VictorJuiz/thesis huggingface dataset:
Development and Preclinical Evaulation of Novel Enzyme-targeting Radiotracers for Positron Emission Tomography

This work sought to radiolabel novel positron-emitting radiotracers and evaluate their utility for quantifying enzymes relevant to neurological and psychiatric disorders via position emission tomography (PET) in preclinical studies. Four enzymes were targeted: glycogen synthase kinase 3 (GSK-3), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and monoamine oxidase B (MAO-B). By adapting a [11C]CO2 fixation method, a GSK-3 inhibitor with a 1-aryl-3-benzyl-[11C-carbonyl]urea scaffold was synthesized and represents a technique for radiolabeling unsymmetrical ureas bearing aromatic substrates. Using a similar method, we were able to prepare a 11C isotopologue of PF-04457845, a new investigation agent targeting FAAH in phase 2 trials. [11C]PF-04457845 was prepared in 5% radiochemical yield (uncorrected, based on [11C]CO2) and high radiochemical purity (>98%) with a specific activity of 74 GBq/µmol. Following ex vivo biodistribution and specificity experiments in rats, it was determined that [11C]PF-04457845 was a promising candidate which should be assessed in higher species. Further expanding the [11C]CO2 fixation method, five candidate radiotracers targeting MAGL were prepared in high radiochemical purity with sufficient yield and specific activity for conducting preclinical evaluations. Although none of these sufficiently penetrated the rodent brain, they represent rare examples for attempting to image this important neurological target with PET. Furthermore, the low nucleophilicity of the alcohol and amines used to prepare the [11C]carbamate- and [11C]urea-based radiotracers broadened the scope of the [11C]CO2 fixation method. Lastly, a [18F]fluoropropyl derivative of a reversibly-binding MAO-B inhibitor, SL25.1188, was synthesized in 52% radiochemical yield (uncorrected, based on [18F]F-) with a specific activity of 109 GBq/µmol and had high radiochemical purity (>98%); however, low MAO-B affinity and rapid metabolism in rat plasma led to poor brain uptake. Our efforts to expand the basic knowledge of new 11C- and 18F-labeled compounds to non-invasively probe important neurological enzyme targets are discussed herein.

Keywords: carbon-11
CNS enzymes
fluorine-18
positron emission tomography
radiotracer development
Advisor: Wilson, Alan A
Vasdev, Neil
Pore Network Modeling and Synchrotron Imaging of Liquid Water in the Gas Diffusion Layer of Polymer Electrolyte Membrane Fuel Cells

Polymer electrolyte membrane (PEM) fuel cells operate at levels of high humidity, leading to condensation throughout the cell components. The porous gas diffusion layer (GDL) must not become over-saturated with liquid water, due to its responsibility in providing diffusion pathways to and from the embedded catalyst sites. Due to the opaque and microscale nature of the GDL, a current challenge of the fuel cell industry is to identify the characteristics that make the GDL more or less robust against flooding. Modeling the system as a pore network is an attractive investigative strategy; however, for flooding simulations to provide meaningful material comparisons, accurate GDL topology and condensation distributions must be provided. The focus of this research is to provide the foundational tools with which to capture both of these requirements. The method of pore network modeling on topologically representative pore networks is demonstrated to describe flooding phenomena within GDL materials. A stochastic modeling algorithm is then developed to create pore spaces with the relevant features of GDL materials. Then, synchrotron based X-ray visualization experiments are developed and conducted to provide insight into condensation conditions.It was found that through-plane porosity distributions have significant effects on the GDL saturation levels. Some GDL manufacturing processes result in high porosity regions which are predicted to become heavily saturated with water if they are positioned between the condensation sites and the exhaust channels. Additionally, it was found that fiber diameter and the volume fraction of binding material applied to the GDL have significant impacts on the GDL heterogeneity and pore size distribution. Representative stochastic models must accurately describe these three material characteristics. In situ, dynamic liquid water behavior was visualized at the Canadian Light source, Inc. synchrotron using imaging and image processing techniques developed for this work. Liquid water primarily originated beneath the flow field landings, sometimes spreading laterally into the less compressed regions of the GDL beneath the flow field channels. Independent water clusters were tightly packed within the GDL, rarely occupying more than 1 mm2 of planar area. These tools and observations provide the capability to predictively design high performance GDL materials.

Keywords: Fuel Cells
Gas Diffusion Layer
Pore Network Modeling
Simulations
Stochastic Modeling
Synchrotron Radiography
Advisor: Bazylak, Aimy M
Decision Support Tools for Sustainable Water Distribution Systems

Sustainability relies on the balance between economic, social, and environmental objectives. Although seemingly divergent at times, the connections between them elucidate opportunities for improving different components simultaneously. In water distribution systems, aging infrastructure, insufficient funds, water scarcity, leakage, and high energy use have prompted the pursuit of sustainability through different strategies. These conditions demand improvement and create the opportunity to rethink the system. The present study proposes five separate decision support approaches that underlie a systems approach. These address current issues of North American water distribution systems and lessen the gap between research and application.The first two focus on the interface between users and networks. The relation between user characteristics and demand is studied by building an integrated database to support planning, especially demand management. Data from three Ontario municipalities are used to define metrics, benchmarks, conservation targets, and user clusters. The relation between users and service requirements is further explored qualitatively through a survey on water user expectations, addressing the disconnection between utilities and stakeholders. Applied to the City of Guelph, it informs the utility of knowledge gaps and preferred solutions.While these approaches concentrate on the needs of the stakeholders, inputs to more thorough planning, the next two assess the resulting systems. A set of energy metrics addresses the issue of inefficient energy use and provides indicators of system capacity, costs, and greenhouse gas emissions. The metrics are applied to the Toronto water network, and allow for the identification of specific areas for improvement. In order to further evaluate how complex networks respond to variations, a more comprehensive set of performance metrics are proposed and applied to two example networks.The final approach seeks to improve the design process by reducing the computational intensity of optimization procedures and thereby allowing for the analysis of more system objectives and uncertainties. The procedure, applied to Anytown, uses shorter time cycles to approximate full costs of systems with varying loads. Overall, the approaches facilitate current-day decision-making by applying systems thinking to the development of new solutions that collect, integrate, analyse, and re-interpret readily available data and models.

Keywords: data mining
energy efficiency
optimization
performance characteristics
stakeholder feedback
Advisor: Karney, Bryan W
Phonological and Morphological Skills in Emerging English-Hebrew Bilinguals

Metalinguistic abilities such as phonological and morphological awareness are important language proficiency components. Three interrelated studies, based on a longitudinal project, investigated the development of phonological and morphological skills in children with English as the home language and Hebrew as an emerging second language. Two cohorts were followed for two years: The first (N= 48) was followed from junior kindergarten (JK) to Grade 1, the second (N= 38) was followed from senior kindergarten (SK) to Grade 2. Order of acquisition of phonological and morphological skills was explored longitudinally and processes of transfer from the strong to the weak language were examined. Data were analyzed by using General Estimating Equations.Findings indicated improvement across grades on final phoneme and syllable deletion tasks and a decline between SK to Grade 1 on initial phoneme task in Hebrew. The decline may reflect a growing exposure to the Hebrew orthography and to its body + coda construct. Performance on final phoneme isolation and syllable deletion was predicted by English phonological awareness, but not initial phoneme isolation performance. In English and Hebrew, a gradual development from SK to Grade 2 was noted on different morphological components (inflections, derivations and compounds). Transfer of inflectional morphology from English to Hebrew was also noted. In Hebrew, children demonstrated the ability to produce nouns spontaneously followed by the ability to produce adjectives and verbs in a learning process that was more sequential than parallel, and that may reflect the method of instruction. The process of learning how to inflect words followed by the ability to derive words was demonstrated in both languages on parallel experimental measures and on the Hebrew narrative task. The children figured out the morphological combinations that were more frequent, consistent, or salient. This explains the relationship between English and Hebrew in terms of order of acquisition. The findings support the effect of cogintive universal processes and language specific characteristics on the developemt of English (L1) and Hebrew (L2). The findings bear theoretical implications and practical implications for school instruction methods, particularly among teachers who work with young bilingual children.

Keywords: bilinualism
development
English
Hebrew
morphology
phonology
Advisor: Geva, Esther
Speckle And Motion Based Vascular Image Analysis for Optical Coherence Tomography

Optical Coherence Tomography (OCT) is an emerging optical imaging modality that is capable of imaging biological tissues with micron resolution and millimeter penetration depth. In clinical diagnostic imaging and pathology, OCT has helped fill a gap in terms of both resolution and imaging depth, in between traditional fluoroescence based microscopes and non-invasive organ level imaging. In this domain, OCT can be used both as an ex vivo pathological examination tool or in vivo imaging modality.OCT has been successful in ophthalmology owing to its excellent in vivo optical sectioning ability and penetration depth. Over the years, OCT has seen substantial progress in terms of application diversification and functionalities. In addition to being able to image more organs and tissues, OCT has been configured to be incorporated inside catheters, enabling wall structure imaging in luminal settings, for example, major blood vessels or the digestive tract. And other than anatomical structures, OCT has also been able to specifically map out flow or elasticity.As OCT becomes more diversified, data obtained also become more diversified in terms of information but more complicated. For instance, in endovascular OCT (EV-OCT), data were acquired radially instead of the traditional raster scanning. Moreover, during the pullback scanning in EV-OCT, motion artefacts are severe and this restricts the amount of functional information to be obtained. Furthermore, as OCT imaging speed becomes faster, reaching as high as 3.2 MHz axial scan rate, flow imaging is obliged to undergo paradigm shift, particularly from conventional ultrasound practices.The main goal of this thesis was to address the development and validation of a set of algorithms that tackle these problems we now face in modern OCT systems and increase the utility of information obtained. In this thesis, an experimental protocol was first developed for proper porcine carotid arterial EV-OCT imaging. The data obtained were then utilized for the first time to dynamically detect microvessels (vasa vasorum) in major arterial wall. Meanwhile optimized digital speckle noise removal was performed for the first time on Fourier domain EV-OCT system data to further facilitate vessel wall evaluation and microvessel detection. Lastly, a novel depth enhanced OCT microangiography algorithm was devised for in vivo microvascular imaging of malformed vascular networks of human skin with genetic origins for the first time. The significance of this thesis lies in the potential of helping better understand the mechanism, progression and the effect of therapeutic intervention on various vascular diseases such as atherosclerosis and hereditary hemorrhagic telangiectasia. Better preventive measures and treatment options can ultimately be devised with advanced understanding of vascular diseases formation.

Keywords: Endovascular Imaging
Microvascular Imaging
Optical Coherence Tomography
Speckle
Advisor: Herman, Peter R
Yang, Victor
Geometry Control System for Exploratory Shape Optimization Applied to High-fidelity Aerodynamic Design of Unconventional Aircraft

This thesis represents a step forward to bring geometry parameterization and control on par with the disciplinary analyses involved in shape optimization, particularly high-fidelity aerodynamic shape optimization. Central to the proposed methodology is the non-uniform rational B-spline, used here to develop a new geometry generator and geometry control system applicable to the aerodynamic design of both conventional and unconventional aircraft. The geometry generator adopts a component-based approach, where any number of predefined but modifiable (parametric) wing, fuselage, junction, etc., components can be arbitrarily assembled to generate the outer mold line of aircraft geometry. A unique Python-based user interface incorporating an interactive OpenGL windowing system is proposed. Together, these tools allow for the generation of high-quality, C2 continuous (or higher), and customized aircraft geometry with fast turnaround. The geometry control system tightly integrates shape parameterization with volume mesh movement using a two-level free-form deformation approach. The framework is augmented with axial curves, which are shown to be flexible and efficient at parameterizing wing systems of arbitrary topology. A key aspect of this methodology is that very large shape deformations can be achieved with only a few, intuitive control parameters. Shape deformation consumes a few tenths of a second on a single processor and surface sensitivities are machine accurate. The geometry control system is implemented within an existing aerodynamic optimizer comprising a flow solver for the Euler equations and a sequential quadratic programming optimizer. Gradients are evaluated exactly with discrete-adjoint variables. The algorithm is first validated by recovering an elliptical lift distribution on a rectangular wing, and then demonstrated through the exploratory shape optimization of a three-pronged feathered winglet leading to a span efficiency of 1.22 under a height-to-span ratio constraint of 0.1. Finally, unconventional aircraft configurations sized for a regional mission are compared against a conventional baseline. Each aircraft is optimized by varying wing section and wing planform (excluding span) under lift and trim constraints at a single operating point. Based on inviscid pressure drag, the box-wing, C-tip blended-wingbody, and braced-wing configurations considered here are respectively 22%, 25%, and 45% more efficient than the tube-and-wing configuration.

Keywords: aerodynamic shape optimization
aircraft design
geometry generation
induced drag
NURBS
shape exploration
Advisor: Zingg, David W.
GABA Receptor and KCa Channel-mediated Electrical Suppression in Anoxic Cortical Pyramidal Neurons of the Painted Turtle (Chrysemys picta bellii)

The high energetic cost of neuronal communication requires large amounts of ATP to maintain function. In mammals, oxidative phosphorylation is required to meet these energy demands and without sufficient oxygen supply neuronal hyperexcitability and excitotoxic cell death occurs. This catastrophic cascade of events does not happen in the freshwater painted turtle Chrysemys picta bellii, instead there is a coordinated downregulation of cellular ATP consuming processes to match the lower anaerobic ATP supply. To reduce the energetic burden during anoxia turtles have evolved a sophisticated network of neuroprotective mechanisms including channel arrest and spike arrest which combine to prevent membrane depolarization and activation of excessive electrical activity. The aim of my research was to identify and elucidate cellular mechanisms responsible for suppression of electrical activity in anoxic turtle dorsal cortical brain pyramidal neurons. Using electrophysiological and fluorescent imaging techniques I demonstrate for the first time that: 1) in turtle dorsal cortex gamma-aminobutyric acid (GABA) release increases during anoxia and enhances a unique GABAA receptor-mediated giant postsynaptic current, and shifts membrane potential to the GABA reversal potential (EGABA), reducing electrical excitability; 2) endogenous GABAergic mechanisms responsible for anoxia-tolerance also protect against a debilitating ischemic solution that mimics the cerebral fluid in the penumbral area that surrounds the infarct core; 3) in pyramidal neurons the open probability of Ca2+-activated K+ channels decreases during anoxia and this is prevented by inhibition of protein kinase C; and 4) anoxia-mediated decreases in mitochondrial reactive oxygen species (ROS) production are sufficient to initiate a redox-sensitive inhibitory GABA signaling cascade that suppresses electrical activity. Together this research significantly contributes to our understanding of the turtle's natural anoxia-tolerant strategy in brain and highlights the integral role of channel arrest and GABAergic spike arrest in prevention of anoxic or ischemic cell damage

Keywords: Anoxia
Channel arrest
GABAA receptor
Pyramidal neuron
Spike arrest
Turtle
Advisor: Buck, Leslie T
The Development of Pragmatic Markers in Canadian English

This thesis examines the mechanisms of linguistic change involved in the actuation and subsequent development of pragmatic markers (PMs). Using the variationist method, I test the predictions of analysts who have argued that the development of PMs unfolds according to grammaticalization theory (inter alia Hopper and Traugott 1995). In doing so, I address two desiderata suggested in the literature for a better understanding of how PMs change: 1) an examination of both real- and apparent-time data (Pichler and Levey 2011), and 2) an examination of multiple features (Tagliamonte and Denis 2010).The data come from several collections of recorded Ontario English. I examine the Toronto English Archive (Tagliamonte 2006b), a contemporary sociolinguistic corpus, and two collections of oral history interviews recorded in 1975 and 1984, the Belleville Oral History Project and the Farm Work and Farm Life Since 1890 Oral History Collection. Together, these represent an apparent-time span of over one hundred years. The features are general extenders and epistemic parentheticals both of which have been argued to show evidence of ongoing grammaticalization (e.g., Cheshire 2007; Thompson and Mulac 1991).The analysis of the general extenders system finds a lack of evidence for phonetic reduction, decategorialization, and semantic-pragmatic shift of the innovative variant 'and stuff' - each of these changes is a critical component of grammaticalization according to grammaticalization theory. I further show that although the epistemic parenthetical system of Ontario English reorganized through the twentieth century, the changes involved were not the result of gradual grammaticalization, as evidenced by a lack of ongoing fusion, a lack of change in syntactic mobility, and a lack of ongoing semantic bleaching. While the two case studies provide evidence against the idea that PMs develop according to grammaticalization theory, there is no denying that grammaticalization, the phenomenon, has taken place: lexical elements have become PMs. I conclude that the evidence suggests the grammaticalization of pragmatic markers as abrupt reanalysis of lexical material, from one syntactic category to some other syntactic category (see Roberts and Roussou 2003).

Keywords: Canadian English
grammaticalization
language change
pragmatic markers
variationist sociolinguistics
Advisor: Tagliamonte, Sali A.
The Role of Leptin-melanocortin System Gene Variants in Antipsychotic-Iiduced Weight Gain

The use of second-generation antipsychotic medications can result in the development of severe side effects such as weight gain and metabolic syndrome. Previous studies have proposed that a genetic component contributes between 40% and 80% to the development of this side effect. However, genetic studies thus far have yielded mixed findings. The genetics of the melanocortin system has not yet been extensively examined in the context of antipsychotic-induced weight gain. Objectives: The first objective was to investigate whether melanocortinergic single nucleotide polymorphisms from genes that were associated with high weight and obesity were also associated with antipsychotic-induced weight gain. The second objective was to determine whether gene-gene interactions better predict the onset of antipsychotic-induced weight gain in psychiatric patients. Hypothesis: It was predicted that the melanocortin-3 receptor, melanocortin-4 receptor, pro-opiomelanocortin, cocaine-amphetamine regulated transcript, and agouti related protein would be associated with antipsychotic-induced weight gain, and that a combination of these genes would provide improved prediction of this phenotype. Results: The melanocortin-3 and melanocortin-4 receptors were associated with antipsychotic-induced weight gain. An additive model did not demonstrate that the combined effect in these genes explains increased variance of the weight gain phenotype. Conclusions: The melanocortin receptor system may have a more substantial role in predicting antipsychotic-induced weight gain, as compared to previously studied gene systems. Though further exploration and functional analyses are required, these findings contribute novel knowledge to the pharmacogenetics of antipsychotic-induced weight gain, and may help to enhance the development of clinical genetic tests to guide medication decision-making in the future.

Advisor: Kennedy, James L.