VictorJuiz/thesis huggingface dataset:
A Novel Model System is Applied to Examine the Interplay of Notch and GATA Factors during T Lineage Committment

T lymphocytes comprise one arm of the adaptive immune system and are critical for immunity to neoplasia and infection. A full understanding of their development has important implications for the treatment of autoimmunity, immunodeficiency, and leukemias arising from T cell developmental intermediates. The Notch signaling pathway is already known to be absolutely required for T cell commitment and development, but its collaboration with other factors is poorly understood. Unfortunately, deficiency in many of the genes critical to hematopoiesis, including Notch, causes early embryonic lethality by disrupting multiple developmental processes. This complicates the study of such genes by in vivo models or ex vivo hematopoietic progenitors. To circumvent these difficulties, this thesis describes the use of in vitro-differentiated embryonic stem cell-derived T progenitors to examine the roles of two GATA family members during early T cell development. GATA-2, while not required for T cell development, is shown to act downstream of Notch signals to inhibit myelopoiesis. These findings both characterize a novel role for GATA-2, and demonstrate that T progenitor maturation and exclusion of non-T cell fates are distinct and separable events. GATA-3, in contrast to GATA-2, is absolutely required for T lymphopoiesis. However, the current literature does not distinguish between a requirement for GATA-3 in homing to the thymic environment, committing to the T cell fate, or surviving such a commitment event. This thesis demonstrates that GATA-3 is dispensable for commitment itself, but required to permit survival and proliferation after commitment. Taken together, the results presented in this thesis employ a novel model system to characterize the interactions of two important collaborators with Notch signals during T cell development, and further dissect the stages through which early T cell development is enacted.

Keywords: lymphopoiesis
T cell development
OP9-DL1
embryonic stem cell
GATA
Notch
Advisor: Zuniga-Pflucker, Juan Carlos
Immune Evasion and Viral Replication: Examining the Pressures that Influence the Evolution of CD8+ T-cell Epitope Sequences During HIV Infection

The evolution of immune escape during HIV infection is well documented, yet some CD8+ T-cell epitopes remain conserved even in the presence of strong cognate responses. This report investigates the frequency of sequence variability within the HLA-A2 restricted immunodominant epitope SLYNTVATL (SL9). Sequencing results, from 15 HIV+ HLA-A2+ individuals, support a very high degree of conservation of this epitope sequence with only focused, conservative changes evident in proviral quasispecies. These observations suggest that changes to the SL9 sequence may have deleterious effects on viral replication and are therefore limited in vivo. To investigate the sequence constraints imposed on the SL9 epitope by HIV replicative fitness, HIV plasmid clones incorporating synonymous and non-synonymous mutations throughout the SL9 epitope region were constructed. Growth of the resultant congenic viruses in mono-infection assays indicated a wide diversity of SL9 variant viruses that grew efficiently. Furthermore, dual-infection viral competition assays demonstrated that SL9 variants known to arise in vivo were equally fit to consensus SL9 virus and several novel epitope variants were also able to compete effectively. Collectively, the data reported in this thesis reveal that the viral pressures acting to conserve the SL9 epitope sequence are less than previously assumed and highlight the lack of understanding of protective CD8+ T-cell action during HIV infection.

Keywords: Immunology
virology
HIV
Advisor: MacDonald, Kelly S.
Luscher, Mark A.
The Quality of Surgical Care for Radical Cystectomy in Ontario from 1992 to 2004

This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.

Keywords: Epidemiology
Medicine and Surgery
Clinical epidemiology
Bladder cancer
Outcomes
Health Services Research
Volume
Wait times
Advisor: Laupacis, Andreas
Fleshner, Neil
Assessment of Operative Strategies to Improve Coronary Bypass Graft Patency

The ultimate success of bypass surgery depends on the construction of a technically perfect bypass graft to an appropriate coronary vessel using a conduit which will remain durable for the lifetime of the patient. This thesis explores methods to improve coronary surgery by enhancing intraoperative imaging and conduit selection in the operating room. It is known that technical errors in graft construction cause failure of up to 12% of coronary bypass grafts in the operating room. We performed investigations of a new technique of intraoperative fluorescence angiography using indocyanine green dye to determine graft patency. We developed optimal methods of obtaining images and preliminary investigations revealed the technique was highly reproducible. In a follow-up trial, we demonstrated that over 80% of technical errors which would otherwise have been missed were identifiable with indocyanine green angiography, while only 25% of these errors were identified by transit-time ultrasonic flow measurement, the current clinical standard. We also determine that coronary surgery with indocyanine green angiographic graft patency verification was associated with less perioperative myocardial injury than bypass surgery without graft patency assessment. The long term graft patency of saphenous vein grafts is sub-optimal, with over 40% of such grafts totally occluded and a further 30% significantly diseased at ten years. We attempted to improve these outcomes by increasing the use of arterial grafts, which are less prone to intimal hyperplasia. In a multicentre clinical trial, we demonstrated a 40% relative risk reduction in graft occlusion at one year when radial arteries were used as bypass conduits versus saphenous veins. We identified that women and patients with small coronary vessels maximally benefited from radial artery bypass grafts. Conversely, in settings of less severe target vessel stenosis or concomitant peripheral vascular disease, saphenous veins performed as well as radial arteries. We have demonstrated that high quality imaging to identify technical errors during the operation, increased use of radial artery grafts and careful consideration of individual patient and target vessel characteristics can all improve graft patency. Future studies will be aimed at identifying the role of intraoperative imaging and arterial grafting in improving long-term clinical outcomes.

Keywords: Coronary Bypass Surgery
Clinical Trials
Imaging
Quality Assurance
Advisor: Detsky, Allan
Fremes, Stephen
Supporting Recent Immigrants in their Effort to Access Information on Health and Health-related Services: The Case Of 211 Toronto

The objectives of this thesis are to: 1) obtain a snapshot of callers of 211 Toronto, a free information and referral service, understanding how representative they are of Toronto’s general population; 2) understand how 211 Toronto callers seeking health-related information use the information they obtain when contacting the service and their overall level of satisfaction, and; 3) better understand the experience and information needs of recent immigrants struggling to navigate an unfamiliar health care system. The study had three phases: 1) a cross-sectional phone interview with 211 Toronto callers; 2) a follow-up phone interview of 211 Toronto callers who had asked health-related questions; and, 3) qualitative interviews with callers who were Spanish speakers from Latin American countries. Participants were randomly selected adult callers living within the boundaries of Toronto’s Census Metropolitan Area (CMA). Respondents were compared with the general adult population living in Toronto’s CMA, using 2001 Census data, to identify under- or overrepresented population groups. A sub-set of callers who had asked health-related questions was followed up to understand how they had used the information received and their level of satisfaction with the service. Qualitative interviews were conducted with callers who were recent immigrants and native Spanish speakers from Latin America to explore their post-migration experiences. Recent immigrants experience significant information challenges. Health-related questions reflect the multifaceted nature of the concept of health in the experience of users. Negative experiences with the health care system are common. Recent immigrants have access to disorganized, confusing, often poor quality information. 211 Toronto represents an efficient and effective way to gain access to information but does not achieve its full potential. Newcomers should receive timely, appropriate, and reliable information on existing health and health-related services as soon as possible after they relocate to Canada. Appropriate information should also be made available to potential immigrants in their countries of origin. Information and communication technologies should be used to support newcomers, increasing the efficiency and effectiveness of services such as 211 Toronto.

Keywords: Access to health services
Health information
Advisor: Jadad, Alejandro R.
Healing the Wounds: Commemorations, Myths, and the Restoration of Leningrad's Imperial Heritage, 1941-1950

This dissertation is a study of Leningrad during World War II and the period of postwar restoration (1941-1950). Leningrad was besieged by the Germans for nearly nine-hundred days. As hundreds of thousands of people died from bombings, shelling, cold, and starvation, local authorities surprisingly instituted measures to ensure that the city’s historic monuments be safeguarded from destruction. When Leningrad was liberated in January 1944, a concerted effort was put into place to breath life into these damaged and destroyed monuments and to heal the wounds inflicted on the city. Instead of using the damage to modernize the city, Leningrad and Soviet authorities opted to privilege the country’s tsarist heritage. In the postwar period, municipal authorities proclaimed that restored monuments commemorate the determination and heroism shown by the people of Leningrad during the war. The memory of the blockade, it was argued, was a “red thread” that must run through and be inscribed in all restoration works. Although this dissertation is a local study of war and postwar restoration, it speaks to broader trends within the Soviet Union before, during, and after World War II. I argue that the care shown for Leningrad’s imperial monuments was the result of an ideological shift that began in the mid-1930s away from iconoclasm toward rehabilitating and respecting certain events and characters from the past. With international tensions rising in the 1930s, this turn to the past acted as a unifying force that had a tremendous influence on the patriotism shown during the war with the Nazis. In the postwar period, as the Soviet state began to redefine its image based on the myth of war and the country’s tsarist heritage, this patriotism was further promoted, resulting in a flurry of work throughout the Soviet Union to restore the vessels of the country’s past. Like many other modernizing states, the Soviet Union looked to its past to create a united and patriotic citizenry.

Keywords: Postwar Russia
Blockade of Leningrad
Historic Preservation
Commemorations
Advisor: Viola, Lynne
Recycling the City: The Impact of Urban Change on the Informal Waste-Recovery Trade in Hanoi, Vietnam

This three-paper dissertation explores how broader (and often unchallenged) changes to political economy at multiple geographic and economic scales impact long-standing ‘informal’ practices of waste recovery and recycling in Hanoi, Vietnam. This research is based on a survey of 575 informal waste collectors and 264 waste intermediaries as well as 73 in-depth interviews. Paper I engages in a critique of methodological disclosure in current academic writings on informal waste-recovery activities and discusses the methodological difficulties of researching informal populations. My aim in this paper is to highlight that the lack of methodological disclosure in waste-recovery literature is problematic because it compromises the academic rigour of this field and impedes the reliability of researchers’ policy recommendations as well as to initiate a dialogue with the aim of improving methodological rigour in waste-recovery literature. Paper II examines urbanization processes in contemporary Vietnam and how these changing spaces accommodate labour, and in turn support livelihoods. I argue that Vietnam’s globalizing economy and urban transition have been a catalyst for the growth of the informal waste collector population in Hanoi, as well as a partial player in the gendering of the industry. Paper III explores how one particular segment of the informal waste-recovery trade, waste intermediaries, is impacted by Hanoi’s rapid urban change. I demonstrate in this paper that 1) waste intermediaries simultaneously gain and lose as a result of Hanoi’s urban transition; and 2) the underlying forces of urban spatial change in different areas of the city are quite distinct, which will have an impact on the future of waste-recovery in Hanoi. The key findings of this dissertation are: 1)A more thorough engagement with methods and a broader approach to understanding waste-recovery actors (through an engagement with political economy at multiple geographic and economic scales) will produce a more context-appropriate and compassionate understanding of this group of urban actors. 2)The livelihoods of informal waste-recovery workers are both directly and indirectly impacted by shifts in political economy, albeit in Hanoi these impacts (both positive and negative) vary by sex and sub-occupation (with respect to waste collectors), and scale of business and location in the city (with respect to waste intermediaries).

Keywords: Waste Management
Vietnam
Informal
Urbanization
Advisor: Maclaren, Virginia W.
Learned Citizenship: Geographies of Education in Ontario Schools

Citizenship study of the past several decades has revealed citizenship as a multi-layered, multiply-scaled, and often exclusionary concept. Despite increasing and multi-disciplinary scholarly interest in the multi-faceted nature of citizenship as a political, social, and identity-oriented construct, it remains true that the majority of citizenship theory has developed in relation to adults, rendering children all but invisible to much citizenship discourse. Traditional citizenship theory has tended to position children as future adults and therefore as future citizens of the nation-state who prepare for citizenship through participation in public schools. Recent scholarship has also advocated children’s rights education as a key priority to help empower children as citizens in the present-day. This project investigates how citizenship in Ontario elementary schools, through curricular learning as well as non-curricular activities. I use multi-method research comprised of discursive analysis of provincial documents, semi-structured interviews with elementary school teachers in three school boards, and interactive activity sessions with elementary school students. These findings consider how provincially-scaled discourses persist through curriculum and policy which situate children as future adults and as responsible, competitive citizens in the present day. Teachers value such responsible citizenship as they negotiate the demands of delivering curriculum and maintaining functional classrooms, but concurrently contribute to local citizenship education through community knowledge and empowering student interaction. Children’s contributions reveal a willingness to associate citizenship with ‘good’ citizenship, law-abiding behaviour, and thus situate the school as a site where citizenship expectations are delineated. While these findings reveal the significant mediating role of local school teachers in delivering citizenship education as a supplement to standardized curriculum, only limited connections between citizenship and rights, and often between citizenship and the nation-state, are present overall. Children do figure as present-day citizens through their ability to perform responsible actions at any age, but this remains at best only tenuously connected to a citizenship of both rights and responsibilities.

Keywords: citizenship
education
Advisor: Gilbert, Emily
Challenges and Opportunities for Implementing Sustainable Energy Strategies in Coastal Communities of Baja California Sur, Mexico

This dissertation explores the potential of renewable energy and efficiency strategies to solve the energy challenges faced by the people living in the biosphere reserve of El Vizcaíno, which is located in the North Pacific region of the Mexican state of Baja California Sur. This research setting provides a practical analytical milieu to understand better the multiple problems faced by practitioners and agencies trying to implement sustainable energy solutions in Mexico. The thesis starts with a literature review (chapter two) that examines accumulated international experience regarding the development of renewable energy projects as a prelude to identifying the most salient implementation barriers impeding this type of initiatives. Two particularly salient findings from the literature review include the importance of considering gender issues in energy analysis and the value of using participatory research methods. These findings informed fieldwork design and the analytical framework of the dissertation. Chapter three surveys electricity generation as well as residential and commercial electricity use in nine coastal communities located in El Vizcaíno. Chapter three summarizes the fieldwork methodology used, which relies on a mix of qualitative and quantitative research methods that aim at enabling a gender-disaggregated analysis to describe more accurately local energy uses, needs, and barriers. Chapter four describes the current plans of the state government, which are focused in expanding one of the state’s diesel-powered electricity grids to El Vizcaíno. The Chapter also examines the potential for replacing diesel generators with a combination of renewable energy systems and efficiency measures in the coastal communities sampled. Chapter five analyzes strategies to enable the implementation of sustainable energy approaches in El Vizcaíno. Chapter five highlights several international examples that could be useful to inform organizational changes at the federal and state level aimed at fostering renewable energy and efficiency initiatives that enhance energy security, protect the environment, and also increase economic opportunities in El Vizcaíno and elsewhere in Mexico. Chapter six concludes the thesis by providing: a summary of all key findings, a broad analysis of the implications of the research, and an overview of future lines of inquiry.

Keywords: Renewable Energy
Mexico
Energy Policy
Climate Change
Energy Security
Efficiency
End-use
Hybrid Renewable Energy Systems
Rural electrification
Sustainable Energy
Advisor: Harvey, Danny
Three Essays on Real Options Analysis of Forestry Investments Under Stochastic Timber Prices

This thesis has applied the theory of real options to study forestry investment decision-making under stochastic timber prices. Suitable models have been developed for the stochastic timber prices, after addressing major issues in characterisation of the price process. First, the assumption of stochastic timber price process was based on detailed unit root tests, incorporating structural breaks in time-series analysis. The series was found to be stationary around shifting mean, justifying the assumption of mean reversion model. Due to shift in the mean, long-run mean to which the prices tended to revert could not be assumed constant. Accordingly, it was varied in discreet steps as per the breaks identified in the tests. The timber price series failed the normality test implying fat tails in the data. To account for these fat tails, ‘jumps’ were incorporated in the mean reversion model. The results showed that the option values for the jump model were higher than the mean reversion model and threshold levels for investment implied different optimal paths. Ignoring jumps could provide sub-optimal results leading to erroneous decisions. Second, the long-run mean to which prices reverted was assumed to shift continuously in a random manner. This was modeled through the incorporation of stochastic level and slope in the trend of the prices. Since the stochastic level and slope were not observable in reality, a Kalman-filter approach was used for the estimation of model parameters. The price forecasts from the model were used to estimate option values for the harvest investment decisions. Third, investment in a carbon sequestration project from managed forests was evaluated using real options, under timber price stochasticity. The option values and threshold levels for investment were estimated, under baseline and mitigation scenarios. Results indicated that carbon sequestration from managed forests might not be a viable investment alternative due to existing bottlenecks. Overall, the research stressed upon the need for market information and adaptive management, with a pro-active approach, for efficient investment decisions in forestry.

Keywords: Real options
forestry investments
stochastic timber prices
mean reversion
jumps
stochastic trend
Advisor: Kant, Shashi