VictorJuiz/thesis huggingface dataset:
Ruthenium-Based Hydrogenation and Frustrated Lewis Pair Chemistry
Keywords: Frustrated Lewis Pair

Since the discovery of catalytic hydrogenation, the field of transition metal-based hydrogenation catalysis has grown significantly. Recently, main group systems have demonstrated the capability to perform some of the same catalytic processes. Frustrated Lewis pairs (FLP), the combination of sterically encumbered Lewis acids and Lewis bases, are able to activate a variety of small molecules. The research presented in this thesis investigates main group and transition metal-based catalytic hydrogenation, as well as stoichiometric transformations with main group systems. A variety of ruthenium N-heterocyclic carbene (NHC) complexes were generated with polyethylene glycol (PEG) on the NHC to impart water-solubility. These hydrogenation catalysts were used to hydrogenate nitrile butadiene rubber (NBR) to hydrogenated nitrile butadiene rubber (HNBR). The PEG lengths had minimal effect on the conversion of NBR in solution phase. For the hydrogenation of NBR latex, a correlation was observed between the PEG length and the activity. A family of phosphinimines with different steric and electronic properties was synthesized from the Staudinger reaction between alkynyl-phosphines and azido-phosphine-boranes. Cyclization of these products can be induced thermally or by the addition of catalytic amounts of B(C6F5)3. Upon cyclization, a net trans-hydroboration was observed on the exocyclic alkene. A novel geminal boron-sulfur FLP was synthesized from the hydroboration of sulfur-alkynes. These systems demonstrated FLP-type chemistry such as the activation of terminal alkynes. Interestingly, the frustration was a result of the steric conflict between the tert-butyl substituent on the carbon and the p-tolyl substituent on the Lewis basic sulfur. This FLP-type reactivity can altered upon isomerization of the complex, forming the classical Lewis pair adduct. Finally, metal-free transformation of 3-ethylidene-6-vinyltetrahydro-2H-pyran-2-one was investigated. The Lewis acid B(C6F5)3 was shown to catalytically hydrogenate the allyl functionality of the substrate, as well as catalytic hydrosilylation of the conjugated alkene.
Development of a Breast Cancer Cell Microenvironment in Three-Dimensional Hyaluronic Acid Based Hydrogels
Keywords: Breast cancer
Epidermal growth factor
Gradients
Hydrogel
Invasion
Photochemistry

Breast cancer cell invasion is influenced by the tumor microenvironment including the extracellular matrix, mechanical properties, stromal cells, and bioactive factors. To elucidate the role of the microenvironment on cell invasion, defined 3-dimensional hydrogel models are required because xenograft models are too complex and 2-dimensional models lack a matrix for cell invasion and often do not recapitulate the appropriate mechanical properties. Breast cancer cell invasion is also influenced by gradients of epidermal growth factor (EGF); however, studying the influence of EGF gradients is challenging due to their transient nature and convoluted in vivo models. In this work, a hyaluronic acid (HA) based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides (HA/MMPx) was developed to study the role of the microenvironment on breast cancer cell invasion. Specifically, crosslink density, adhesive ligand density, and MMP cleavable peptides were evaluated. Defined EGF gradients were photochemically immobilized into HA/MMPx hydrogels to evaluate the invasion and drug response of breast cancer cells with different EGF receptor (EGFR) expression levels. The crosslink and ligand densities of HA/MMPx hydrogels were decoupled to elucidate their effect on the invasion of MDA-MB-231 breast cancer cells. Increasing crosslink density decreased MDA-MB-231 invasion because more crosslinks had to be degraded for the cells to move through the hydrogel. Increasing adhesive ligand (GRGDS) density did not effect MDA-MB-231 invasion, but did increase cell number. The MMP cleavable crosslinker increased MDA-MB-231 cell invasion relative to a non-cleavable control, confirming that invasion is facilitated by cell-mediated matrix degradation. Immobilized EGF gradients in the HA/MMPx hydrogels differentially affected breast cancer cells with varying levels of EGFR expression: EGF gradients increased the invasion of moderate EGFR expressing MDA-MB-231 cells, decreased the invasion of high EGFR expressing MDA-MB-468 cells, and had no effect on low EGFR expressing MCF-7 cells. The EGFR inhibitor cetuixmab reversed the effects of EGF, decreasing MDA-MB-231 and increasing MDA-MB-468 cell invasion on EGF gradients. With these studies, we developed a versatile platform to study the influence of the microenvironment on breast cancer cell invasion and demonstrated the importance of including microenvironmental factors in culturing platforms when evaluating drugs that target these interactions.
In Vivo Role of Hepatic JAK2 and IGF-1 in Atherosclerosis
Keywords: Atherosclerosis
IGF-1
JAK2
NAFLD

Non-alcoholic fatty liver disease (NAFLD) is an emerging independent risk factor for cardiovascular disease (CVD). However, our current understanding of the underlying mechanism by which fatty liver per se increases atherosclerosis risk remains unclear and is difficult to delineate due to its common association with other metabolic abnormalities. In this thesis, genetically modified atherosclerosis-prone ApoE-null and Ldlr-null mouse models were used to investigate the essential role of hepatic Jak2 in atherogenesis. I assessed the role of circulating IGF-1 as a mechanistic link between NAFLD and atherosclerosis. In chapter 4, I describe the consequences of deleting hepatic Jak2 on atherosclerosis development and progression. I show that hepatic Jak2-deficiency resulted in profound fatty liver without other confounding cardiovascular risk factors, and this was accompanied by accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. Furthermore, I demonstrate that reduced circulating IGF-1 played a causal role in exacerbating atherosclerosis that occurred with hepatic Jak2-deficiency, which was attenuated by pharmacologic or genetic restoration of circulating IGF-1. I next assessed the essential role of hepatic IGF-1 in atherogenesis. In chapter 5, I show that disruption of hepatic Igf1 and reduction of circulating IGF-1 did not phenocopy hepatic Jak2-deficient mice with accelerated atherosclerosis. In fact, hepatic Igf1-deficiency led to a significant reduction in atherosclerosis particularly in female mice. Interestingly, female hepatic Igf1-deficient mice also displayed profound hepatic steatosis with reduced circulating IL-6 and triglycerides. Taken together, the results presented in this thesis reveal a novel mechanistic link between NAFLD and atherosclerosis through hepatic Jak2 that provides atheroprotection. While restoration of IGF-1 partially attenuates the accelerated atherosclerosis in hepatic Jak2-deficient mice, endogenous hepatic IGF-1 does not appear to be essential in atheroprotection. These results illustrate the complexity in the regulation of atherosclerosis that is mediated by hepatic JAK2 signaling. Clear understanding of how hepatic signaling affects atherosclerosis can lead to novel therapeutic strategies to combat CVD.
A Multi-scale Metabolic Model of the Whole-Human Body
Keywords: Genome-scale Model
Human Metabolism
Inborn Error of Metabolism
Multi-Scale Modelling
Precision Medicine
Quantitative Pharmacology

Model-based design (MBD) is a well-known approach in the biomedical and health sciences research community. It has a significant impact for answering important questions related to human metabolism, systems pharmacology, precision medicine, epidemiology and public health. Multi-scale modelling is one of the MBD approaches to analyze and study complex biological systems like the human body. However, there are some challenges associated with this approach. For instance, a lack of systematic integration methods, a lack of efficient computational algorithms, and difficulty for model validation. This thesis aims to meet these challenges. First, I present a multi-scale modelling framework that was developed using a dynamic parsimonious flux balance analysis technique. The mechanistic model integrates the metabolomic and genomic data with human physiology. Simulations are performed to demonstrate the computational efficiency of integration algorithm. Then, I use the proposed model to identify biomarkers for inborn errors of metabolism. I explore how the developed model can be used to predict blood alcohol concentrations. Here, in vivo data are integrated with the metabolic model to validate the prediction results. In the next section of the thesis, I develop a mathematical model for low-density lipoprotein cholesterol (LDL-C) regulation in the body. The proposed model integrates the metabolic pathway for cholesterol synthesis, hepatic LDL receptor (LDLRs) signaling pathway, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mechanism to degrade LDLRs at the surface of the hepatocyte cells. Circulating PCSK9 increases endosomal and lysosomal degradation of hepatic LDL receptors, resulting in the decreased ability to clear LDL-C from the circulation. Experimental evidence and previous studies are used to obtain the parameters of the model. The LDL-C model is employed to predict the effect of anti-PCSK9 and statin drugs on LDL-C levels in a certain populations with hypercholesterolemia. In the next part of the research, I develop an algorithm to estimate drug dosage for individual patients with hyperuricemia. The proposed computational algorithm uses the multi-scale modelling framework to create individual disease models. An in silico study shows the potential of proposed modelling framework in precision medicine. Finally, aligned with the research objective, I develop a new modelling framework to capture multiple functions of the liver cells simultaneously. The simulation results show that the developed model has promise with respect to computational efficiency, convergence and robustness. The proposed multi-scale metabolic modelling framework integrating genomic and metabolomic data presented in this thesis should aid biomedical engineers and clinicians to address different health-related problems such as obesity, diabetes, cardiovascular, and genetic diseases.
Modelling Hospital Surge with Data-Driven Discrete Event Simulation
Keywords: generic discrete event simulation
Healthcare
Hospital modelling
Operations Research
Surge modelling

Many Canadian hospitals run at or near capacity, frequently experiencing congestion due to surges in demand. “Surge Protocols” that formally define when and what kind of operational steps can be taken to alleviate congestion are routinely in use. Decisions across the hospital, regarding bed capacity and allocation, staffing levels, and the surgical block schedule influence the frequency and severity of congestion, which in turn manifests in high bed occupancy, delayed admissions, a crowded Emergency Department, surgical cancellations and increased use of surge protocols. A generic, data-driven, discrete event simulation is presented that helps hospitals assess the impact of hospital wide decisions and surge policies on each area of the hospital. The model was developed in cooperation with two hospitals, and then applied at two additional hospitals.
Advancing Microfluidic Assays toward Personalized Multiple Myeloma Cancer Therapy Selection
Keywords: Co-culture
CSRA
Microengineering
Microfluidics
Multiple Myeloma
personalized

Cancer treatment selection is hindered by a lack of personalized data, relying instead on empirical evidence to justify treatment selection. For multiple myeloma (MM), a hematologic cancer, treatment selection is complicated by the occurrence of drug resistance, and patients have been observed to respond in an unpredictable fashion. To address these challenges, there is a need for more personalized treatment selection methods. Since the 1950’s, tools and assays for testing individual patient samples with a variety of drug treatments, called chemosensitivity and resistance assays (CSRAs), have been under development. There are currently no CSRAs approved for clinical use due to a lack of data supporting improved clinical outcomes compared to current empirical methods. A lack of improved clinical outcomes has been linked to limitations associated with the tools and methods used to perform these assays, as they require higher quantities of patient sample than some patients can provide, and they do not sufficiently mimic in vivo conditions. To address these limitations, my objective was to produce several individual advances for a platform previously developed to study MM. Using microfabrication and device material characterization, poly(dimethylsiloxane) (PDMS) drug absorption and its impact on cytotoxicity assays was studied. Diffusion modelling and analysis was performed alongside physical experiments to confirm near-uniform soluble factor diffusion across microsystems. Cell population heterogeneity measures were used to study the effects of varying cell population to assess the feasibility of reducing cell seeding populations. Finally, the importance of accurately mimicking in vivo drug treatment concentrations was assessed by comparing two approaches for analyzing cytotoxicity assay data. The combination of these advancements positions the platform for further application in clinical studies, and to further our basic understanding of MM, with a specific focus on disease progression and drug resistance.
A Case Study in Meaning-making in a University-level Expressive Writing Class
Keywords: Composition
Editing
Editorial practice
Expressivism
reading-writing connections
writing instruction

In this dissertation, I address this concern and extend the literature on writing-reading connections by examining literacy in an expressivist classroom. The study sought to answer three questions: 1) What is each student’s understanding of reading, writing, and editing before, during, and after taking Expressive Writing? 2) How does each student conceptualize the roles of reader, writer, and editor, and how do these concepts change over the life of the course? 3) What are the characteristics of each student’s writing at the beginning, middle, and end of the course? To answer these questions, I observed a section of Expressive Writing at the University of Toronto Mississauga, wrote a series of case studies detailing the experiences of three students, and analyzed writing students produced for the course. The study showed that Expressive Writing connects reading and writing through editing. The course taught students editorial technique and strategy, and by learning how to edit, students learned new ways of reading, writing, and discussing a text. My observations indicate that the course influenced the students’ writing by compelling them to write for an actual rather than imagined audience and to alter (or edit) their texts to appeal to their audience. By the end of the term, the students I observed worked with editors to produce “clear” prose that “connected” readers to the writer. The students saw the editor as essential in helping them to relate to their readers. This dissertation provides support for the argument that reading and writing are inextricably connected, with editing and the role of the editor as the connective tissue. Educators must teach reading and writing together, as two parts of single communication circuit.
Placefull Spaces: Queer Women and Non-Binary Artists Resisting an Emptied Stage
Keywords: Lesbian theatre
Queer geography
Queer theatre in Canada
Queer women
Theatre space

For marginalized queer artists, inequitable distribution of and access to performance space impact both the development process and production of artistic works. While a lack of ongoing or resident performance space for women’s productions in Canada has been documented (see, for example, Rina Fraticelli; Rebecca Burton; and Michelle MacArthur), less research has been conducted on queer women’s and non-binary artists’ experience of space in the industry. Theatre and performance scholars (see, for example, Gay McAuley, Una Chaudhuri, Jill Dolan, and Laura Levin) have provided the groundwork for exploring the relationship among theatre sites, identities, and productions; and queer geographers such as Natalie Oswin, Julie Podmore, Catherine Nash, and Kath Browne have developed invaluable theories and methodologies to unsettle the assumed neutrality of space. However, few scholars have brought these fields together, particularly in the context of performance in Canada. This doctoral project applies queer and feminist theories of geography to queer women’s and non-binary artists’ performance to explore how insecure and inequitable access to physical space affects both experiences of finding one’s place in the theatre industry and articulations of an imagined place on stage. The germinal Western conceptions of the stage as placeless or “empty” (Brook) work to neutralize the theatre space by assuming all creators, performers, and audience members are easily oriented within it. For marginalized bodies, which are simultaneously hyper-visualized and unseen in dominant cultural spaces, the necessary conditions to access placelessness may be unobtainable, or may be experienced as a form of violent erasure of histories. Through a process of “unmapping” venues and close description and analysis of performances, this doctoral study questions how an intentional engagement with space and place on stage can actively destabilize the presumed universality and neutrality of performance space and combat broader gendered spatial inequities. Focusing on performances and events in Toronto, Ontario and Vancouver, British Columbia, this project develops a theory of “placefullness” as a means of understanding how artists actively resist spatial inequities in the theatre and performance industry in Canada.
Medical Explanations in Evolutionary Medicine, Network Medicine, and Medically Unexplained Physical Symptoms
Keywords: epistemology
evolutionary medicine
medically unexplained physical symptoms
network medicine
philosophy of medicine
scientific explanations

This dissertation is a philosophical exploration of the limits of medical explanations. I examine three case studies to explore these limits: evolutionary medicine, network medicine, and the medically unexplained. Evolutionary medicine and network medicine exemplify modern attempts to develop new explanatory strategies in clinical research and practice. They are burgeoning, nascent fields that challenge our conventional understanding of health and disease. I am critical of the former and optimistic about the latter. I argue that the ultimate explanations posed by evolutionary medicine are pragmatically and epistemically inadequate as medical explanations. Explanations that appeal to our ancestral past are speculative, often based on adaptationist assumptions, and empirically suspect—we cannot rely on them to develop medical interventions. Network medicine aims to map the connections between the causes of disease and pathophenotypes. It has the potential to reconceptualize diseases as emergent topologies of these networks. I discuss the role of mechanisms in these models and how multi-level, context-sensitive networks aim to be empirically robust. Medically unexplained syndromes, in contrast, are an obscure class of illnesses that cannot be explained by somatic biomedicine. Like complex chronic diseases, these syndromes are a thorn in the overwhelming success of medical progress. Patients with unexplained syndromes are often diagnosed with psychiatric illnesses, and I argue that it is an epistemic injustice to pathologize such gaps in medical knowledge. Rather than diagnosis these conditions by exclusion, we need to embrace epistemic humility when confronted with such medical uncertainty. This dissertation adds to the literature on medical explanations, exploring their unique virtues and clinical implications.
THE LIVING WITH SICKLE CELL QUESTIONNAIRE: PSYCHOMETRIC PROPERTIES OF A NEW DISEASE- SPECIFIC SELF-REPORT MEASURE OF HEALTH-RELATED QUALITY OF LIFE FOR PEDIATRIC SICKLE CELL DISEASE
Keywords: Health-related quality of life
measurement
pediatrics
sickle cell disease

Health-related quality of life (HRQoL) remains a relatively new area of investigation in pediatric sickle cell disease (SCD).The purpose of this study was to determine the reliability, validity, and sensitivity to change of the Living with Sickle Cell Questionnaire (LSCQ), a new disease-specific HRQoL self-report instrument for children and adolescents with SCD. The LSCQ was constructed using a ‘clinimetric’ approach, which assigned items identified as important by patients to one of four traditional domains of HRQoL: Somatic Sensation, Cognitive/Psychological Functioning, Social Functioning, and Physical Functioning. Self-report versions of the PedsQL, a generic HRQoL questionnaire for children and adolescents, were co-administered in counterbalanced fashion to help establish questionnaire properties. One hundred children and adolescents with SCD (mean age: 11.7 years) participated in the study at two time points approximately two weeks apart. At the second visit, patients were asked to estimate change in their overall health since the first administration. Parents provided demographic information. High internal consistency (Cronbach’s alpha > .70) was found for each LSCQ domain at both timepoints. The LSCQ instrument’s sensitivity to patient-reported change in health between testing timepoints was only weakly demonstrated. Child demographic and disease-related factors predicted LSCQ Total Score and PedsQL About My Feelings and About School scores at Time 2 only. Confirmatory factor analyses performed at Time 1 and Time 2 showed high intercorrelations among items belonging to the same parent domain for the four-factor traditional HRQoL model, but indicated poor model fit at both time points. Follow-up Principal Component analyses for the LSCQ computed at Time 1 and Time 2 yielded four-factor solutions that accounted for 68% and 71% of the variance explained, respectively, but did not confirm the hypothesized four-domain generic HRQoL model. Rather, the four factors organized around themes of treatment, impact of fatigue, and pain and mobility, with some variation at each time point. High item loadings on the first factor suggest that a unidimensional structure might underlie HRQoL as measured by the LSCQ. Hypothesized associations between LSCQ and the PedsQL domains did not emerge as predicted. Findings are discussed in the context of disease-specific HRQoL conceptualization, instrument construction and child response style.