VictorJuiz/thesis huggingface dataset:
Observations concerning the mechanism of action of glyceryl trinitrate
Keywords: aldehyde dehydrogenase
glyceryl trinitrate
mechanism of action
nitrate tolerance
nitroglycerin
vascular endothelium

Clinical observations suggest that aldehyde dehydrogenase-2 (ALDH-2) Glu504Lys polymorphism, a genetic mutation that renders a substantial loss of enzymatic function, does not always result in a reduced effectiveness of glyceryl trinitrate (GTN). We found no significant impact of the polymorphism on the hemodynamic responses to systemic administrations of GTN. However, the response of resistance vessels to local intra-arterial infusions of GTN was significantly blunted in subjects with the ALDH-2 polymorphism. ALDH-2 polymorphism also reduced the production of 1,2- and 1,3-glyceryl dinitrate (GDN), two common GTN metabolites, while having no effect on the overall biotransformation of GTN in whole blood. Finally, disulfiram, a non-selective inhibitor of ALDHs, was shown to significantly decrease the effectiveness of sublingual but not intravenous GTN. Furthermore, this inhibitor decreased the metabolism of GTN and the production of 1,2-GDN while increasing the generation of 1,3-GDN in whole blood of all subjects. Our results suggest that the biotransformation of GTN leading to its vascular effects is a complex phenomenon that involves multiple isoforms of ALDH expressed in various cellular compartments within diverse cell types located in different blood vessels. The therapeutic effectiveness of chronic GTN treatment is tremendously limited by the rapid loss of its hemodynamic and anti-ischemic effects, a phenomenon known as “nitrate tolerance”. Recent studies suggest that ALDH-2 mediated GTN biotransformation might be source of oxidative stress that leads to nitrate tolerance during sustained GTN therapy. We found that ALDH-2 polymorphism had no effect on preventing the development of nitrate tolerance and endothelial dysfunction, the latter of which is commonly associated with chronic GTN treatment. Our results suggest that ALDH-2 is unlikely to play a role in these phenomena. GTN has been long considered an endothelium-independent vasodilator; however, chronic GTN treatment has been shown to induce endothelial dysfunction, suggesting a potential interaction between GTN and the vascular endothelium. We found that in vivo inhibition of vascular endothelium by reducing the production of endothelium-derived vasodilators nitric oxide, prostacyclin and epoxyeicosatrienoic acids did not decrease GTN-mediated vasodilation of forearm resistance vessels, suggesting that the vasodilatory effect of GTN on resistance vessels is independent of vascular endothelium.
They Did the Police in Different Voices: Representations of the Detective on the Victorian Stage
Keywords: British
Detective
Drama
Police
Theatre
Victorian

In the spring of 1863, Detective Jack Hawkshaw strolled carelessly onto the stage of the Olympic Theatre. The first British stage detective of any significance, Hawkshaw ushered in the beginning of a detective era on the London stage. Established quickly as a significant part of the nineteenth-century theatrical scene, the stage detective was swiftly codified into a theatrical “line.” Always happy to adopt a fictional persona or throw off a disguise, to play with performance conventions or manifestly observe his theatrical counterparts, the stage detective spoke the language of nineteenth-century theatre. More than this, he became an integral part of contemporary dramatic structure and style, both facilitating melodramatic resolution and looking forward to the dandiacal style of Wilde’s society comedies. The plays which form the focus of this work are a mixture of the canonical and those unknown to modern scholarship: from Tom Taylor’s well-known 1863 play, The Ticket-of-Leave Man, to Clement Scott’s long-forgotten The Detective (1875), from Wilkie Collins’s stage adaptation of The Moonstone (1877) to two adaptations of Charles Dickens’s Bleak House. To build a clear picture of English attitudes to the new detective and his appearance on the London stage I draw from contemporaneous newspaper articles and accounts, critical reviews and essays dedicated to theories of performance, as well as acting manuals and official police orders. Understanding the detective’s dramatic purpose and theatrical positioning sheds light on nineteenth-century theatrical conventions – from the complex interplay between representation and authenticity to the ways in which the melodramatic universe was conceived – as laid out by scholars such as Lynn Voskuil, Martin Meisel, Peter Brooks and Elaine Hadley. It also better illuminates the epistemological frameworks of the period – from questions of deception and fraud to concerns about omniscience and earned authority – as explored by Audrey Jaffe, Lorraine Daston, Peter Galison and others. Despite his significance, the figure of the stage detective has received scant scholarly attention. By pursuing original archival research as well as revisiting the stage detective’s appearance in the more canonical work of the period, I aim to reinstate the detective in the theatre history of the period.
The Affective Point of View: Cross-Cultural Philosophical Investigations of Embodiment, Feeling, and Consciousness
Keywords: Affect
Consciousness
Embodiment
Subjectivity

This dissertation uses the conceptual resources of affective neuroscience and Indian Buddhist philosophy to explain the relationship between subjectivity and affect. I analyze subjective character in terms of an organism’s embodied first-personal perspective on the world. Further, I claim that the embodiment of the organism needs to be understood in terms of our ability to feel; our evolved capacity to be affected or ‘hedonically perturbed’ by our interactions with the world. An organism is hedonically perturbed or affected if it feels something as being positive or negative in response to the world’s sensory solicitations, pleasure and pain are paradigm examples. On my view, to be conscious is not just to be in contact with some object in perception, but to feel a certain way in virtue of being so related. It is tempting to think of affect exclusively in terms of short-lived episodes like strong emotions and novel sensory affects. When affect is thought of in this way, it can lead to the idea that affects in general are a kind of episodic modification of an otherwise non-affective stream of consciousness. On my view, which offers a reconstruction and interpretation of Indian Buddhist philosophy, experience is always affective in various ways. These include sensory, emotional, and homeodynamic affects that give the world value and meaning.
Realizing the Right to Health Care in Canada
Keywords: Economic
social
and cultural rights
Health law
Health rights
Human rights
Philosophy of law
The right to health care

International and domestic laws increasingly recognize health rights; international law clearly recognizes a right to health that includes health care entitlements and approximately 69% of domestic constitutions include a right to health care. Recognition of a positive right to health care has been slower to emerge in Canada, but there are nascent signs that the judiciary is receptive to the idea in principle. Challenges nonetheless remain – existing articulations of rights to health care do not easily fit the traditional ‘claim-right’ model of rights and questions remain over how to operationalize health rights, including how to do so without overwhelming the public fisc. It is difficult to resolve these issues in a manner that accounts for the structure of health rights in domestic constitutional laws, international human rights law, and philosophy. This work addresses these challenges and offers an account of the right to health care that is philosophically sound and operationalizable by courts and policymakers. I argue that a positive right to health care is best understood as a set of claims to related morally important goals. This pluralist understanding of the right can fit a modified version of the claim-right model and is independently justifiable. It is also consistent with the structure of health rights in international human rights law and some existing positive constitutional health rights. I next explain how to measure compliance with this pluralist right, providing an account of what the right to health care must accomplish in concrete terms. I then apply the metrics that I developed to the Canadian health care system and explore how three branches of public law (constitutional law, human rights law, and administrative law) can improve Canada’s scores on those metrics. I ultimately argue that all three branches can be reformed to better realize the pluralist right to health care.
From Strangers to Partners: Canadian-Korean Relations (1888-1978)
Keywords: Canada-ROK Trade
Canadian-Asian Relations
Canadian foreign policy
Canadian-Korean Relations
CANDU
Missionaries

From Strangers to Partners: Canadian-Korean Relations (1888 – 1978) Jiwon Tina Park Doctor of Philosophy Department of History University of Toronto 2018 Abstract This dissertation focuses on the transformation of Canadian-Korean relations between the 1880s and the 1970s. Drawing on archival materials from both Ottawa and Seoul, the study approaches the bilateral relationship primarily through the lens of Canadian attitudes, priorities and policies. Canadian missionaries, who first travelled to Korea in 1888, established the earliest bridges between the two countries. Canada’s official engagement with Korea began with its participation on the UN Temporary Commission on Korea (1947-48), followed closely by the Korean War (1950-53), which elevated South Korea’s geostrategic importance for Ottawa. Over the course of the Cold War, these humanitarian concerns soon blossomed into significant commercial and political interests, a change aided by South Korea’s remarkable economic growth under President Park Chung Hee’s leadership. By the 1970s, Canada and South Korea saw each other as significant partners and allies, marked by a rapid expansion in trade and immigration. Shifting alliances and geopolitical interests of the Cold War had important consequences for bringing the two nations together, as South Korea searched for new partners to counterbalance American dominance and expand into new markets. From Seoul’s perspective, Canada, in addition to growing commercial interests, was an important ally for its diplomatic competition against North Korea. The case of the CANDU nuclear reactor sales to Korea at the height of the détente era clearly demonstrate the shifting dynamics in Canadian-Korean relations. Ultimately, this study concludes that comprehensive study of the evolution of Canadian-Korean relations enriches our understanding of Canadian history, Canadian-Asian relations, and international history.
Back to the Future: Edwardian Comedy and Progressive Politics
Keywords: Comedy
Crisis of Liberalism
Edwardian
Fabian Society
Liberalism
Social Welfare

The Edwardian period is often figured as a garden party broken up by the First World War. Looking back on the early twentieth century from the perspective of the twenty first, a different, strikingly contemporary picture emerges: amidst social and technological change, world capitals were haunted by the threat of instability and economic inequality, while the political left faced urgent questions about its continued relevance. Contrary to the image of the period as complacent on the brink of disaster, my dissertation asserts that the Edwardians were deeply invested in building a better future through both political reform and literary comedy. Both comedy and progressive reform look toward the future; in both cases, the Edwardians negotiated between convention and innovation to attempt to create a more equitable future. The dissertation ultimately illustrates the crucial role of the period in literary history and how its lessons may inform our own, which it much resembles. In order to do so, my readings of specifically Edwardian texts are situated in relation to larger historical narratives of both comedy as a genre and political reform. The first chapter reads George Meredith’s “Essay on Comedy” (1877) and The Egoist (1879) alongside Gladstonian Liberal reforms. Like those interventions, the “Essay” looks toward beneficial changes within existing traditions, while The Egoist puts them into practice. The second chapter analyzes George Bernard Shaw’s Major Barbara (1905; 1907) alongside Edwardian discussions of social welfare. Shaw’s fictional Perivale St Andrews, patterned on contemporary company towns, critiques the shortcomings of Edwardian New Liberalism’s approach to a better future. The third chapter situates E.M. Forster’s Howards End (1910) in relation to the cascading crises engendered by the 1909 “People’s Budget.” Like its political moment, Forster’s novel makes failure the precondition of ameliorative possibility, a vision Forster carried beyond the writing of fiction. The persistence of Forsterian concerns is further examined in the final chapter on Zadie Smith’s NW (2012). Foregrounding Smith’s use of Forsterian elements to critique both the limitations of Forster’s vision and the attenuated futurity of neoliberalism, this final chapter asserts the resonances of the Edwardian period with our contemporary moment.
Inhibitory Dysfunction in the SOD1-ALS Motor Cortex
Keywords: Amyotrophic Lateral Sclerosis
Hyperexcitability
Inhibition
Interneuron
Motor cortex
Neurodegeneration

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of the motor system, typically affecting individuals over 60 years of age (Eisen et al. 1993; Brettschneider, Kurent, and Ludolph 2013). It results from motor neuron degeneration in the cortex and spinal cord and is characterized by catastrophic muscle weakness and atrophy that eventually spreads across the body as it progresses into later stages (Kiernan et al. 2011). Without any effective treatments available, ALS is 100% fatal with a median survival of 3 years following the onset of physiological symptoms (Talbot 2009, 2014). Recent studies on cortical dysfunction in ALS have reported anomalies in inhibitory synaptic transmission; however, little is known regarding the role of inhibition in ALS. Sufficient GABAergic inhibitory neurotransmission is not only critical for maintaining a balance between excitation and inhibition, but it is also capable of providing protective effects from excitatory motor neurons in the cortex (Bae et al. 2013). Thus, it is critical to understand how inhibition is affected in ALS and whether the inhibitory circuit can be manipulated to alter the outcome of the disease. The main objective of my PhD project was to determine if parvalbumin-positive (PV+) interneurons in layer 5 (L5) of the primary motor cortex (M1) regulate the pyramidal cell hyperexcitability in the SOD1G93A mouse model of ALS, which has been tightly linked to excitotoxic cell death (Foran and Trotti 2009; Bae et al. 2013). Additionally, using newly developed chemogenetic tools, I aimed to increase PV+-interneuron activity with the goal of reducing pyramidal cell hyperexcitability and delay the onset of ALS-associated symptoms. The principle novel discoveries from my thesis research are: (i) PV+ interneurons are hypoactive in the pre-symptomatic SOD1G93A mouse model of ALS; (ii) increasing PV+ interneuron-mediated inhibition onto L5-M1 pyramidal cells not only rescues M1 pyramidal cell hyperexcitability, it also delays the onset of ALS-associated motor deficits, preserves cortical neuronal populations, and significantly increases the lifespan of SOD1G93A mice; and (iii) tissues from the motor cortex of post-mortem SOD1-ALS patients and SOD1G93A mice show a marked decrease in key inhibitory proteins known to regulate inhibitory function.
Flipping The Secondary Mathematics Classroom: Teachers’ Perceptions on the Use of Video Instruction
Keywords: Flipped Classroom
Mathematics
Secondary School
See regulated Learning
Student Engagement
Video Instruction

The Flipped Classroom is an instructional strategy that reverses the traditional classroom that is more teacher-directed learning, to an environment where it is more student-centred and the instructor acts a facilitator. This is achieved through technology, where students can access teacher instructional videos online through different media sources. Four secondary school mathematical teachers took part in the initial stages of the research study, where I conducted face-to-face semi-structured interviews. Out of the four participants, one participant went further with this research study, that included observing his class, viewing his videos, post interviews after each class, and perceptions of student surveys once the observation period was completed. The observation period took place over five months, which included reviewing instructional videos used in the participant’s flipped classroom along with in-class observations of the participant’s teaching. At the end of the observation period, students took an online survey based on their engagement and experiences regarding the flipped classroom. An exit interview was also conducted at the end of the observation period with this participant, in order to get a better understanding of their experiences and challenges within the flipped classroom. The themes reported as strengths of video instruction included: flipped classroom engagement, student interactions, and mitigating learner challenges. However, when identifying challenges, themes included: technology, lack of student engagement, time, and buy-in. The main four findings of this research are: (1) students were in favour of shorter video instruction; (2) videos that provided multiple examples with different levels of difficulty helped with learning; (3) students preferred a blend between the non-flipped classroom as well as a flipped classroom format; and (4) students benefited from having teacher-directed instruction at the beginning of class as a way to engage with the material. The flipped classroom is a model of teaching that could help teachers implement strategies that hold students accountable for their learning. The flipped classroom can provide opportunities for students to become more familiar and comfortable with the use of technology. Flipped learning can provide students that may struggle with mental health, like student anxiety, a pathway to learning through a combination of independent learning and reflection, collaboration, active learning and one-on-one conversations with their teacher.
Targeting Neogenin as a Novel Therapeutic Approach for the Treatment of Retinal Degeneration
Keywords: cAMP
Neogenin
Rd1
Rd10
Retinal Degeneration
Retinitis Pigmentosa

Retinitis Pigmentosa (RP) is a genetically inherited condition characterized by progressive loss of photoreceptor cells and represents one of the most prevalent causes of blindness among working age populations. The mechanisms leading to photoreceptor death remain largely unknown and there are no available treatments. We have previously shown that the protein Neogenin is involved in regulating cell survival in the CNS. Here we show that Neogenin expression is induced in degenerating photoreceptors in two mouse RP models (Rd1 and Rd10). Degenerating photoreceptors have abnormally high levels of cGMP and cAMP, and here we demonstrate that 8-Bromo-cAMP administration was sufficient to induce Neogenin expression in-vivo in wild type mouse photoreceptors and in-vitro in human photoreceptor surrogate cells. Using targeted in-vivo electroporation, we then demonstrate that i) overexpressing Neogenin in mouse photoreceptors induces cell death and ii) that silencing Neogenin in degenerating Rd1 photoreceptors promotes survival. This suggests Neogenin acts as a previously unidentified pro-death signal in RP. To develop a potential therapeutic approach for targeting Neogenin in RP, we utilized a Neogenin function blocking peptide (4Ig) we developed that is capable of blocking Neogenin’s pro-apoptotic activity. Intravitreal injections of 4Ig were administered at the onset of photoreceptor degeneration in Rd1 and Rd10 mice. When assessed at advanced stages of disease progression, 4Ig treatment significantly improved rod photoreceptor survival and cone photoreceptor survival. Photoreceptor function was also significantly improved following 4Ig treatment as demonstrated by i) improved light-evoked ganglion cell recordings, ii) improved scotopic/photopic electroretinogram recordings and iii) improved visual acuity (OptoMotry; CerebralMechanics). Targeting Neogenin therefore represents an exciting new approach for the treatment of RP.
Class I Viral Fusion Glycoproteins: Structural Insights into Viral Entry Strategies and Immune Evasion
Keywords: gp41
Infectious Salmon Anemia Virus
Orthomyxovirus
Retrovirus
X-ray Crystallography

Class I viral glycoproteins (GP) facilitate entry via the catalytic fusion of the viral envelope with host cell membrane through irreversible conformational changes in the viral GP. Outside of their functions in entry, these GPs often contribute to viral pathogenesis through antibody evasion and direct modulation of the host immune response. In this thesis, we employed structural and biophysical techniques to generate insights into Class I viral GP-mediated entry strategies and immune evasion with the aim of defining molecular targets for fusion inhibition and rational vaccine design. We first set out to identify the stabilization strategies that promote the adoption of the final irreversible six-helix bundle conformation necessary for Class I viral fusion. We characterized structural features of several post-fusion Class I viral entry GPs; we found that viruses that fuse in a pH-dependent manner utilize carboxyl-carboxylate interactions to stabilize the Class I entry GP during fusion, whereas viruses that fuse in a pH-independent manner use a distinct strategy involving classic electrostatic interactions to provide the required stability. Our results provide the basis for future studies aimed at targeting the inhibition of viral fusion through the destabilization of the post-fusion conformation. The next set of studies focuses on generating new insights into two-component Class I entry systems. We provide a structural description of the hemagglutinin-esterase (HE) GP from the infectious salmon anemia virus (ISAV), generating insights into the ISAV fusion mechanism and defining a molecular blueprint for the rational design of ISAV entry inhibitors that target the viral receptor binding pocket. Our final set of studies illustrates the structural determinants of immunodominance associated with the Class I viral fusion GP from HIV-1. Using X-ray crystallography, we demonstrate that the HIV-1 gp41 immunodominant region 1 (IR1) presents two distinct conformations to the host humoral immune system, potentially driving an ineffective response.