VictorJuiz/thesis huggingface dataset:
Characterizing the Role of the DNA Damage Response in Class switch recombination

B cells undergo secondary antibody diversification to elicit an effective immune response. Secondary antibody diversification generates antibodies with high affinity for the cognate antigen, and antibodies of different classes. Different classes of antibodies mediate different effector functions, enabling the humoral response to be fine-tuned to the infection at hand. The different classes are generated by a process called class switch recombination (CSR), which requires the generation and repair of double-stranded DNA breaks (DSBs) at the antibody heavy chain locus, and relies on the 53BP1-dependent DNA damage response (DDR). However, the molecular mechanism and function of DDR in CSR is not fully understood. To characterize the role of DDR in CSR, we first established an in vitro CH12F3-2 mouse B cell line/ RNA interference system and used this system to demonstrate that the DDR factors RNF8 and RN168, play a role in CSR. Using this system, we then developed and conducted a genome-wide screen to identify novel CSR factors, followed by a secondary screen to identify DDR factors among the CSR candidates. Based on this study, we selected one candidate, the Drosophila enhancer of yellow 2 homolog (Eny2), for further characterization. Eny2 is a structural component of the H2B-deubiquitination module of the SAGA complex. We found that Eny2 likely acts downstream of the DSBs generated for CSR, and that Eny2 might act with the SAGA complex in mediating H2B-deubiquitination to facilitate CSR. We also provide evidence that, in addition to its role in CSR, Eny2 is important for H2B-deubiquitination upon irradiation-induced DNA damage, and may be required for optimal DNAPK activation.

Keywords: Class switch recombination
DNA damage response
Advisor: Martin, Alberto
Investigation of the Mechanism of Idiosyncratic Drug-induced Liver Injury

Idiosyncratic drug reactions represent a special problem because of their unpredictable nature, and idiosyncratic drug-induced liver injury (IDILI) is a major reason for drug withdrawal. Our objective was to investigate the mechanism of IDILI caused by isoniazid and amodiaquine. Isoniazid-induced liver injury was believed to be due to bioactivation of N-acetylhydrazine, a metabolite of isoniazid; however, that conclusion was based on a rat model with characteristics very different from isoniazid-induced IDILI in patients. I found that isoniazid is directly bioactivated and covalently binds to hepatic proteins; furthermore, mice are a better model for human isoniazid metabolism than rats. We found that mild isoniazid-induced liver injury in patients is associated with an increase in Th17 cells and IL-10-producing T cells. I also found anti-isoniazid antibodies in the serum of patients with isoniazid-induced liver failure. These results suggest that isoniazid-induced IDILI is immune-mediated rather than metabolic idiosyncrasy as previously believed. Treatment of mice with isoniazid failed to lead to significant liver injury. We postulated that this was because of immune tolerance; however, attempts to develop an animal model using mice with impaired immune tolerance were unsuccessful. Treatment of mice with amodiaquine resulted in mild liver injury that resolved despite continued treatment similar to the more common type of IDILI observed in humans. In this model, liver injury is immune-mediated with the initial injury mediated by natural killer cells, while the resolution of liver injury appears to involve the adaptive immune system because resolution was slower in Rag-/- mice. In summary, my studies have resulted a change in what is considered to be the mechanism of isoniazid-induced IDILI. We have developed an animal model of mild immune-mediated amodiaquine-induced liver injury, but we failed to develop a valid animal model of severe IDILI, most likely because the dominant immune response in the liver is tolerance.

Keywords: Idiosyncratic drug reactions
reactive metabolites
immunotoxicology
immune mediated
tolerance
bioactivation
covalent binding
autoimmunity
liver injury
hepatotoxicity
liver failure
animal model
autoantibodies
anti-drug antibodies
adaptation
T helper 17 cells
natural killer cells
interleukin 10
Advisor: Uetrecht, Jack
Characterization and Development of a Novel Cytomegalovirus for Evaluation as an HIV Vaccine Viral Vector in a Non-Human Primate Model

Within the field of HIV vaccine design, it has been recognized that there is a real need to diversify the pool of vectors undergoing testing and to utilize vectors that can induce durable immunity. Herpesviruses, such as cytomegalovirus (CMV), show much promise as viral vectors, as they establish lifelong latency with periodic reactivation, enabling persistent expression of vaccine antigens. We propose that using CMV as a lifelong reactivating HIV viral vector will generate a robust and persistent effector memory T cell response at the mucosa and thus, may impair HIV replication at its earliest stage. In an effort to evaluate CMV-based HIV/SIV vectors in a non-human primate (NHP) model, I isolated CMV from cynomolgus macaques (CyCMV), and performed preliminary phenotypic and genomic classification of the novel virus. To characterize the CyCMV genome, facilitate targeted recombination for vaccine construction, and inform possible attenuation strategies, I sequenced and annotated the complete viral genome using next-generation sequencing. Furthermore, I compared and contrasted the structural and functional genes of CyCMV to human and rhesus macaque CMV with respect to genes involved in pathogenesis, immune evasion, species-specificity, and more. In order to maximize the ability to manipulate the virus for vaccine purposes, I cloned CyCMV as a Bacterial Artificial Chromosome (BAC). The cloning of CyCMV-BAC enabled the virus to be transformed into a bacterial system for downstream insertion of vaccine antigens, as well as future viral manipulations, including attenuations. This newly characterized CMV provides a novel model in which to study HIV/SIV CMV-based vaccines in hopes of informing forthcoming human clinical trials. Additionally, CyCMV-BAC will provide an invaluable resource for CMV biologists allowing for virus manipulation studies, functional characterization of CMV genes, as well as HCMV pathogenesis and vaccine development research.

Keywords: HIV
Vaccine Viral Vector
Cytomegalovirus
Non-Human Primate
Herpesvirus
Cynomolgus Macaque
Advisor: MacDonald, Kelly
Health Systems Integration: Competing or Shared Mental Models?

For over two decades, health services researchers and managers have focused on improving integration between organizations and levels of care. Yet, healthcare systems capable of delivering integrated care have not developed widely. This dissertation argues that structural and process strategies for integration need to be supplemented by attention to the social cognitions that characterize the behaviours of actors within healthcare systems. The aim of this dissertation is to explore how Shared Mental Model Theory might advance our understanding and measurement of integration processes and performance. The first paper in this dissertation examines the evolution of healthcare integration strategies over twenty-five years as reported in the academic literature. Six major, inter-related shifts were identified in strategy content. This evolution in conceptualization and practice highlights the importance of attention to meanings and perceptions. The second paper draws from Shared Mental Model Theory, and an exploratory, theory-driven literature review, to identify mental model content specific to system-level integration efforts, and to develop a theoretical framework of the antecedents, moderators and outcomes of shared mental models of integration. The final paper validates and improves the proposed content framework using a two-round, web-based modified Delphi process with a diverse, pan-Canadian group of integration experts, including policymakers, planners, managers, care providers, educators, researchers and patient advocates. The proposed “Integration Mindsets Framework” may be used to facilitate the planning, implementation, management and evaluation of integration initiatives. A shared mental models lens complements and fills the gaps of current approaches to the study of integration in the healthcare sector by focusing attention on the evolution and interplay of meanings, interpretations and knowledge about integration – and their potential impact on practice. Together, these studies provide theory-based, expert-validated constructs and frameworks that enable researchers and practitioners to describe, conceptualize and analyze health systems integration from a socio-cognitive perspective.

Keywords: integrated care
shared mental models
health systems integration
large-scale change
Advisor: Baker, G. Ross
“A Dream of the Future”: Race, Empire, and Modernity at the Atlanta and Nashville International Expositions, 1895-1897

For a region often viewed as outside the processes of modernization, the United States South’s international expositions were symbolic opportunities to demonstrate its embrace of a narrative of industrial, cultural, and racial progress. Taking the 1895 Atlanta Cotton States and International Exposition and the 1897 Nashville Tennessee Centennial Exposition as an analytical basis, this dissertation investigates how southerners transformed modernity by making it “Jim Crow.” It explores the ways white and African American southerners performed a variety of racialized and classed identities that embraced and critiqued modern progress. Responding to the dissolution of old certainties, southerners turned to science and technology as a stable site of truth and meaning. At the same time, their response to modernity was rooted in the South and its developing “New South” cities. In these cities southerners formulated a distinctive modernity that was compatible with the region’s racial dynamics and was adopted by the North as the nation expanded and encountered non-white colonial subjects. This dissertation makes clear the ways in which southerners, often considered on the periphery of change, responded to dislocating events by rooting their responses in the local. The specific economic, social, racial, and political realities of the South all shaped southerners reactions to and articulations of modernity and empire. By narrowing the question of southern modernity to a specific time and space this dissertation redefines a key moment in southern and American history, showing how responses to the dislocating effects of modernity were grounded in the specific temporal and spatial contexts of the South and were exported as American empire.

Keywords: World's Fairs
International Expositions
Southern Expositions
U.S. South
Atlanta
Nashville
Negro Buildings
Jim Crow
Modernity
Race
Empire
Cotton States Exposition
Cotton States and International Exposition
Tennessee Centennial Exposition
Progress
New South
Civil War Reunion
African Americans
Booker T. Washington
Atlanta Compromise
Modernization
Industrialization
Southerners
Advisor: Halpern, Rick
Molecular Mechanism of Amyloid Inhibition

Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized pathologically by the presence of extracellular fibrillar deposits of -amyloid (A), a 38 to 42 residue protein that is produced normally as part of the cellular metabolism.

Keywords: aggregation
amyloid
binding
carbohydrates
inhibition
inositol
Advisor: PomĂ¨s, RĂŠgis
Revisiting the Power-duration Relationship and Developing Alternative Protocols to Estimate Critical Power Parameters

Critical Power concept is used extensively in sport to characterize an individual's fitness by estimating the anaerobic and the aerobic component of the energy system, anaerobic work capacity (W') and Critical Power (CP). The model makes an assumption that all types of athlete have the same pattern of responses when it comes to power and time to exhaustion, however recent study showed different observation. Therefore, a more generalized model was proposed with a relationship constant, n, that can freely describe the relationship and the model demonstrated no difference between types of athlete across swimming (n=0.29) and cycling (n=0.48), but the relationship is significantly different from traditional assumption (p

Keywords: critical power
exercise
modeling
performance
testing
Advisor: Thomas, Scott G
Benefits of a Mindfulness-based Program in Early Childhood Classrooms

The effects of a 6-week mindfulness-based intervention program on children's social and emotional functioning in kindergarten classrooms were examined in two related studies. Eight Ontario full-day kindergarten (FDK) classrooms were randomly assigned to either the Mindfulness Group or to a Control Group. The first study examined the effects of the intervention on a direct performance-based measure of self-regulation and a behavioral screening questionnaire completed by teachers. The analyses revealed that the Mindfulness Group showed stronger self-regulation skills, more prosocial behaviors and less hyperactive behaviors relative to the Control Group after receiving the mindfulness-based program. The Control Group showed limited change in the dependent variables over the course of this study. Thus, the results offer preliminary support of implementation of a mindfulness-based program in kindergarten classrooms. The second study examined children's sharing behavior. The analyses of the results from a task designed to examine children's sharing behavior showed no significant differences in general sharing behavior between the Mindfulness Group and the Control Group. However a general pattern of differences in sharing behavior emerged, offering some support for the hypothesis that children participating in the mindfulness-based program would share more than children who did not participate in the program. Further, in part of the task involving sharing behavior with a "sick stranger" (one of the recipients included in the task), analyses revealed that more children from the Mindfulness Group shared with the sick stranger than children from the Control Group. This finding suggested that the mindfulness-based program increased children's empathy. Furthermore, children's reasons for sharing were recorded, coded and analyzed. Two distinct reasons for sharing emerged: reasons related to (1) Characteristics of the Recipient and reasons related to (2) Wanting to Behave Prosocially. However no significant between-group differences were found in children's reasons for sharing. As such, both groups were collapsed and reasons for sharing for all children participating in the study were reported both quantitatively and qualitatively. Implications of this study and directions for future research on mindfulness-based programs in early childhood classrooms are discussed.

Keywords: mindfulness
prosocial behaviour
self-regulation
Advisor: Perlman, Michal
Sleep in Adults with Attention-deficit/Hyperactivity Disorder of the Predominantly Inattentive and Combined Subtypes

Subjective and objective data on correlates of sleep were collected from adults with Attention-Deficit/Hyperactivity Disorder (ADHD) to determine whether ADHD of the Predominantly Inattentive (ADHD-I) and Combined (ADHD-C) subtypes differ with respect to the nature, prevalence, and impact of sleep disturbances on the core symptoms of ADHD. Subjective data were collected from 45 ADHD-I (mean 40 ± 11 years, 24% female) and 81 ADHD-C (mean 37 ± 10 years, 27% female) adults. A high proportion of ADHD subjects had complaints of excessive daytime sleepiness, poor sleep quality and fatigue. Sleep quality and fatigue were worse for ADHD-I than for ADHD-C subjects. The interrelationships between daytime sleepiness, sleep quality, and fatigue also differed between ADHD subtypes, suggesting differences in the interplay of sleep and wakefulness in ADHD-I and ADHD-C. The idea that the interplay of sleep and wakefulness differs in ADHD subtypes was further supported by findings associated with objective measures of sleep in 27 ADHD-I (mean 39 ± 12 years, 33% females) and 41 ADHD-C (mean 37 ± 9 years, 20% females) adults. Specifically, dim light melatonin onset (DLMO) time was found to be associated with inattention in ADHD-I, and with hyperactivity/impulsivity in ADHD-C. Regarding polysomnography (PSG) measures of sleep, symptoms of inattention were found to be associated with respiratory-event related arousals (RERA) in ADHD-I, and symptoms of hyperactivity/impulsivity were found to be associated with correlates of REM sleep in ADHD-C. These findings suggest a differential role of circadian cycles and sleep in the neuromodulation of the core symptoms of ADHD in ADHD subtypes.Taken together, the findings suggest that ADHD subtype differences extend to the realm of sleep. Importantly, subtype differences lie, not in measures of sleep per se, but rather in the interrelationships between measures of sleep and the core symptoms of ADHD, suggesting ADHD-subtype differences in the interplay of sleep and wakefulness.

Keywords: ADHD
sleep
subtypes
Advisor: Shapiro, Colin M
Human Capital and Occupational Mobility

This thesis contains three chapters. Chapter 1 uses underutilized SIPP to analyze occupational mobility in the U.S. from 1988 to 2003. I propose two additional mobility rates to do robustness check, with careful treatment of the coding error. I classify all occupational switches into three categories: horizontal, vertical and special. I find horizontal switches dominate the other two in shares; aging decreases mobility while education's role ambiguous. I examine the interaction between occupational mobility and labor market status. Developing an algorithm to extract nonemployment information from SIPP, I find most occupational switchers do not experience nonemployment between jobs, similar to job-changing occupational stayers, but duration variation is less for the former. As time goes by, the job-job mobility fraction declines for both.Chapter 2 utilizes SIPP to uncover additional occupational mobility facts. I find occupational behavior exhibits strong persistence among nonemployed as well as employed workers; occupational switchers do not always switch to an occupation similar to previous one; and average length of transition duration between jobs varies with previous occupation. Motivated by these facts I build a directed search model that includes aggregate and idiosyncratic shocks, occupational human capital and search frictions. The model can account for the bulk of data. I use the model to study relative importance of idiosyncratic vs. aggregate shocks, and barriers to occupational mobility. I find idiosyncratic shocks are much more important than aggregate ones in generating mobility; fixed mobility costs and search frictions constitute significant barriers to mobility while transfer loss of occupational human capital does not.Chapter 3 studies returns to occupational human capital assuming all occupations are distinct and occupational human capital is partially transferable. I name the associated tenure variable "General Occupational Tenure" and propose an empirical Transfer Rate function that relates its transferable portion with occupation distance. Combining SIPP and DOT, I perform a generalized wage regression under 1-, 2-, and 3-digit occupational classifications and find three patterns: returns to General Occupational Tenure demonstrate great variation across occupations; fixed returns generally dominate variable returns; and they are negatively correlated. Finally I generalize the result to a larger family of Transfer Rate functions.

Advisor: Kambourov, Gueorgui
Restuccia, Diego
Practical Virtues: An Evidence-based Ethical Framework for Approaching End-of-Life Care in the Neonatal Intensive Care Unit

The challenges surrounding end-of-life care in newborns, including the moral weight of decisions, best interest standards, and parental involvement in decision-making, require an interprofessional approach in order to minimize moral distress and moral residue. The objectives of this project were to describe professional perspectives on end-of-life care in the neonatal intensive care unit, to compare and contrast these perspectives with the identified needs and perspectives of parents, and to construct a framework based on these to aid health care professionals in the approach to neonatal end-of-life care. First, using qualitative interviews, the attitudes and experiences of 43 health care professionals were explored. Participants identified the roles, challenges, and quality indicators related to meeting parents' and infants' needs at end-of-life. Broad categories included: clinical expertise and moral sensitivity; communication; guidance, support, and relationships; shared decision-making; and end-of-life planning and care. Health care professionals identified challenges to team function and quality of care related to consistency of caregivers, communication, and consensus on the interprofessional team. Next, using ethical analysis based in virtue theory, the experiences of 11 parents of infants who died following withholding/withdrawal of life-sustaining treatment were compared to those of the 43 health care professionals and used to inform a framework for approaching neonatal end-of-life care. Both individual virtues of character and virtues ascribed to the interprofessional team were important to providing good quality communication, shared decision-making, and care at end-of-life. The resulting ethical framework involves five steps: i) identifying the components of moral event(s); ii) defining the virtues important in meeting parents' and baby's needs; iii) applying combinations of these virtues in clinical context in order to iv) practice moral action; and iv) reflect on the process. Next steps include the application and evaluation of this virtue-based ethical framework to end-of-life care in the neonatal intensive care unit.

Keywords: End of life
Ethical framework
Interprofessional
Newborn
Parents
Virtue ethics
Advisor: Laupacis, Andreas