VictorJuiz/thesis huggingface dataset:
New Strategies for C–O and C–C Functionalization in the Contexts of Cyclopropanol Chemistry, Transnitrilation, and Ni Catalysis

This thesis describes new methods for C–O and C–C functionalization in the contexts of cyclopropanol and homoenolate chemistry, transnitrilation, and Ni catalysis. These strategies represent novel approaches to synthetic problems and may be of interest to chemists tasked with reaction design in these areas. Chapter 1 provides an overview of the chemistry in this thesis and highlights its common themes and synthetic strategies. Chapter 2 describes a new method for the Ni-catalyzed β-functionalization of cyclopropanol-derived homoenolates with redox-active N-hydroxyphthalimide esters, which are derived from carboxylic acids and act as alkylating reagents. Chapter 3 describes new methods for the conversion of cyclopropanols and α-chloroaldehydes to trans-2-substituted cyclopropylamines, which products are valuable from a pharmaceutical perspective. Key intermediates that enable the success of these reactions are electrophilic Zn homoenolates. Chapter 4 outlines the rational design of a new redox-active leaving group to enable Ni-catalyzed carbon–oxygen bond arylation of cyclopropanols, leading to arylcyclopropane products. Chapter 5 describes a new protocol for synthesizing malononitriles from benzyl cyanides. This protocol follows a transnitrilation mechanism involving anion relay. Chapter 6 describes a new protocol for Ni-catalyzed reductive cyanation of aryl (pseudo)halides, using a malononitrile derivative as a new, electrophilic cyanating reagent. This malononitrile reagent enables access to valuable benzonitrile products without the use of cyanide.

Keywords: catalysis
cross-coupling
cyclopropanol
homoenolate
nickel
nitrile
Advisor: Rousseaux, Sophie A. L.
Perceptions of Individuals in Mixed-race Relationships

Although the number of mixed-race couples is increasing at an exponential rate in North America, these couples continue to experience stigma and discrimination, which can have deleterious effects on the physical and mental health of the individuals in these relationships. Given that first impressions of individuals can be formed instantaneously and that these first impressions can greatly influence subsequent attitudes and behaviours, in three studies I examined perceivers’ first impressions of targets in mixed-race romantic relationships when viewed on their own versus with their romantic partners. In three studies, I examined perceivers’ first impressions of targets in mixed-race relations when viewed on their own versus with their romantic partners, including perceptions of targets’ warmth and competence (Study 1), global morality (Study 2), and sub facets of morality (i.e., likelihood to betray, to conform, and prejudice level; Study 3). I found that perceptions of warmth and competence did not differ based on whether targets were viewed alone or with their partners, however, perceptions of morality did. In particular, all targets viewed with their partners were perceived as more moral and less likely to betray close others than when viewed alone, however, individuals with same-race partners were perceived as most moral and least likely to betray. Furthermore, individuals in mixed-race couples were rated as less conforming and less prejudiced than individuals in same-race couples when viewed with their partners. In sum, when viewed with their romantic partners, individuals in mixed-race dyads were perceived less favourably than those in same-race dyads in terms of morality, betrayal likelihood, and conformity. However, individuals in mixed-race dyads were perceived more favourably than those in same-race dyads in terms of prejudice. These results were largely driven by the presence of romantic partners given that perceptions of global morality, betrayal, conformity, and prejudice were similar across targets viewed alone. Together, these studies suggest that evaluations of targets’ morality are affected by whether their romantic partner is same- or other-race. These studies lay the foundation for understanding the unique challenges faced by members of mixed-race couples.

Keywords: Intergroup Relations
Mixed-Race/Interracial
Person Perception
Relationships
Stereotyping
Advisor: Chasteen, Alison L
Core Values: Cider Production, Agrarian Livelihoods and Tuning Tastes in the Pacific Northwest

This dissertation draws on a case study of emerging craft cider production in the U.S. and Canadian Pacific Northwest. It is guided by the overarching question: To what extent has the contemporary craft cider industry in the Pacific Northwest constrained or enabled agrarian change in land, labour, livelihoods and consumer embodiment? Through a regional analysis encompassing British Columbia, Washington State and Oregon, I draw on ethnographic data from participant observation and in-depth interviews with actors across the craft cider industry from 2017-2019. This dissertation is organized into three distinct analytic chapters. First, I find that while craft cider has helped buffer some farm producers against the volatility of selling raw fruit to large commodity markets, the benefits of this value-added niche market do not widely support continued primary production or farm succession. Some young cidermakers wish to maintain a connection to agrarianism but are shifting away from full-time farming due to lifestyle preferences and political-economic constraints, as exemplified by token forms of on-site production that carry great symbolic weight. Given the craft industry’s emphasis on elevating performances of manual labour intensity and ethical ingredient sourcing, a second analytic chapter focuses on how cidermakers account for the labour of predominantly racialized (im)migrant farmworkers. I find that actors in the craft cider industry engage with inequalities affecting farmworkers through structural obfuscation, ideological justification, and ambivalence or critique. This analysis illuminates both barriers and opportunities to strengthen equity for farmworkers as part of movements to advance food system sustainability. Third, I investigate how actors who are attempting to “tune” people’s tastes away from industrial-scale production navigate the contradictions of their simultaneous dependence on an industrial food system. I find that cidermakers attempt to re-tune consumers’ tastes by appeasing consumers, whose bodies reflect the influence of food system industrialization in the form of taste preferences. Simultaneously, cidermakers endeavour to ease consumers into more diverse possibilities for taste and ecologically resilient farming. Taken as a whole, this dissertation advances scholarly understandings of rural livelihoods, labour in alternative food initiatives, and embodied social change.

Keywords: Agrarian
Craft Cider
Farmworkers
Food and Agriculture
Pacific Northwest
Rural Sociology
Advisor: Johnston, Josée
Distant Neighbours: Social Distance, Mobility Prospects, and Government Redistribution

This dissertation is about income inequality – how it shapes preferences for redistribution, whether governments are responsive to these preferences, and whose preferences matter most. Income inequality has become a salient topic in recent decades, as the gap between rich and poor has widened across advanced industrial economies. Models of rational self-interest would predict that the increased concentration of income at the top of the distribution would increase public demand for government action to redress this inequality, yet public support for redistribution in many advanced economies has remained constant or even declined. At the same time, governments have often pursued greater redistribution in low rather than high market inequality settings. How can we understand these trends? This dissertation addresses this question by focusing on the Canadian provincial context, examining both demand for, and supply of, government redistribution. On the demand side, I argue that social distance – perceptions of similarity or difference among groups – affects how people think about their own economic prospects, in turn shaping their preferences for redistribution. Demand for redistribution depends not only on an individual’s position in the income distribution; instead, the distribution of income within neighbourhoods, among income groups, and across ethnic groups all influence preferences for government inequality reduction. On the supply slide, this dissertation also examines how micro-patterns of preferences and inequality are translated into government supply of redistribution, and in particular whether governments are more responsive to middle- or high-income groups. Despite concern in recent American politics research about the outsized influence of high-income voters on government policy, I show that provincial governments are responsive to the economic conditions of the middle class. However, high-income voters are often as – or more – responsive than middle-income voters to shifts in the income position of the middle class, suggesting that governments can respond to the middle class without opposition from higher-income voters. This dissertation contributes to our understanding of the relationship between group membership and redistributive preferences, the other-regarding versus self-interested bases of support for redistribution, and research on unequal government responsiveness to the public’s preferences.

Advisor: Haddow, Rodney
The Effect of Hypoxia Mimetic and Laminar Flow on Islet of Langerhans Beta-Cell Function and Endothelial Cell Morphology

Pancreatic islets are highly vascularized in vivo, ensuring proper blood glucose sensing and insulin secretion directly into the blood stream. Islet vascularity is determined by several factors including blood flow, endocrine tissue, and endothelial cells (ECs). However, once islets are isolated and cultured under static conditions (petri dish), their microenvironment is disrupted, and vascularity is quickly lost. Therefore, we designed and manufactured a microfluidic device to mimic nutrient flow in ex vivo islet culture for short- and long-term (Chapter 2). We found that culturing islets in the device resulted in twice the maintained EC-density and -connected length compared to static culture. This positive effect was due to the penetration of serum albumin, an anti-apoptotic signal for ECs, into the tissue. We then observed maintained function of islet beta-cells via two-photon NAD(P)H response and insulin secretion. In chapter 3, we investigated the combined effect of the hypoxia mimetic, cobalt chloride (CoCl2) and microfluidic flow. We found that CoCl2 induced hypoxia did not affect beta cell metabolism, insulin secretion, or survival. CoCl2 stimulated HIF-1α, PDK-1, and LDHA mRNA and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2); which was mirrored in the glucose-stimulated cytoplasmic NAD(P)H response. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static and microfluidic flow culture. The EC response appeared to be mechanistically independent from survival induced by the penetration of serum albumin. Lastly, in chapter 4, we conducted preliminary experiments to investigate the role of CoCl2 induced angiogenic factors regulation of VE-cadherin, as a possible mechanism in islet EC maintenance. We found several angiogenic factors and their receptor mRNA present in islets and focused on VEGF-A and FGFs as possible candidates. However, results around their regulation of VE-cadherin were inconclusive. Future studies are required to determine the mechanism of the CoCl2 induced EC maintenance. Taken altogether, these studies are important for long-term ex vivo studies to understand the function of islets and they are also important for the clinical implications of islet transplantation.

Keywords: Angiogenesis
Endothelial cells
Hypoxia
Islets
Microfluidic
Advisor: Rocheleau, Jonathan V
Neural Correlates of Self-regulatory Fatigue and the Role of High Affinity Striatal Dopaminergic Receptors in Tourette Syndrome and Healthy Subjects

Tourette syndrome (TS) is a developmental neuropsychiatric condition characterized by motor and vocal tics. Tics are semi-voluntary movements or vocalizations that are stereotyped, repetitive and non-rhythmic. They usually occur in response to a premonitory urge, and can be suppressed temporarily. TS typically involves multiple comorbidities, in particular obsessive-compulsive disorder, attention deficit/hyperactivity disorder, and emotional dysregulation. Given the clinical phenomenology, TS has been conceptualized as a syndrome of inhibitory deficits involving motor, cognitive, emotional and behavioral domains. Neuroimaging studies have implicated the cortico-striato-thalamo-cortical circuitry, in particular the striatal dopamine system, and cortical control areas. However, despite numerous studies, findings have been mixed, and a definitive explanation of the neurobiology underlying TS has remained elusive. The objective of this body of work was to utilize novel neuroimaging approaches in an attempt to identify neural mechanisms that could contribute to the manifestation of TS. In a positron emission tomography (PET) imaging study of the striatum, I investigated striatal D2/3 dopamine receptors in TS using the radioligands [11C]raclopride and [11C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [11C]raclopride and [11C]-(+)-PHNO PET scans. There were no significant group differences between TS and HC participant binding potentials (BPND) in ventral, motor and associative striatum. In a functional magnetic resonance imaging (fMRI) study of self-regulatory fatigability using an eye blink inhibition paradigm, high-performing HC participants had relatively higher activation in known prefrontal cortex (PFC) control areas – inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC), and supplemental motor area (SMA) – whereas self-regulatory fatigability was associated with relatively higher activation in ventromedial PFC, rostroventral anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Based on these findings, I carried out a region of interest (ROI) analysis comparing 19 HC and 12 TS participants. There was substantially less percent signal change in the DLPFC/IFG and SMA ROIs in the TS group in comparison to the HC group. These findings suggests that self-regulatory deficits in TS arise from fatigability in cortical control.

Keywords: functional magnetic resonance imaging
positron emission tomography Imaging
prefrontal cortex
self-regulatory fatigability
striatum
Tourette syndrome
Advisor: Sandor, Paul
A Theory of Nanoparticle Dosing

Cancer nanomedicine has been impeded by poor delivery to target tumours. Many efforts have been made to modify nanoparticles to increase tumour delivery, including their sizes, shapes, and surface chemistries. These efforts have had minor payoffs. At the root of this problem is poor pharmacokinetics mediated by preferential nanoparticle accumulation in the liver. In Aim 1, I determined the reason for preferential accumulation of nanoparticles in livers away from tumours. Liver macrophages were intravascular and had direct access to nanoparticles, while tumour macrophages were extravascular and could only access nanoparticles that penetrated through cellular and stromal barriers. In Aim 2, I leveraged this preferential accumulation to develop a theory of nanoparticle dosing. There was a fundamental dose threshold of one trillion nanoparticles that overwhelmed the liver to enable prolonged circulation times and enhance tumour delivery. In Aim 3, I explored the therapeutic potential of this dose threshold concept. Caelyx’s antitumour efficacy could be improved by simply increasing the dose of nanoparticles without increasing the dose of doxorubicin. The work in this thesis overcomes a major part of the liver barrier and achieves meaningful nanoparticle delivery to tumours for cancer nanomedicine.

Keywords: Biodistribution
Cancer
Dose
Nanotechnology
Pharmacokinetics
Advisor: Chan, Warren CW
Directional Shift in Mitochondrial Heteroplasmy

Diseases due to mitochondrial DNA (mtDNA) mutations are lethal and few therapeutic options are available. Because these mutations often exist in a state of heteroplasmy, the coexistence of wild-type and mutated mtDNA, strategies that can alter this ratio in favor of wild-type mtDNA (“heteroplasmy shifting”) may be therapeutically useful. We found that the Leigh syndrome (LS)-associated m.10191C variant promotes G-Quadruplex (GQ) formation within local sequence in vitro. The GQ formed at m.10191C differentially impeded the processivity of the mitochondrial DNA polymerase gamma (POLG) in vitro, providing a potential means to favor replication of the wild-type allele. Treatment of patient fibroblasts with GQBA induced alternating mtDNA depletion and repopulation and was effective in shifting heteroplasmy towards the non-pathogenic allele. Following treatment, heteroplasmic m.10191T>C cells had increased in maximal mitochondrial oxygen consumption. We developed a high-throughput assay to screen 23,000 GQBA for preferential binding to m.10191C allele with minimal off-target effects and two compounds were identified with favourable characteristics. We observed that mitochondria in patient cells harbouring pathogenic heteroplasmic mtDNA mutation are hyperfused compared to controls. Fragmenting mitochondria by knock down of fusion genes led to shift in mitochondrial heteroplasmy. This study demonstrates the potential for using small-molecule GQ-binding agents to induce genetic and functional shift in m.10191T>C mutation and mitochondrial fragmentation may have synergistic effects.

Keywords: G-Quadruplex
Leigh Syndrome
m.10191T>C
Mitochondria
Mitochondrial Disease
mtDNA
Advisor: Sondheimer, Neal
Evaluating the Construct of Emotion Differentiation: Methodological Considerations and Extension of Current Theory

Emotion differentiation is a multifaceted construct, referring to the ability to make fine-grained distinctions between emotional experiences as well as the ability to describe individual emotional experiences with a high degree of nuance and specificity. Studies to date have demonstrated that emotion differentiation is associated with indices of psychological well-being, such that greater emotion differentiation performance is presumed to be adaptive. Theory posits that emotion differentiation functions as a precursor to more successful emotion regulation by providing the experiencer with more precise information to contextualize their emotional experience and respond to it more optimally, but this relationship needs further empirical support. Several other issues persist with the construct as currently operationalized, including: (1) it is unknown how the underlying construct empirically relates to similar constructs in the literature, and if it uniquely relates to psychological well-being incrementally beyond these other constructs; (2) it is unknown if emotion differentiation can be measured via self-report and do such measures correlate with performance-based approaches; and (3) emotion differentiation lacks measures in the context of individual emotional experiences, suggesting the full theoretical construct is not being captured. This research was therefore undertaken with the goal of systematically addressing each of these lingering issues. Results of Study 1 suggested that emotion differentiation is best conceptualized as an aspect of emotional complexity, separate from emotional awareness, and that it does not uniquely relate to psychological well-being after accounting for empirical overlap with awareness. Study 2 results indicated that a coding-based measure of differentiation within individual emotional experiences related to indices of psychopathology but did not relate to emotion differentiation between emotional experiences. All associations between indices of emotion differentiation and psychopathology were accounted for by mean affect intensity. In Study 3, those who were instructed to appraise their emotions with less nuance reported more emotion regulation success following one negative emotion-inducing video, and those from this group who reported high trait emotional awareness reported the greatest emotion regulation success following the other negative video. Collectively these results highlight continuing concerns with emotion differentiation theory and measurement.

Keywords: emotion differentiation
emotion regulation
emotional awareness
emotional complexity
Advisor: Uliaszek, Amanda A
Process Development for Quadruple Fortification of Salt

This process was developed to simultaneously deliver iron, iodine, folic acid, and vitamin B12 for holistic prevention of anaemia and other risk factors for prenatal complications in vulnerable populations. Salt was chosen as the ‘vehicle’ for the micronutrients because ‘doses’ of the micronutrients can be predicted. The process was based on a cold forming extrusion-based microencapsulation (for making premix) that ensures that added micronutrients are stable, indistinguishably mixed with salt, do not segregate, and do not cause changes to the sensory characteristics of salt and foods. The dusting of the micronutrient premix with titanium dioxide masked its brown colour while its coating with soy stearin prevented the adverse moisture aided interaction between iron and iodine. The hydrophobic nature and the initial amount of soy stearin used for coating caused the micronutrient premix to float; contamination of TiO2 due to its recycling caused dark spots on the surface premix. Double coating with 5% hydroxypropyl methylcellulose and 5% soy stearin solved the floating problem; coating with a mixture of 15% TiO2 and 10% soy stearin solved both problems. The required pH (≥ 8) for full dissociation of folic acid, its solubility, and stability caused vitamin B12 instability; hence, both micronutrients cannot be added to salt through a solution. In salt, they were lost through oxidative degradation. The coextrusion of folic acid and vitamin B12 with ferrous fumarate (a reducing agent) minimized the oxidative degradation of the micronutrients. The colour masking and coating of the premix ensured that the micronutrients did not affect the colour of the salt. Also, the coextrusion prevented the micronutrients from photodegradation. The salt samples can deliver 50-200% recommended dietary allowances of the micronutrients based on the consumption of 10g of salt per day. The micronutrients were very stable in the salt and met the set target (70% retention after 6-month storage). Over 85% of the micronutrients were retained in salt after 6-month storage, even at 45 oC/60-70% RH. The micronutrients were stable in cooking and did not cause any changes to the sensory properties of the salt or food.

Keywords: Folic Acid
Iodine
Iron
Process Development
Salt Fortification
Vitamin B12
Advisor: Diosady, Levente L.