VictorJuiz/thesis huggingface dataset:
Understanding the Experiences of Individuals in Midlife Living with Anorexia Nervosa: A Constructivist Grounded Theory Study
Keywords: Anorexia nervosa
Grounded theory
Midlife

Understanding the Experiences of Individuals in Midlife Living with Anorexia Nervosa: A Constructivist Grounded Theory Study Doctor of Philosophy, June 2019 Leslie Ann McCallum Factor-Inwentash Faculty of Social Work University of Toronto Background Anorexia nervosa (AN) is a complex, life-threatening mental illness with high comorbidity rates. This disorder has one of the worst prognoses of all mental illnesses, with a mortality rate of 10.5%. It affects people of varying socioeconomic statuses, cultures, sexes, genders, and ages. There is no universally effective treatment for adults living with AN. Despite the high percentage of individuals who continue to live with AN for decades, there is limited understanding of what it means to be in midlife living with a disorder that is more commonly noted to occur among adolescents and young adults. The purpose of this dissertation research was to build understanding of the experiences of adults in midlife (40 to 65 years of age) living with AN to inform clinical practice and support for this population. Methods A qualitative study design was chosen using constructivist grounded theory methodology. This dissertation research was conducted in accordance with the ethics protocol approved by the Health Sciences Research Ethics Board of the University of Toronto. Nineteen individuals in midlife (40 to 65 years of age) living with AN participated in individual, in-depth interviews to explore their experiences of living with AN in midlife. Results Four main findings emerged from this study. First, based on comparing narratives of participants’ accounts of their experiences of living with AN in midlife and as young adults, important differences exist between living with AN in midlife versus when one is younger. Second, based this sample and their retrospective accounts, complex trauma is common among individuals in midlife living with AN. Third, midlife can act as a barrier to seeking treatment and/or facilitate disengaging from treatment. Fourth, shifts occur in midlife that can act as catalysts to fully engaging in recovery. Implications Findings from this dissertation research provide a framework for understanding the unique qualities and experiences of individuals in midlife living with AN, and their capacity for treatment engagement. Honouring the added challenges that come with midlife, as well as harnessing qualities developed in midlife, will help this older age group move forward with their recovery journey.
Becoming Saints: Coptic Orthodox Monasticism, Exemplarity, Negotiating Christian Virtue
Keywords: Anthropology of Ethics
Diaspora
Exemplarity
Orthodox Monasticism
Transnationalism

Based on 13 months of transnational ethnographic fieldwork between Egypt, Southern California, and Toronto, this dissertation examines questions around exemplarity, morality, and the cultivation of virtue among Coptic Orthodox Christians. Specifically, this thesis investigates the relationship between Coptic monks and the wider Coptic community. Many Copts view monasticism as a morally exemplary way of life. The monk as one who has forsaken all social ties and lives in the desert is regarded as one who has attained the highest form of virtue. This view results in different levels of engagement with monastic practice and competing voices for what it means to be a Coptic Christian. As will be demonstrated through ethnographic details, there is a gap between the ideals of the Coptic monastic imaginary and the lived reality of negotiating Christian virtue for monks and laity alike. Furthermore, this dissertation unpacks the ways in which Coptic monasticism is (re-)imagined and (re-)produced in North America and how Coptic subjectivity is (re-)negotiated in relation to Egypt and the Mother Church.
Chaperone Systems in Model Organisms
Keywords: Chaperones
Homeostasis
Proteins
Proteomics
Saccharomyces cerevisiae
Systems Biology

Molecular chaperones are typically promiscuous interacting proteins that function globally in the cell for quality control and maintenance of protein homeostasis. They are highly conserved across all organisms. A comprehensive view of their cellular function was obtained through a systematic global integrative network approach. We deciphered interactions involving all core chaperones of Saccharomyces cerevisiae. Our analysis revealed the presence of a large chaperone functional supercomplex encompassing Hsp40, Hsp70, Hsp90, AAA+, CCT, and small Hsps, that is central to the topology of the proteome network. Chaperone interactor properties demonstrate preferential protein domains and folds such as the WD40 repeat domain. We further found that many chaperones interact with proteins that form condensates under stress conditions. This expanded view of the chaperone network in the cell clearly demonstrates the distinction between chaperones having broad versus narrow substrate specificities. From an extensive genomic analysis in bacteria we demonstrate the conservation of the close proximity of the tig gene, coding for the ribosome-associated chaperone trigger factor (TF), and the genes coding for the ClpXP proteolytic complex suggesting a possible functional association between the protein folding and the protein degradation systems. The effect of TF on ClpXP-dependent degradation varied depending on the nature of the substrate. For a class of substrates, TF increased the degradation rate. The ClpXP-dependent degradation was enhanced for the λ phage replication protein λO, the master regulator of stationary phase RpoS, and SsrA-tagged proteins by TF in vitro and in vivo. Globally, it is estimated that TF enhances the degradation of about subset of newly synthesized E. coli proteins. Through extensive biochemical and structural analyses, it was found that TF interacts through multiple sites with the ClpX oligomer in a highly dynamic fashion. TF binds the ATPase-domain of ClpX and consequently promotes the movement of the protruding N-terminal zinc binding domain (ZBD) of the chaperone towards the ClpP cylinder. With this movement, TF enhances the degradation of ZBD-bound substrates. These results reveal a novel function of TF as a ClpXP adaptor protein and highlight its broad substrate specificity. This chaperone-protease cooperation constitutes a novel aspect of cellular protein homeostasis.
Characterization of Slam-mediated Surface Lipoprotein Translocation across the Bacterial Outer Membrane
Keywords: Gram negative bacteria
In vitro reconstitution
Outer membrane
Outer membrane proteins
Protein translocon
Surface lipoproteins

Surfaces of many Gram-negative bacteria are decorated by peripheral membrane proteins that are anchored in the membrane by a lipid group, commonly referred to as surface lipoproteins or SLPs. SLPs play key role in nutrient acquisition, immune evasion and have been proposed as excellent vaccine antigens. Previously our lab had shown that the proper display of host transferrin binding SLP TbpB in Neisseria meningitidis required an outer membrane protein called Slam. The aim of the present study was to investigate the role Slam plays in SLP biogenesis. Using bioinformatic analysis, we show that Slams are present in a number of Gram-negative bacteria. Putative Slam genes are often found adjacent to their putative SLP substrates. In N. meningitidis, we discovered two Slam paralogs, Slam1 and Slam2, that are specific for SLPs TbpB and HpuA respectively. All putative Slam-dependent SLPs contain a C-terminal 8-stranded soluble barrel domain. The last two strands of the SLP were found to be essential for TbpB translocation and the C-terminal 8-stranded barrel domain mediated Slam specificity. Using GST-fused TbpB, we showed that the Slam-dependent translocation occurs from the C-terminus to the N-terminus. To investigate Slam mechanism, we developed an in vitro translocation system. Upon the addition of the periplasmic chaperone LolA, SLPs can be released from spheroplasts into the supernatant. We discovered that Slam containing proteoliposomes can successfully translocate spheroplast released SLPs into the liposomal lumen. Addition of other outer membrane factors such as the Bam complex did not increase the efficiency of SLP insertion and Slam12 retained their specificity in the assay. Interestingly, Slam1 proteoliposomes were also able to translocate purified unfolded TbpB into the lumen. Collectively, these findings show that Slams are both necessary and sufficient for the translocation of SLPs across the outer membrane, indicating that they act as translocons.
Investigating the Neural Circuits that Control Cataplexy
Keywords: cataplexy
muscle tone
narcolepsy
REM sleep
subcoeruelus
sublaterodorsal tegmentum

In this thesis I explored a long-standing hypothesis that the paralysis occurring during REM sleep and cataplexy share a common neural mechanism. Cataplexy, a debilitating symptom of narcolepsy, is the abrupt onset of skeletal muscle paralysis during wakefulness. Under normal conditions, neurons of the sublaterodorsal tegmental region have been shown to be active during REM sleep and either activate GABA/glycine neurons of the ventral medulla or inhibitory interneurons in the spinal cord which in turn silences motoneurons and results in REM sleep muscle paralysis. The mechanism mediating the paralysis of cataplexy has not been fully characterized but is hypothesized to result from the abnormal activation of SLD neurons during wakefulness. First, I investigated if activation of all cells in the SLD nucleus could trigger cataplexy in wildtype (hypocretin-intact) mice and narcoleptic (hypocretin knockout) mice. Next, I investigated if glutamatergic, VGLUT2-expressing, neurons of the SLD were the cellular phenotype responsible for triggering cataplexy in wildtype and narcoleptic mice models. This final investigation required the development of a new hypocretin knockout mouse line (hypocretin -/- , VGLUT2-Cre mice). This new model is scientifically important as it provides an innovative toolkit for neuroscientists to examine the role of glutamatergic cell populations throughout the brain of mice with a narcolepsy phenotype. Several major conclusions can be drawn from my results: 1. Cataplexy and REM sleep share a common neural mechanism that generates muscle paralysis. Activation of the SLD nucleus triggered cataplexy in wild type mice. This is a significant finding as it is the first time that cataplexy has been triggered in wildtype mice. Similarly, narcoleptic mice experienced an increase in the number of cataplexy episodes after activation of the SLD nucleus. 2. Activation of VGLUT2-SLD neurons in VGLUT2-Cre (hypocretin intact) mouse results in overall muscle weakness during wakefulness but does not trigger cataplexy episodes. 3. The VGLUT2-expressing SLD neurons are a component of the neural circuit that triggers cataplexy. Activation of the VGLUT2-SLD neurons in hypocretin knockout mice resulted in increased number of cataplexy attacks without altering the duration of the episode.
Relationships between Urban Environments and Crdiovascular Disease Risk
Keywords: Air Pollution
Built Environment
Canada
Cardiovascular
Risk Factors
Walkability

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.
Managing Multimorbidity in Primary Care: Measuring Collaboration Efforts within and across Organizational Boundaries
Keywords: collaboration
interorganizational
interprofessional
network analysis
Ontario
primary care

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.
Accounting for Variability and Uncertainty in Life Cycle Assessments: Oil Sands Case Studies
Keywords: Greenhouse gas emissions
Life cycle assessment
Oil sands
Uncertainty
Variability

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.
A Gentlewoman's Profession: The Emergence of Feminized Publishing at Richard Bentley and Son, 1858-1898
Keywords: Book History and Print Culture
Gender History
Publishing
Victorian Women's Literature
Women's Movement
Women's Professionalization

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.
Engineering Diphtheria Toxin as an Intracellular Protein Delivery Platform
Keywords: Intracellular delivery
toxin delivery

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.