VictorJuiz/thesis huggingface dataset:
The Role of Stat3 in Mouse Models of Inherited Photoreceptor Degeneration
Keywords: Retina
Photoreceptor
Neuron death

Inherited photoreceptor degeneration (IPD) is characterized by progressive death of mutant photoreceptors (PRs). To date, mutations in over 186 genes have been associated with IPD. Unfortunately, little progress has been made towards treatment to prevent PR death. Here I show that expression of the signal transducer and activator of transcription 3 (STAT3) is increased and activated by tyrosine phosphorylation in both PRs and Müller glia of three mouse models of IPD (Tg(RHO P347S), Prph2rds+/- and Pde6brd1/rd1). To determine whether this endogenous activation of Stat3 expression influence PR degeneration, I genetically manipulated Stat3 expression in these two cell types in three IPD models. PR-specific deletion of Stat3 significantly accelerated PR death in Tg(RHO P347S) and Prph2rds+/- retinas. These data revealed, for the first time, that the increased expression of endogenously activated PR-STAT3 is a survival response in mutant PRs. Accordingly, increases in Stat3 expression may form the basis of a PR protective therapy in IPDs. To examine this hypothesis, I transgenically expressed various Stat3 alleles specifically in the PRs of wild type and IPD mice. The expression of a wild type Stat3 allele or a constitutively active Stat3 allele (Stat3C) in the PRs increased their survival in Tg(RHO P347S) mice at PN30 and in Prph2rds+/- mice at 6 months. Phosphorylation of STAT3 at tyrosine 705 was required for the pro-survival effect as the introduction of a Stat3Y705F allele was not protective. Unexpectedly, the deletion of Stat3 from PRs of Pde6brd1/rd1 mice improved PR survival. The basis for this contrasting result is unclear. However, as with the other two IPD models, PR survival was increased with expression of wild type Stat3 or Stat3C alleles in the PRs of Pde6brd1/rd1 mice. When Stat3 was deleted specifically in Müller glial cells in Prph2rds+/- retinas, a small but significant increase in PR survival was observed at 6 months of age, suggesting that the increased expression of Stat3 in Müller glial in IPDs may be pathogenetic. In summary, I have demonstrated that the increased expression and activation of STAT3 is a survival response in mammalian IPDs, a finding with important therapeutic implications for human retinal degenerations.
Early Employment Experiences of Canadian Young Adults Living with Systemic Lupus Erythematosus, Juvenile Arthritis and Spinal Cord Injury
Keywords: Employment
Productivity
Young adulthood
Work and health
Disabled workers
Systemic lupus erythematosus
Juvenile arthritis
Spinal cord injury

Background: Participating in employment is an important milestone signaling the transition to adulthood. Few studies have examined how chronic diseases influence early work experiences. Purpose: This study examined barriers and facilitators to the employment status of young adults, ages 18-30 years, with systemic lupus erythematosus, juvenile arthritis and spinal cord injury; researched employment outcomes like work-health conflict, absenteeism, job disruptions and perceived productivity loss; and investigated barriers to employment among those not working. Methods: 155 participants were recruited from clinics in four Canadian provinces. Participants completed a 30-minute online cross-sectional survey of their work experiences. Demographic, health, psychosocial and work context information was collected. Bivariate and multivariable analyses were performed. Results: Over half of respondents were employed; a quarter of respondents were enrolled in school. Older participants, those reporting greater independence/autonomy, and participants reporting that fewer job accommodations would help them work, were more likely to be employed. Employed participants reported moderate work-health conflict and close to half reported absenteeism, job disruptions and some productivity losses. Greater perceived independence/autonomy, less fatigue and disease activity, and disclosing to others was related to lower work-health conflict. Less fatigue and social support, and greater self-disclosure and job control were related to absenteeism. Job control also was associated with less productivity loss. Among respondents not working, health was generally not a perceived barrier to employment, but drug benefits and work scheduling flexibility were desirable accommodations. Conclusions: Respondents were able to work and be productive despite health problems like pain, fatigue and activity limitations. Relationships with others that were supportive but also fostered independence/autonomy were important to the employment experiences of respondents and deserve greater attention in research. Policies and practices that emphasize work scheduling flexibility and recognize the importance of ongoing health management may help young adults with chronic diseases find and maintain work.
A Multi-Dimensional Outcomes Study in an Inception Cohort of Patients with Interrupted Aortic Arch
Keywords: Surgery
Cardiac surgery
Congenital cardiac surgery
Congenital heart disease
Interrupted aortic arch
Subsequent interventions
Functional health status
Transition to adult care

The fundamental goal of pediatric cardiac surgery is to enable patients with congenital heart disease to achieve a long and healthy life; hopefully, one comparable to that of their peers. While there is an understanding that long-term assessment is required over the course of a patient’s lifetime, the manner in which the success of surgical intervention is measured in these patients should be multi-dimensional with outcomes measured in numerous domains. This thesis explores the outcomes of patients within a multi-institutional prospective inception cohort of patients with interrupted aortic arch in relation to the durability of surgical intervention, functional health status, and transition to adult care from pediatric care. We first demonstrate that there is a persistent risk of subsequent procedures and mortality in patients after interrupted aortic arch repair. We also demonstrated that interrupted aortic arch is a chronic disease of a complex nature whereby patients often require multiple procedures after their index repair, that the risk of aortic arch and left ventricular outflow tract procedures varies by phase (time-related), and the factors associated with both of these in addition to mortality. Our study on functional health status demonstrates that both adolescents and young adults with interrupted aortic arch primarily rated themselves the same or better than their normal peers. Our study on transition to adult care demonstrates that transition occurred in only 32% of patients by age 21, and was associated with Canadian residence. Questionnaire results also demonstrated poor levels of patient knowledge regarding their disease and strong parental involvement. The studies presented represent the diversity of long-term outcomes that should be analyzed in order to improve patient care using a multi-dimensional approach. Future studies will focus on definitive repair techniques, ameliorating factors associated with poor functional health status, and improving transition to adult care.
Homelessness, Health, and Literacy: An Institutional Ethnographic Study of the Social Organization of Health Care in Ontario, Canada
Keywords: health care
access

This thesis presents findings from an institutional ethnographic study that examined the experiences of 27 individuals who frequented an Open Access homeless shelter in Greater Toronto, Ontario. Many participants interviewed in the study either lacked an Ontario Health Insurance Card, or they expressed little interest in acquiring one. Individuals who had chosen not to seek reissuance of their health cards either implicitly or explicitly self-excluded themselves from participation in programs and services that, although useful to them, might be seen to regulate, control, and thereby subordinate their interests to those of the dominant institution. This study sought to map, locate, and make visible the local, everyday experiences of individuals at an Open Access shelter, and to situate that map within the translocal and often invisible realm of broader neoliberal ideologies and their related bureaucratic health care policies and directives. Neoliberal doctrines have also been evidenced in recent health care reforms, including the reduction in welfare spending and social subsidies, the centralization of federal power and authority over provincial mandates, and the implementation of high-tech computerized monitoring and management systems designed to reduce fraudulent access to health care. This study not only explicated the different forms of literacy (organizational, technological and health literacies) that are both employed and reproduced in institutional settings, but it also examined the role of literacy within larger social, political, and economic contexts. Using an institutional ethnographic method of inquiry, this study examined the ways in which literacy (or the lack of literacy) shapes and mitigates the experiences of homeless individuals attempting to gain access to health care. This study asked: How are institutional health policies evidenced in the everyday, material lives of real people? Are such policies potentially exclusionary?
Masks and Masked Performance in Giorgio Strehler's Vision of the Commedia dell'Arte
Keywords: Giorgio Strehler
Masks
Amleto Sartori
Donato Sartori
Piccolo Teatro of Milan
Carlo Goldoni
The Servant of Two Masters
Masked Performance
Performance History

This thesis examines the role of solid and painted masks in Giorgio Strehler's successive stagings of Carlo Goldoni's "Servant of Two Masters" at the Piccolo Teatro of Milan between 1947 and 1997. Through my description and analysis of documentary evidence about these stagings, the Piccolo Teatro, Giorgio Strehler, his mask-makers Amleto and Donato Sartori, his actors, and lighting designer, I demonstrate that masks were used in the above-mentioned productions as rhetorical tools that expressed Strehler's relationship with Goldoni (the man and his work), communicated his political convictions on stage, partook in his attempted reform of the Italian theatre after World War II, displayed his vision of theatre history, proved his endorsement of the actors' potential in performance, and helped position the Piccolo Teatro within an Italian and pan-European artistic elite. My examination of video recordings and photographs of the productions, letters of personal correspondence, theatre reviews, transcriptions of interviews, and programme notes, among other documents, traces the evolution of Strehler's interpretative vision of the Commedia dell'Arte over fifty years. This vision, as I argue in the introduction and conclusion to my thesis, helped shape how other theatre directors, educators, as well as actors, mask-makers, and, arguably, academics have come to imagine Goldoni's work, Commedia dell'Arte, and masked performance. A close study of Strehler's successive stagings of "The Servant of Two Masters" and of the use of masks within them will therefore allow for a better understanding of Strehler's trajectory in the theatre, but will also exemplify how the use of a particular theatrical object (the mask) in a series of productions that were successful worldwide influenced how many of us now perceive a performance tradition (Commedia), a theatre (the Piccolo Teatro), and a play ("The Servant of Two Masters").
Mereological Nihilism: Substance and Matter in Leibniz's Metaphysics
Keywords: Leibniz
Matter
Substance
Unity
Part
Whole
Mereology
Nihilism
Plurality
Metaphysics
Logic
Mathematics

Central to Leibniz's philosophical system is his view that substances must have genuine unity, that they must be simple or indivisible. In this dissertation, I argue that Leibniz's well-known view that substances must be simple, i.e. without parts, follows from his commitment to mereological nihilism--the view that nothing with a plurality of parts is truly one being. I begin by offering a detailed analysis of Leibniz's view that matter or body is inherently plural. I argue that the reasons for this view have not been fully understood, and are rooted in Leibniz's claim that matter is discrete. I then defend Leibniz's commitment to the plurality of matter against what I call the 'Spinozistic Challenge' according to which the entire physical world is a single substance, a view sometimes attributed to Descartes. This challenge alleges that since the physical world is a plenum, the parts of matter can't exist without the entire physical world, and as such the physical world is really one thing, not many things. I argue that, for Leibniz, the sort of dependence involved here does not undermine the plurality of matter. After establishing the reasons for Leibniz's view that matter is inherently plural, I turn to Leibniz's frequent talk of composite, corporeal substances. How can Leibniz account for such substances given his views that matter is inherently plural and that no substance--no true unity--has a plurality of parts? I first examine Leibniz's view that composite substances have bodies that are actually infinitely divided. It seems that this view conflicts with Leibniz's explicit rejection of infinite number. I defend the claim that Leibniz can accept infinite pluralities without accepting infinite number. Finally, I analyze Leibniz's attempt to reconcile the existence of composite substances with his view that no substance has parts. Ultimately, I argue, this attempt fails to offer a real account of the per se unity of composite substances, and this leads Leibniz to a theory where only monads are genuine substances.
Molecular insights into the mechanisms underlying the pleiotropic functions of Munc18-1 in dense-core vesicle exocytosis
Keywords: Munc18-1
exocytosis
dense-core vesicle

Exocytosis refers to a cellular process in which an intracellular vesicle fuses its membrane with the plasma membrane to release its contents to the extracellular space. This process underlies diverse physiological processes such as communication between neurons, hormonal regulation, and immune responses. Munc18-1 is an indispensible protein that regulates exocytosis during neuronal communication and hormonal signaling. It is known to specifically interact with one or more SNARE proteins (syntaxin-1, SNAP-25, and synaptobrevin-2) through diverse binding modes. Multiple lines of evidence suggest the pleiotropic functions of Munc18-1 although they are sometimes contradictory: as a molecular chaperone of syntaxin-1, in priming of dense-core vesicles (DCVs) to fusion competent state, and in docking of DCVs to the plasma membrane. Munc18-1 consists of multiple domains: domain-1, -2, -3a, and -3b. However, the molecular mechanisms underlying the functions of Munc18-1 in exocytosis remain unclear. It was hypothesized that the multiple roles of Munc18-1 occur through its distinctive binding modes with SNARE proteins, which in turn are mediated by its specific domains. The structure and interactive properties underlying its essential roles were investigated through detailed phenotypic analyses of various domain-specific Munc18-1 mutants upon re-expression in Munc18-1/-2 double knockdown PC12 cells through lentivirus mediated infection. The results demonstrate that domain-1 and domain-3a of Munc18-1 are critical for a high affinity binary interaction with the closed form of syntaxin-1, which is crucial for syntaxin-1 trafficking and consequently in DCV docking and secretion. Furthermore, domain-3a of Munc18-1 additionally plays a crucial role in priming exocytosis by regulating SNARE complex interaction, which occurs independently from its role in syntaxin-1 stabilization and trafficking. Taken together, we postulate that Munc18-1 sequentially adopts distinctive binding modes at different stage of exocytosis that enable it to regulate each step through highly specialized mechanisms. The findings from this study provide novel insights into the obscure mechanisms underlying the functions of Munc18-1 in regulated exocytosis.
MicroRNAs as Biomarkers in Mantle Cell Lymphoma
Keywords: microRNA
lymphoma
mantle cell
non-Hodgkin
prognosis
biomarker
pathogenesis

Mantle cell lymphoma (MCL) is diagnosed through its distinctive immunophenotype and recurrent t(11;14)(q13;q32) translocation. This translocation causes the juxtaposition of CCND1 and the IGH promoter leading to cyclin D1 over-expression. MCL is incurable with conventional chemotherapy however survival varies significantly and ranges from 1-10 years. Accurately determining patient prognosis would enable tailoring of therapeutic regimens to individual patients. Although the presence of the t(11;14) translocation and subsequent up-regulation of cyclin D1 is found in a majority of MCL, it is not necessary for disease development, as evidenced by the existence of cyclin D1-negative MCL, and also because in vivo MCL animal models demonstrate that further cellular pathway deregulation is required for pathogenesis. We wanted to determine whether microRNAs (miRs) could be used to determine MCL prognosis and pathogenesis. Our study examined a quantitative real-time PCR-based platform for miR expression profiling in both fresh-frozen and formalin-fixed, paraffin-embedded (FFPE) tissues. We demonstrated that miR expression profiles of FFPE samples are comparable to those of fresh-frozen samples, with a correlation of up to 0.87 (p<0.001), when examining all miRs, regardless of RNA extraction method used. We also wanted to examine miR profiles in aggressive and indolent non-Hodgkin lymphoma (NHL) to generate a signature that defines aggressiveness and to see whether or not this could predict prognosis in MCL patients. Using our platform, we determined that eleven miRs are differentially expressed between aggressive and indolent NHL. Two miRs were associated with overall survival in MCL and were combined with clinical prognostic factors to generate novel prognostic data for MCL patients. Finally, we wanted to determine if a miR signature characteristic of MCL could be discovered by comparing the miR profiles of MCL to those of aggressive and indolent NHL. Our study discovered an 8-miR signature characteristic of MCL, consisting of 3 miRs under-expressed relative to aggressive NHL and 5 miRs over-expressed relative to indolent NHL. These miRs may be involved in transcription regulation, protein kinase signaling, cell survival and proliferation, cellular senescence, and regulation of cell migration and invasion, suggesting the need for further study into these pathways and their roles in MCL pathogenesis.
When Beruriah Met 'A'isha: Textual Intersections and Interactions Among Jewish and Muslim Women Engaged with Religious Law
Keywords: Jewish Studies
Islamic Studies
Gender Studies
Law
Scriptural Interpretation
Ethnography

This study explores various understandings of religious authority, law and empowered textual interpretation among two distinct yet inter-related groups of Jewish and Muslim women: contemporary academics and laywomen in North America who are engaged in the study of classical religious texts. There are two modes through which I examine these interpretive activities by women: the first approach involves a comparative textual analysis of academic writings on religious texts by women, while the second utilizes feminist ethnography to zero in on the textual experiences of Jewish and Muslim laywomen who spent time studying religious texts together. Although the entitlements offered to women under secular laws in North America generally surpass those granted to them under Jewish and Islamic law, rather than abandoning religious laws entirely, Jewish and Muslim laywomen and exegetes continue to grapple with religious legal texts and praxis, since these are bound up with notions of identity, community and belonging. But rather than accepting the status quo, this highly-educated subset of Jewish and Muslim women empower themselves to reinterpret traditional texts and adapt communal practices to better reflect more inclusive and egalitarian values. Through their academic works, scholars such as Amina Wadud, Tikva Frymer-Kensky, Judith Hauptman, Fatima Mernissi, Kecia Ali and Rachel Adler revisit religious law and succeed in broadening the communal spaces, leadership roles and personal status entitlements available to Jewish and Muslim women. Similarly, when Toronto-based laywomen challenge the ideas coming from the pulpits of their local mosques and synagogues, or use their own knowledge of texts and other extra-textual sources to redefine how they eat, dress and pray as Muslims and Jews, they are pushing the boundaries of how each community views women, traditional praxis and authority, forcing us to confront what it means to be a Jewish or Muslim woman scholar in the twenty-first century. These acts of empowered interpretation and religio-legal reform among both laywomen and exegetes arise from a similar source: a "textual confidence", which is a strange alchemy of a solid traditional and secular education, strong familial and communal supports, but is equally related to one's geography, conceptions of gender and perceptions of authority.
Analysis, Systematicity and the Transcendental in Hermann Cohen's System of Critical Idealism
Keywords: Idealism
Cohen
Neo-Kantianism

The dissertation provides a systematic, critical analysis of Hermann Cohen's System of Critical Idealism. The first chapter establishes Cohen's reading of the a priori of Kant's Transcendental Aesthetic as founding the possibility of intuition in mathematics, rather than the possibility of mathematics in intuition. The second chapter then investigates the problem of the unity of the transcendental object, or, more specifically, the conditions under which the intelligible predicates of the functions of judgement can be applied to an objective unity. Chapters three and four compare the idealist responses of Salomon Maimon and G.W.F. Hegel to the problem of objective unity. Both Maimon and Hegel attempt to provide a logic (and a manifold of reality) grounded in the Spinozistic principle of determinability. Ultimately, this leads to the conflation of the totality of intuition with the domain of the intelligible thereby reducing Kant's infinite judgement to a positive assertion. Cohen, however, rejects this solution, and insists that the manifold of reality (or the real continuum of calculus) is the product of continuous thinking. Cohen's principle of production implies an indeterminably determinable manifold, thus providing the intelligible foundations for the eventual set-theoretic foundation of arithmetic and analysis. The final chapter of the dissertation investigates the consequences of Cohen's innovation for the prospects of systematic idealism as a framework within which normative, theoretical and aesthetic claims may be raised and justified. Since logic does not determine a priori the structure of the intelligible whole, Cohen cannot assume a convergence between natural and ethical representations. The free production of laws, Cohen argues, is the practice of jurisprudence, or, the construction and reconstruction of assertoric statements (universal claims) with the aim of limiting contradictions. If, in the natural sciences, we call this aim truth, in ethics, we call it the good, guided by the idea of the end of humanity.