nicotine group and a control (no drug) group. Ethanol (10% ethanol in sucrose solution) was voluntarily self-administered by the monkeys and nicotine was given as subcutaneous injections (0.5 mg/kg bid). Protein levels and/or in vitro activity were assessed in liver and brain tissue. Also, in vivo pharmacokinetics for chlorzoxazone (metabolized selectively by CYP2E1) and nicotine (metabolized primarily by CYP2A6 and to a lesser extent CYP2B6) were assessed. Hepatic CYP2E1 protein levels, in vitro hepatic CYP2E1 activity and in vivo chlorzoxazone metabolism were increased by ethanol and nicotine, alone and in combination. Hepatic CYP2B6 protein levels and in vitro hepatic CYP2B6 activity were increased by ethanol alone or combined ethanol and nicotine exposure, but were unaffected by nicotine alone. Hepatic CYP2A6 protein levels and in vitro hepatic CYP2A6 activity were decreased by nicotine alone or combined ethanol and nicotine exposure, but unaffected by ethanol alone. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6 activity. Ethanol, alone or combined with nicotine, resulted in lower nicotine plasma levels, an effect that was not mediated by changes in CYP activity. Protein levels of CYP2E1 and CYP2B6 were induced in specific regions and cells in the brain as a result of ethanol self-administration, nicotine treatment and the combined exposure to both drugs. In summary, ethanol and nicotine can alter the expression and/or activity of several important CYP2 family enzymes in primate liver and/or brain.

Keywords: metabolism
ethanol and nicotine
Advisor: Rachel, Tyndale
An Investigation of Vascular Strategies to Augment Radiation Therapy

Radiation therapy is administered to more than 50% of patients diagnosed with cancer. Mechanisms of interaction between radiation and tumour cells are relatively well understood on a molecular level, but much remains uncertain regarding how radiation interacts with the tumour as a whole. Recent studies have suggested that tumour response to radiation may in fact be regulated by endothelial cell response, consequently stressing the role of tumour blood vessels in radiation treatment response. As a result, various treatment regimens have been proposed to strategically combine radiation with vascular targeting agents. A great deal of effort has been aimed towards developing efficient vascular targeting agents. Nonetheless, no optimal method has yet been devised to strategically deliver such agents. Recent evidence suggesting that these drugs may “normalize” tumour blood vessels and enhance radiosensitivity, is supporting experiments where anti-angiogenic drugs are combined with cytotoxic therapies such as radiotherapy. In contrast, ultrasound-stimulated microbubbles have recently been demonstrated to enhance radiation therapy by biophysically interacting with endothelial cells. When combined with single radiation doses, these microbubbles are believed to cause localized vascular destruction followed by tumour cell death. Finally, a new form of ‘pro-angiogenics’ has also been demonstrated to induce a therapeutic tumour response. The overall aim of this thesis is to study the role of tumour blood vessels in treatment responses to single-dose radiation therapy and to investigate radiation-based vascular targeting strategies. Using pharmacological and biophysical agents, blood vessels were altered to determine how they influence tumour cell death, clonogenicity, and tumour growth, and to study how these may be optimally combined with radiation. Three-dimensional high-frequency power Doppler ultrasound was used throughout these studies to investigate vascular response to therapy.

Keywords: Tumour Vasculature
Radiation Therapy
Ultrasound Doppler
Anti-Vascular
Microbubbles
Delta Like Ligand 4
Advisor: Czarnota, Gregory
Understanding Biofilms of Anaerobic, Thermophilic and Cellulolytic Bacteria: A Study towards the Advancement of Consolidated Bioprocessing Strategies

The anaerobic, cellulolytic bacterium Clostridium thermocellum formed biofilms on cellulose consisting of a single layer of cells which did not secrete an extracellular polymeric matrix. Sporulation occurred under normal growth and was believed to assist with biofilm translocation to new substrates. Although the cell-substrate distance was less than 210 nm, the biofilm layer lost up to 29% of hydrolyzed oligomeric products when reactors were loaded with extreme concentrations of cellulose (up to 200 g/litre). This effect was much less severe at lower cellulose concentrations. Of the total cellulose carbon, 4% (gC/gC) was utilized for cell mass production and up to 75% was converted into primary metabolites (ethanol, acetic acid, lactic acid, carbon dioxide). Increasing the starting cellulose concentration shifted the ethanol-to-acetic acid ratio from 0.91 g/g to 0.41 g/g. Such high substrate loadings and metabolite shifts have not been previously reported and may be of interest for consolidated bioprocessing strategies. Cellulose conversion was initially limited by microbial growth, with a biofilm development rate estimated at 0.46h-1 to 0.33h-1 and where up to 20% of the substrate was consumed. Subsequently, substrate-limited conditions determined the rate kinetics. Surface accessibility for microbial colonization was the dominant rate limiting factor, while mass imposed constraints very late towards the end-point fermentation. CO2 was found to be an excellent reporter molecule for cellulose consumption and biofilm growth. Online CO2 tracking may also be used to assess the digestibility of substrates with unknown surface properties. A mathematical model that described biofilm growth, substrate consumption and product formation was found to have an excellent fit with experimental data of CO2 production which reinforced the previous findings on the cellulolytic biofilm form and function. Together, these results demonstrate that biofilms are undeniably the key to understanding the effective microbial conversion of cellulosic substrates.

Keywords: biofilm
cellulolytic
bioethanol
biocatalyst
Advisor: Allen, Grant
Adjusting for Selection Bias Using Gaussian Process Models

This thesis develops techniques for adjusting for selection bias using Gaussian process models. Selection bias is a key issue both in sample surveys and in observational studies for causal inference. Despite recently emerged techniques for dealing with selection bias in high-dimensional or complex situations, use of Gaussian process models and Bayesian hierarchical models in general has not been explored. Three approaches are developed for using Gaussian process models to estimate the population mean of a response variable with binary selection mechanism. The first approach models only the response with the selection probability being ignored. The second approach incorporates the selection probability when modeling the response using dependent Gaussian process priors. The third approach uses the selection probability as an additional covariate when modeling the response. The third approach requires knowledge of the selection probability, while the second approach can be used even when the selection probability is not available. In addition to these Gaussian process approaches, a new version of the Horvitz-Thompson estimator is also developed, which follows the conditionality principle and relates to importance sampling for Monte Carlo simulations. Simulation studies and the analysis of an example due to Kang and Schafer show that the Gaussian process approaches that consider the selection probability are able to not only correct selection bias effectively, but also control the sampling errors well, and therefore can often provide more efficient estimates than the methods tested that are not based on Gaussian process models, in both simple and complex situations. Even the Gaussian process approach that ignores the selection probability often, though not always, performs well when some selection bias is present. These results demonstrate the strength of Gaussian process models in dealing with selection bias, especially in high-dimensional or complex situations. These results also demonstrate that Gaussian process models can be implemented rather effectively so that the benefits of using Gaussian process models can be realized in practice, contrary to the common belief that highly flexible models are too complex to use practically for dealing with selection bias.

Keywords: selection bias
confounding bias
Gaussian process models
Bayesian analysis
sample survey
causal inference
observational studies
Advisor: Neal, Radford
Role of the Anterior Cingulate Cortex in Fear Learning and Sensation Related Behaviors

Neural activity within the brain underlies complex behavior that allows us to interact with our environment. The anterior cingulate cortex (ACC) is believed to mediate appropriate behavioral responses by integrating emotional and cognitive information about external stimuli. If this understanding is correct, then neural activity within the ACC must therefore correlate with behavioral output in response to external experience. The aim of this thesis is to bridge mechanisms identified in vitro with behaviors observed in vivo to determine the neural substrates of ACC mediated behavior. This thesis focuses on glutamatergic receptors that have been established as mediators of excitatory transmission in the ACC. Through a combination of behavioral, pharmacological, biochemical, and electrophysiological methods, this thesis examined how behaviors observed in mouse models of fear learning, chronic pain, and itch correspond with in vitro observations of ACC neuronal activity. Three sets of experiments are presented. The first set investigated cortical LTP-like mechanisms, and assessed whether they could mediate fear learning. These sets of experiments provide in vivo evidence that trace fear learning requires rapid, NMDA receptor dependent, cortical AMPA receptor insertion. The second set of experiments investigated the contribution of forebrain CREB-mediated transcription in behavioral manifestations of chronic pain. These experiments show that forebrain overexpression of CREB is sufficient to enhance mechanical allodynia in animal models of chronic inflammatory or neuropathic pain. Lastly, the final set of experiments show that pruritogen-induced scratching corresponds with enhanced excitatory transmission in the ACC through KA receptor modulation of inhibitory circuitry. Through investigations of multiple behaviors linked to ACC activity, this thesis presents evidence that manifestations of behavior can be observed at the molecular level, and indicates that molecular mechanisms involved in ACC synaptic activity are a good target for translational research into pathological conditions that are related to abnormal ACC activity.

Keywords: ACC
fear learning
chronic pain
itch
glutamatergic receptors
behavior
Advisor: Zhuo, Min
The Spatial Ecology of Predator-prey Relationships in Lakes

The pelagic zone of lakes is defined as the water column over the area of the lake benthos that does not receive enough light from the sun to allow macrophytes to grow. The four chapters of this thesis explore the spatial ecology of predator-prey interactions between schooling fish and their fish predators in this featureless environment. We first developed novel hydroacoustics methods to study fish and fish school swimming behaviour in the pelagic zone (Chapter 1 and 2). Then we characterized our in-situ school formation and prey movement observations using an ideal gas model to better understand the mechanisms that lead to fish and school densities during the daytime (Chapter 2 and 3). With this model we estimated the functional relationship between the schooling prey densities and predator encounter rates, and verified with empirical data a counterintuitive relationship that encounter rates decreased as overall prey densities increased (Chapter 3). The encounter rates suggested that predation within the pelagic zone might be greatly influenced by external forces if they provide spatial structure which encourages greater degrees of prey aggregation in predictable locations. In this regard we examined the predator-prey dynamics under wind and found large redistributions of prey and predators under windy conditions leading to greater aggregations in downwind locations. Further, we found that our study fish were larger in lakes that were oriented into the wind, perhaps demonstrating a benefit to fish growth under windy conditions (Chapter 4).

Keywords: fish
spatial ecology
predator-prey
hydroacoustics
ideal gas model
wind
pelagic zone
functional response
Advisor: Abrams, Peter
Shuter, Brian
Being Brazilian, Becoming Canadian: Acculturation Strategies, Quality of Life, Negative Affect, and Well-being in a Sample of Brazilian Immigrants Living in the Greater Toronto Area

Acculturation is a predominant feature of today’s society and one that has unique implications for immigrants’ mental health. Given that two thirds of Canada’s population growth is due to immigration, understanding the effects of acculturation on newcomers should be a central focus of academic research. The present study utilized an exploratory quantitative method to investigate the associations between acculturation strategies, quality of life, and negative affect in a sample of 180 Brazilian immigrants living in the Greater Toronto Area. The mediating and moderating roles of quality of life (QOL) were explored, as well as which patterns of acculturation strategies were associated with enhanced well-being, represented by low negative affect (NA), high QOL, and high Satisfaction with Life in Canada (SLCI). Clusters analysis identified patterns of acculturation strategy use, resulting in four acculturation profiles: integrated, assimilated, separated, and marginalized. Results indicated that QOL did not act as either a mediator or moderator of the relationship between acculturation profiles and NA. With regard to well-being indicators, acculturation profiles successfully predicted NA and SLCI, with the Assimilated being the most favourable profile evidenced by its lowest NA and highest SLCI levels. While acculturation profiles did not predict QOL, the trend of the Assimilated profile being predictive of favourable well-being was also present as its members reported slightly higher QOL than their counterparts from other profiles. Well-being risk and protective factors are presented. The results highlight the importance of including control variables in future research in order to uncover the unique impact of acculturation on the mental health of immigrants. Implications for practice and future research are also discussed.

Keywords: acculturation
acculturation strategies
quality of life
negative affect
depressive symptoms
anxiety symptoms
well-being
Brazilian immigrants
Greater Toronto Area
Advisor: Moodley, Roy
Heresy, Authority and the Bishops of Rome in the Fifth Century: Leo I (440-461) and Gelasius (492-496)

This dissertation investigates how two fifth-century bishops of Rome, Leo I (440-461) and Gelasius (492-496) understood and opposed heresy. More specifically, by stressing the contested character of heresy and the at times optative nature of the bishop of Rome’s opposition to it, this dissertation hopes to provide a new perspective on how Leo and Gelasius imagined and justified the authority of the Apostolic See in an uncertain world. To accomplish this task, this dissertation considers Leo and Gelasius’ opposition to various different heresies and details the methods by which they were opposed. This will be done through an examination of the records of synods, Roman law, other contemporary narrative sources, but especially through the letters and tractates of Leo and Gelasius themselves, carefully read and considered in their fifth-century context. Furthermore, it is argued that the history of the development of the ideas of heresy and orthodoxy were profoundly connected with Rome’s emerging importance as a locus of authentic Christian teachings; the history of the bishops of Rome cannot be told without examining the history of heresy and orthodoxy and vice versa. Because orthodoxy and heresy were not tangible historical phenomena but rather were malleable categories that emerged as part of a wider discourse of Christian identity construction, the bishops of Rome were not in every case the unqualified enemies of heresy. Instead, their definition of heterodox belief and their opposition to religious deviance were complex, often qualified and always historically contingent. This study seeks to investigate the way in which Leo and Gelasius mobilized the language of heresiology in order to convince Christians in the Latin west and the Greek east, as well as the imperial authorities, that Rome’s interpretations were legitimate and binding.

Keywords: Gelasius
Leo I
Italy
Late Antiquity
Authority
heresy
Ostrogoths
Theoderic
Arianism
Eutyches
Manichaeism
Rome
Pelagianism
papacy
orthodoxy
Acacian Schism
Advisor: Everett, Nicholas
Rac GTPase Regulation of GLUT4 Traffic in Muscle Cells: Mechanisms and Implications

One of the hallmarks of postprandial glucose homeostasis is the ability of insulin to promote glucose uptake into skeletal muscles. Insulin achieves this feat by enhancing the recruitment of glucose transporter 4 (GLUT4) from an intracellular compartment to the plasma membrane of muscles in order to create a net increase in surface GLUT4, which results in elevated glucose uptake. From a molecular perspective, this insulin-regulated GLUT4 traffic action requires the independent activation of Akt and Rac-1 in muscle cells because perturbation of either molecule results in an impaired response. Although Rac-1 has been validated as key component of insulin response, its downstream signalling capacity contributing to GLUT4 translocation remains unexplored. Studies on Rac-1 have shown that it is responsible for the formation of cortical remodelled actin that facilitates GLUT4 translocation following insulin stimulation. However, the downstream Rac-dependent molecules governing this actin remodelling are undetermined. Here we identified Arp2/3 and cofilin as the Rac-dependent regulators of insulin-induced actin remodelling in muscle cells. While Arp2/3 acts to initiate a burst of actin polymerization, cofilin balances out the actin dynamics through its severing/depolymerizing activity. Inhibition of either molecule’s function leads to defective GLUT4 translocation mediated by insulin in muscle cells, suggesting the requirement of actin dynamics to facilitate GLUT4 traffic to the plasma membrane. Furthermore, given the importance of Rac-1 in insulin-mediate GLUT4 traffic, its application potential to reverse insulin resistance has never been explored. We discovered that providing muscle cells with additional Rac-1 activity produces an insulin-independent gain in surface GLUT4 with magnitude comparable to that normally elicited by insulin. This phenotype is accomplished because of the concomitant cross-activation of Akt pathway when supplying the cells with active Rac-1. Interestingly, this response can bypass signalling defects imposed by cellular insulin resistance conditions, leading to restoration of GLUT4 translocation in muscle cells. Overall, these results not only reinforce the functional impact of Rac-1 on GLUT4 traffic but also identify additional molecules governed by Rac-1 contributing to the integrity of this insulin-mediated response in muscle cells.

Keywords: Rac
GTPase
GLUT4
Insulin
Muscle
Actin
Advisor: Klip, Amira
A Unified Geometric Framework for Kinematics, Dynamics and Concurrent Control of Free-base, Open-chain Multi-body Systems with Holonomic and Nonholonomic Constraints

This thesis presents a geometric approach to studying kinematics, dynamics and controls of open-chain multi-body systems with non-zero momentum and multi-degree-of-freedom joints subject to holonomic and nonholonomic constraints. Some examples of such systems appear in space robotics, where mobile and free-base manipulators are developed. The proposed approach introduces a unified framework for considering holonomic and nonholonomic, multi-degree-of-freedom joints through: (i) generalization of the product of exponentials formula for kinematics, and (ii) aggregation of the dynamical reduction theories, using differential geometry. Further, this framework paves the ground for the input-output linearization and controller design for concurrent trajectory tracking of base-manipulator(s). In terms of kinematics, displacement subgroups are introduced, whose relative configuration manifolds are Lie groups and they are parametrized using the exponential map. Consequently, the product of exponentials formula for forward and differential kinematics is generalized to include multi-degree-of-freedom joints and nonholonomic constraints in open-chain multi-body systems. As for dynamics, it is observed that the action of the relative configuration manifold corresponding to the first joint of an open-chain multi-body system leaves Hamilton's equation invariant. Using the symplectic reduction theorem, the dynamical equations of such systems with constant momentum (not necessarily zero) are formulated in the reduced phase space, which present the system dynamics based on the internal parameters of the system. In the nonholonomic case, a three-step reduction process is presented for nonholonomic Hamiltonian mechanical systems. The Chaplygin reduction theorem eliminates the nonholonomic constraints in the first step, and an almost symplectic reduction procedure in the unconstrained phase space further reduces the dynamical equations. Consequently, the proposed approach is used to reduce the dynamical equations of nonholonomic open-chain multi-body systems. Regarding the controls, it is shown that a generic free-base, holonomic or nonholonomic open-chain multi-body system is input-output linearizable in the reduced phase space. As a result, a feed-forward servo control law is proposed to concurrently control the base and the extremities of such systems. It is shown that the closed-loop system is exponentially stable, using a proper Lyapunov function. In each chapter of the thesis, the developed concepts are illustrated through various case studies.

Keywords: Open-chain multi-body systems
Kinematics
Hamiltonian dynamics
Differential geometry
Lie groups
Concurrent control
Advisor: Emami, M. Reza
Karshon, Yael