VictorJuiz/thesis huggingface dataset:
Relationships between Urban Environments and Crdiovascular Disease Risk

Background Cardiovascular disease (CVD) remains one of the leading causes of mortality and morbidity globally. An environmental approach to increasing physical activity, by creating walkable neighbourhoods where individuals can accumulate active minutes by walking to work, local stores, and appointments may have more success in sustainably increasing activity than traditional exercise programs. Further evaluation is needed to understand the potential benefits of walkable neighbourhood environments in reducing CVD risk to inform its role as a target for public health policy. Methods Results Data were drawn from the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) cohort, derived from health administrative databases. The population studied were community-dwelling, working-age adults. The first study examined cross-sectional associations between neighbourhood walkability and predicted CVD risk. High neighbourhood walkability was associated with a lower predicted 10-year risk of CVD but a higher odds of smoking. The second cross-sectional study focused on interactions between neighbourhood walkability and traffic-related air pollution and their association with hypertension and diabetes. Significant interactions were identified; while high walkability was associated with a lower odds of hypertension and diabetes at low levels of pollution, these exposures were no longer protective in highly polluted areas. The third study explored associations between walkability and the occurrence of major adverse cardiovascular events (MACE) using a retrospective cohort study design. Over a median follow-up of 5 years, adults residing in a highly walkable neighbourhood had a lower rate of MACE, but a higher rate of cardiovascular death than individuals residing in less walkable areas. Subgroup analyses suggested that the increased mortality observed in highly walkable neighborhoods was limited to individuals with psychiatric comorbidities. Conclusions The results of this dissertation suggest that adults who reside in highly walkable neighbourhoods have fewer CVD risk factors and a lower likelihood of experiencing a major cardiovascular event.

Keywords: Air Pollution
Built Environment
Canada
Cardiovascular
Risk Factors
Walkability
Advisor: Booth, Gillian L
Managing Multimorbidity in Primary Care: Measuring Collaboration Efforts within and across Organizational Boundaries

In Ontario, there has been widespread investment and reform to enable collaboration between providers in interdisciplinary primary care teams (Family Health Teams [FHT] and Community Health Centres [CHC]), alongside partnerships to promote collaboration between primary care teams, hospitals, and community agencies. However our understanding of the factors associated with interprofessional collaboration within primary care teams, the association between interprofessional collaboration and patient outcomes, and the interplay between interprofessional and interorganizational collaboration as it relates to the primary care sector is still in its early stages. Study 1 examined which organizational characteristics are associated with interprofessional collaboration that was assessed via the Collaborative Practice Assessment Tool (CPAT) in CHCs and FHTs across Ontario. Study 2 involved analyzing linked administrative data to assess the association between interprofessional collaboration and emergency department (ED) visits, hospitalizations and 30-day readmissions for adults with multimorbidity. Study 3 adopted a network analysis lens to examine regular contact, level of integration, and four types of relationships (referrals, information sharing, joint care planning and shared resources) between organizations. Two care coordination initiatives (Health Links) were selected as case studies. One case was led by a lead agency with a low CPAT score and the second case was led by a lead agency with a high CPAT score. The use of formal and informal mechanisms of information sharing, a strong commitment to quality improvement and years since practice establishment were positively associated with interprofessional collaboration. Increasing team size, high levels of information exchange, a mixed governance board, and greater centralization of administrative processes had a negative association with CPAT score. The extent of interprofessional collaboration was not associated with the likelihood of having an ED visit, hospitalization or readmission. Results indicate no statistically significant association between interprofessional collaboration and healthcare utilization for patients with multimorbidity. The low-CPAT led case showed greater connectivity pertaining to regular contact and integration between organizations, compared to the high-CPAT led case. Mixed trends were observed for the four types of relationships examined. Network analysis findings offer key insight into how organizations in Health Links are interacting to better coordinate services for this unique patient population.

Keywords: collaboration
interorganizational
interprofessional
network analysis
Ontario
primary care
Advisor: Wodchis, Walter P
Accounting for Variability and Uncertainty in Life Cycle Assessments: Oil Sands Case Studies

Along the life cycle of oil sands-derived products, variability in terms of resource heterogeneity, operating decisions, as well as extraction and processing technologies affect a project’s GHG intensity. Previous LCAs that have quantified emissions from bitumen production and processing have not captured all sources of variability along the life cycle, either by including only some projects or employing simplified refinery modeling or modeling refining only of some crude types. Three studies are completed to address this literature gap. In the first study, a statistically-enhanced version of the GreenHouse gas emissions of current Oil Sands Technologies model (GHOST-SE) is developed. Median lifetime GHG intensities for projects producing synthetic crude oil (SCO) range from 89-137 kg CO2eq/bbl SCO and for the project producing dilbit are 51 kg CO2eq/bbl dilbit. Projects show significant temporal variability. No project reaches steady-state in terms of GHG intensity. Next, GHOST-SE is integrated with a pipeline transportation model (COPTEM) and a refinery model (PRELIM) and variability in life cycle emissions intensities are quantified. Allocation to products affects the relative GHG intensities of different projects (e.g., Project 1 has lowest median life cycle GHG intensity per MJ gasoline but highest per MJ diesel). These results demonstrate that there is no representative project or crude type, even across projects within the same pathway (e.g., Mining SCO pathway). In the final study, expert elicitation methods are employed to assess the potential role for emerging technologies to decrease upstream GHG intensity between 2014 and 2034. Experts surveyed do not expect emerging technologies to play a major role in reducing upstream oil sands energy consumption but are more likely to be applied to access marginal resources not economic with current production technologies. Accurate characterizations of the emissions from the life cycle of oil-sands derived fuels has the potential to assist oil sands operators and policymakers to: set benchmarks, develop projections of future emissions, and identify opportunities for GHG intensity reductions along the life cycle of the fuel. The findings of this thesis can also inform operators and policymakers about the potential unintended consequences of policy decisions.

Keywords: Greenhouse gas emissions
Life cycle assessment
Oil sands
Uncertainty
Variability
Advisor: MacLean, Heather L
A Gentlewoman's Profession: The Emergence of Feminized Publishing at Richard Bentley and Son, 1858-1898

Publishing has evolved into a feminized profession, with women filling approximately 84 percent of positions under the managerial level. Well into the twentieth century, however, it was men publishers, booksellers and librarians who dominated the book trade. Histories of the publishing industry have not explored this gendered shift in depth. Using the London-based firm of Richard Bentley and Son (1829-1898) as a site of investigation, this dissertation considers the gender identity of publishing processes, organizations, and labour through the history of the firm’s women publisher’s readers. Drawing primarily on archival materials, I explore how the women publisher’s readers gained power and influence over the publishing process and used their positions as gatekeepers to challenge traditional gender ideology. This shift in the gendering of publishing and print materials at Bentley and Son reflects changes within the broader industry, and the evolution of gender ideology within the nineteenth-century social, cultural, political and legal landscapes. Beyond attending to a gap in historical scholarship, this exploration of the feminization of the publishing industry illuminates how gender ideology has shaped women’s entrance into, and movement within, professional environments, and provides a framework for analyzing print production through a gendered lens. Chapter one examines how women publishing workers have been constructed and represented within scholarship and popular culture. In chapter two, Bentley and Son’s organizational structure is analyzed to highlight women’s labour and demonstrate the impact of gender on the circuit of literary production. Women’s professionalization within the firm and the industrialization of publishing is considered in tandem in chapter three. Chapters four and five explore how women’s entrance into publishing has impacted the nature of print. Microanalyses of individual titles’ publication histories show how Bentley and Son’s women publisher’s readers perpetuated the values and ideologies of the Victorian women’s movement through the publication of print materials that supported women’s empowerment. A macroanalysis of the firm’s publishing lists further showcases the feminization of the firm, revealing an increase in fiction titles for women in gender-progressive genres, and the publication of women-oriented works in previously masculinized non-fiction categories.

Keywords: Book History and Print Culture
Gender History
Publishing
Victorian Women's Literature
Women's Movement
Women's Professionalization
Advisor: Galey, Alan
Engineering Diphtheria Toxin as an Intracellular Protein Delivery Platform

Despite enormous efforts, delivery of protein-based therapeutics into the cytosol of target cells remains one of the greatest challenges facing biotechnology. The inability of proteins to readily cross plasma membranes restricts access to a wealth of intracellular targets that can be employed for therapeutic intervention. Several protein carriers have been explored, however, no single platform possesses the attributes of target specificity, delivery efficiency and passenger protein versatility. Bacterial toxins, which naturally cross biological membranes and deliver a large protein into the cytosol of target cells in a receptor-dependent manner, have great promise as protein delivery platforms. This dissertation focuses on the development of diphtheria toxin as an intracellular delivery vector for protein therapeutics. Through protein engineering and cell biology approaches, I first demonstrated that diphtheria toxin can deliver structurally diverse and large proteins as amino-terminal fusions into monkey kidney Vero cells. Next, I showed that engineered diphtheria toxin is capable of delivering a trimeric human enzyme into deficient lymphocytes and neurons, resulting in restoration of functional defects associated with the deficiency. Using a bacterially-derived enzyme that targets the intracellular small GTPases, Ras and Rap1, the remarkable potency of an appropriately designed diphtheria toxin chimera was demonstrated and shown to be far superior to existing protein carriers. Overall, the results of these studies demonstrated that engineered diphtheria toxin is a highly efficient and specific vector that can deliver versatile passenger proteins into cells to replace or modulate the activities of intracellular molecules. The high delivery efficiency and target specificity of diphtheria toxin offer immense therapeutic opportunities to treat diseases with intracellular targets that were once considered unreachable.

Keywords: Intracellular delivery
toxin delivery
Advisor: Melnyk, Roman A
Using The Protein Corona to Train Deep Neural Networks and Build Patient-specific Nanomaterials

When nanoparticles are exposed to biological environments, proteins rapidly adsorb to the surface and form a structure known as the protein corona. The protein corona always forms irrespective of the material composition, surface chemistry, size and shape. This interfacial network of protein is one of the biggest banes to nanomedicine as it mediates how nanoparticles behave in the body despite our synthetic control. Investigations outside the body have shown that it is possible to predict protein corona adsorption based on nanoparticle size, shape and surface chemistry. At present, no insight and forecast exists of protein assembly patterns in vivo, nor has this interfacial chemistry been used toward building new applications in medicine. This thesis presents an original contribution to biomedical nanotechnology as it exploits the protein corona across two themes with a collective effort to improve translation of nanomaterials into the clinic. First I demonstrate that the protein corona can be deciphered and used as input data to train a neural network that is able to predict nanoparticle biodistribution in an animal model. Second, a new class of nanomaterial is created by isolation, separation and materials ligation of the protein corona from a nanoparticle template. The latter provides a solution to a major problem facing nanomaterial design; the engineering of size and shape tunable organic nanomaterials under 100 nm. They are biodegradable and do not activate innate or adaptive immunity following single and repeated administrations in vivo. Together, these findings provide insight and foundational materials design to create a patient-specific nanomaterial that can have predictable biodistribution inside of the body.

Keywords: Mass Spectrometry
Nanoparticles
Neural Networks
Personalized Nanomaterials
Predictive Biology
Protein Corona
Advisor: Chan, Warren CW
Model-Guided Transdermal Formulation of 1α,25-Dihydroxyvitamin D3 for Improved Safety and Efficacy

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active ligand of vitamin D receptor (VDR), is useful for the prevention and treatment of various diseases, including chronic kidney disease (CKD), cardiovascular disease, hypercholesterolemia and neurodegenerative diseases. However, the therapeutic utility of 1,25(OH)2D3 is limited due to its propensity to cause hypercalcemia. Our aim is to develop a transdermal formulation of 1,25(OH)2D3 that allows for controlled drug delivery with minimal stimulation of the intestinal calcium ion channel (TRPV6), thereby avoiding the toxic outcome of hypercalcemia. By incorporation an ethylene vinyl acetate (EVA) rate-controlling membrane to slow down and regulate the rate of drug release, we were able to control the slow release from the patch not skin as the rate-limiting step for permeation. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model was further established to interpret the complex PK and PD interplay of 1,25(OH)2D3 and guide dosing selection. Based on the modeling and studies in vivo, we were able to determine that patches containing loadings of 70-560 pmol‧cm-2 1,25(OH)2D3 (or ~0.0004-0.0048% w/w) to be noncalcemic. The apparent half-life of 1,25(OH)2D3 in mice following the patch formulation was prolonged when compared to the repeated intravenous (IV) and intraperitoneal (IP) doses, due to the more gradual release of 1,25(OH)2D3 from the patch, rendering lesser stimulation of the degradation enzyme, Cyp24a1, for 1,25(OH)2D3 elimination and Trpv6 for calcium absorption. Additionally, the 1,25(OH)2D3 transdermal patch (~0.0004-0.0048% w/w) provided sustained, desirable pharmacodynamic effects in the suppression of the parathyroid hormone (PTH) in CKD mice in vivo for the correction of secondary hyperthyroidism (SHPT) without notable toxicity. In conclusion, our transdermal 1,25(OH)2D3 delivery system provides a safe and effective way for the delivery of 1,25(OH)2D3.

Keywords: chronic kidney disease
Controlled drug delivery
Model-guided drug formulation
Pharmacokinetics/Pharmacodynamics
Physiologically-based Pharmacokinetic Modeling
vitamin D
Advisor: Pang, K. Sandy
Lee, Ping I
Targeting Metabolic Dysregulation for the Treatment of Radiation Fibrosis

Extracellular matrix (ECM) homeostasis is essential for normal tissue function. Disruption of homeostasis by iatrogenic injury, trauma, or disease can lead to fibrosis. Skin ECM homeostasis is maintained by a complex process involving an integration of cytokine and environmental mediators. It is currently unclear, in both normal and disease states, as to how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. In this study, an interplay between fatty acid oxidation (FAO) and glycolysis was observed to be a key convergence point governing ECM homeostasis in skin. A consistent shift from FAO to glycolysis was observed in human and murine skin with ECM accumulation, and in dermal fibroblasts induced to upregulate ECM production by multiple mediators (TGF-Β1, PDGF-BB, hypoxia). Pharmacologic inhibition and genetic knockdown of key FAO and glycolysis pathway enzymes in dermal fibroblasts confirmed that FAO and glycolysis have opposing roles in ECM regulation. Specifically, glycolysis induced an anabolic fibroblast that upregulated ECM production. This was counteracted by shifting fibroblasts to FAO, which induced a catabolic phenotype inhibiting both transcription of components of the ECM, as well as enhancing ECM internalization and lysosomal degradation. CD36, a multifunctional fatty acid transporter, was discovered to be a critical mediator connecting the metabolic state of fibroblasts with their capacity for ECM regulation. CD36 promoted the catabolic effect of a FAO fibroblast, as its knockdown abrogated the internalization and degradation of collagen-1. Restoring FAO and upregulating CD36, either through pharmacotherapy or by autologous transplantation of CD36high fibroblasts, reduced ECM accumulation in murine radiation fibrosis. Our data demonstrate that metabolic regulation may be an integration point downstream of molecular signaling pathways that govern ECM homeostasis by shifting fibroblasts between anabolism and catabolism. These results have broad implications for therapies aimed at ECM reduction, such as fibrosis, or ECM buildup, such as regenerative medicine and aging.

Keywords: Cell therapy
Fatty acid oxidation
Fibrosis
Glycolysis
Metabolism
Pharmacogenomics
Advisor: Liu, Fei-Fei
Molecular Mechanisms of Bone Destruction and Central Nervous System Invasion in B Cell Acute Lymphoblastic Leukemia

The use of intensified multiagent and prophylactic central nervous system (CNS)-directed chemotherapy has achieved improved survival for pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). However, skeletal morbidities and CNS leukemia continue to pose significant clinical challenges in B-ALL patients underscoring the need to identify the underlying mechanisms and to develop effective targeted therapies. My thesis project aimed to elucidate molecular mechanisms of bone destruction and CNS invasion in B-ALL and to provide evidence for potential targeted therapies to ameliorate these complications. Using a genetically sensitized mouse model of spontaneous B-ALL and primary patient-derived xenograft (PDX) mouse models, we demonstrated that B-ALL cells cause bone destruction and identified the receptor activator of nuclear factor kappa-B (RANK-RANKL) ligand axis as critical in these effects. Treatment of PDX mice with a RANKL antagonist recombinant Osteoprotegerin-Fc (rOPG-Fc) conferred robust protection from bone destruction. We examined routes of leukemic cell entry into the CNS and demonstrated that both mouse and primary human B-ALL cells migrated to the skull and vertebral bone marrow (BM) and further transited into the subarachnoid (SA) space of the CNS. Strikingly, rOPG-Fc protected both skull and vertebral BM from human B-ALL cell invasion and prevented transit into the SA space. Moreover, pharmacological inhibition of the C-X-C chemokine receptor type 4 (CXCR4) in human BCR-ABL+ PDX mice prevented leukemic cell migration from skull/vertebral BM into the SA space. Overall, these findings demonstrate two mechanisms of CNS invasion by B-ALL that can be opposed by targeted treatments. Finally, we identified unique transcriptional and functional signatures in pediatric mixed lineage leukemia (MLL) which reveal distinct cell intrinsic behavior of lymphoid- and myeloid-like MLL populations and striking adaptations to the CNS microenvironment. Collectively, this thesis reports novel molecular mechanisms of B-ALL mediated bone destruction and CNS invasion and identifies actionable therapeutic targets to reduce these morbidities.

Keywords: Acute Lymphoblastic Leukemia
B-ALL
CNS leukemia
CXCR4
RANKL
Advisor: Danska, Jayne S
The Dearest Butterfly: A Nonlinear, yet Stratified, Human-butterfly Ethnography

This dissertation is a multi-sited and multi-species ethnography which follows the migration of the monarch butterfly across the East Coast of Canada and the United States to the Oyamel Forest of central Mexico. The project builds upon ethnographic research at four nodal locations for monarch conservation: Point Pelee National Park in Ontario, Canada; Monarch Lab in Minnesota, U.S.; The Monarch Butterfly Biosphere Reserve in Mexico; and an online community named DPlex-L. The thesis develops the concept of the “Dearest Butterfly” to index the emergence of a new way of valorizing this migratory insect after it entered international networks of species conservation and to navigate what I call a non-linear and stratified assemblage that exists around the aspirations of conserving this charismatic insect. Along with this proposition, I chronicle and utilize the monarch’s sharp population decline as a means to unearthing North America’s devastated socioecology. The thesis argues that the insect’s falling numbers are related to the outcomes of nature-extensive exploitation and displacement of indigenous forms of knowing nature at the sites of study. In a non-linear fashion, I connect these outcomes with NAFTA’s circulation of goods and new forms of human displacement from Mexico to its northern neighbors to argue that protecting this tri-national butterfly was part of a plan to consolidate the North American region as an economic block that prizes mobilities of goods even while it seeks to prevent the movement of people, and, ironically, of monarchs. The thesis engages with the field of Science and Technology Studies by describing the everyday tensions of rendering the iconic monarch as a working and captive insect in the laboratory in order to conserve it. From the introduction Pendant Egg to the conclusion chapter Egg Under Review, I maintain that thinking with monarchs and their exceptional life cycle achieves a twofold outcome for anthropological research: it approaches the devastated monarch migratory corridor as an ecological, social, and technological assemblage; and it investigates existent cooperative and often uncooperative relations to critique this crisis, and hopefully re-vitalize it through a proposition of an ecosophy for migrating humans and nonhumans of North America.

Keywords: Animal Studies
Multi-sited Ethnography
Multi-species Ethnography
NAFTA
North American Nature Conservation
Posthumanities
Advisor: Cunningham, Hilary