VictorJuiz/thesis huggingface dataset:
UHRF1 and the DNA Damage Response

Our DNA is under constant threat from endogenous and exogenous damaging agents. Our cells have evolved a network of signaling pathways and repair mechanisms that detect and counteract this threat, collectively referred to as the DNA damage response. Cells that lose the ability to cope with DNA damage risk the acquisition of deleterious changes to DNA sequence or structure. I initially set out to identify and characterize candidate proteins that interact with Mus81-Eme1, an endonuclease that processes DNA intermediates that arise from aberrant or stalled DNA replication. I focused on one interesting candidate protein known as Nuclear protein 95 (Np95) which now is called UHRF1 (Ubiquitin-like, containing PHD and RING finger domains, 1). Although previous studies demonstrate the importance of Mus81-Eme1 enzyme in DNA repair, genome integrity, and tumor suppression, little is known about how the enzyme acts together with other components of signaling pathways that comprise the DNA damage response. My findings in chapter two characterized this interaction and linked Mus81-Eme1 with UHRF1 in the cellular response to DNA damage. Although UHRF1 levels have been linked with sensitivity to antineoplastic agents, a direct role for UHRF1 in the DNA damage response had not been elucidated or reported. Accordingly, the third chapter of my thesis focuses on investigating the role of UHRF1 in the cellular response to DNA damage caused by exposure to γ-irradiation. Our findings for chapter three indicate that (i) UHRF1 is crucial for the cellular iii response to double strand breaks caused by γ-irradiation and that (ii) UHRF1 is critical for maintenance of chromosome integrity. Recent studies have now implicated UHRF1 in processes required for heterochromatin replication. This protein has been shown to play a role in the replication of heterochromatin by helping to replicate DNA methylation patterns and playing a role in propagating the epigenetic mark known as histone 3 lysine 9 trimethylation (H3K9me3). H3K9me3 has been shown to play a role in a signaling pathway involved in the repair of DNA damage in heterochromatic regions. In the fourth chapter of my thesis, we hypothesize that UHRF1 is playing a role in a pathway that responds to DSB damage in heterochromatic regions of chromatin. Our results indicate that a loss of UHRF1 results in a loss of heterochromatic H3K9me3 and heterochromatin associated HP1β. Our findings support the idea that epigenetic alterations maintained by UHRF1 contribute to signals that relax heterochromatin to facilitate access for repair factors. In summary, findings presented in this thesis shed light on processes that protect cells from DNA damage caused by radiation and chemotherapy and safeguard genome integrity.

Advisor: McPherson, John Peter
Using Peer Firms to Examine whether Auditor Industry Specialization Improves Audit Quality and to Enhance Expectation Models for Analytical Audit Procedures

This dissertation investigates how economically-comparable peer firms can be used to obtain inferences about a company’s accounting quality in two different research settings. The first Chapter examines whether auditor industry specialization, measured using auditor market share by industry, improves audit quality. After matching clients of specialist and non-specialist auditors according to industry, size and performance, there are no significant differences in audit quality between these two groups of auditors. In addition, this Chapter uses two analyses that do not rely primarily on matched samples. First, examining a sample of Arthur Andersen clients that switched auditors in 2002, there is no evidence of industry-specialization effects following the auditor change. Second, using a simulation approach, this study shows that client characteristics, and particularly client size, influence the observed association between auditor industry specialization and audit quality. Overall, these findings do not imply that industry knowledge is not important for auditors, but that the methodology used in extant studies examining this issue may not fully parse out the effects of auditor industry expertise from client characteristics. The second Chapter examines whether account-level expectation models for analytical audit procedures can be enhanced by using information from economically-comparable peer firms. This Chapter assesses the effectiveness of three main types of expectation models, with and without including information from peer firms: heuristic, time-series, and industry cross-sectional models. Information from peer firms improves the accuracy of all models and improves the detection power of time-series and industry cross-sectional models. Comparing between models, one-period heuristic models are generally unreliable, and industry cross-sectional models can be more effective than time-series models. These findings may help auditors of public companies and financial analysts in selecting expectation models and finding peer firms to assess the reasonability of a company’s financial information at the account-level.

Keywords: Auditor industry specialization
Analytical audit procedures
Audit quality
Matching
Peer firms
Earnings management
Advisor: Richardson, Gordon
Zhang, Ping
Cognitive Context Elicitation and Modeling

As computing becomes ubiquitous and intelligent, it is possible for systems to adapt their behavior based on information sensed from the situational context. However, determining the context space has been taken for granted in most ubiquitous applications, and so that context-adaptive systems often miss the situational factors that are most relevant to users. The mismatch between a system's computational model and users' mental model of the context may frustrate and disorient users. This thesis describes the CCM (cognitive context model)-based approach for eliciting individual cognitive views of a context-aware task and selecting an appropriate context space for context-aware computing. It captures the situational and cognitive context for each task, using a structural architecture in which individual participants use a context view to describe their situational perspective of the task. Clustering and optimization techniques are applied to analyze and integrate context views in CCM. Developers can use the optimization output to identify an appropriate context space, specify context-aware adaptation policies and resolve run-time policy conflicts. This approach simplifies the task of context elicitation, emphasizes individual variance in context-aware activity, and helps avoid user requirements misunderstanding.

Keywords: context-aware
adaptation
context elicitation
context modeling
policy rule
multiple views
Advisor: Easterbrook, Steve
Investigting the Cytoprotective Mechanisms of VIitamins B6 and B1 against Endogenous Toxin-induced Oxidative Stress

Recent epidemiological evidence suggests that many chronic health disorders in the developed world are associated with endogenous toxins formed from the Western diet. The Western diet, which encompasses calorie dense foods, processed foods and increased quantities of red meat, can cause intracellular oxidative stress through increased formation of reactive oxygen species(ROS) and reactive carbonyl species (RCS). A number of micronutrients have been investigated for their protective capacity in in vitro and in vivo models of oxidative stress. This thesis investigated the cytotoxic targets of Fenton-mediated ROS and RCS and the subsequent protective mechanisms of vitamins B1 (thiamin) or B6 (pyridoxal, pyridoxamine or pyridoxine) in an isolated rat hepatocyte model. The approach was to use an “accelerated cytotoxicity mechanism screening” technique (ACMS) to develop an in vitro cell system that mimicked in vivo tissue cytotoxicity. Using this technique, we investigated the protective mechanisms of vitamins B1 and/or B6 against the cytotoxic effects of two endogenous toxins associated with the Western diet: 1) RCS, as exemplified by glyoxal, a glucose/fructose autoxidation product and 2) biological ROS induced by exogenous iron. Firstly, we developed an understanding of the sequence of events contributing to glyoxal-induced oxidative stress, with a focus on protein carbonylation. Next, we determined the mechanisms by which carbonyl scavenging drugs (vitamin B6 included) protected against the intracellular targets of glyoxal-induced toxicity. Our results suggested that the agents used were cytoprotective by multiple mechanisms and glyoxal trapping was only observed when the agents were administered at concentrations equal to glyoxal. We also evaluated the protective capacity of vitamins B1 and B6 against iron-catalyzed cytotoxicity and found that hepatocytes could be rescued from protein and DNA damage when vitamins B1 or B6 were added up to one hour after treatment with iron. The vitamins also varied in their primary mechanisms of protection. Our improved understanding of Western diet-derived endogenous toxins enabled us to identify and prioritize the specific inhibitory mechanisms of vitamins B1 or B6. The ability to delay, inhibit or reverse toxicity using multi-functional B1 or B6 vitamins could prove useful as therapy to minimize oxidative stress in diet-induced chronic conditions.

Keywords: Isolated rat hepatocytes
Oxidative stress
B vitamins
Advisor: O'Brien, Peter J.
Regenerative Medicine Innovation in Emerging Economies: A Case Study Comparison of China, Brazil and India

Regenerative medicine (RM) has the potential to develop new treatments for chronic disease and injury that are desperately needed in developing countries. Several emerging economies are actively participating in RM, producing new knowledge and initiating clinical trials. This thesis presents case studies of RM in China and Brazil and a comparative analysis of RM across Brazil, China and India. I aim to better understand the state of RM, how it has developed and what is needed for RM innovation to succeed within these countries. Case studies were conducted using face-to-face in-depth semi-structured interviews with RM experts from different areas including research institutes, hospitals, firms, educational institutes, government, policy agencies, and bioethics groups. Interviews were analysed using thematic analysis and triangulated with the analysis of research articles, government reports, laws and other primary and grey literature. China is now the 5th most prolific publisher on stem cells in the world. Chinese RM benefits from permissive regulations and the expertise of Chinese returnees that have trained abroad, but the field’s reputation is challenged by a weak regulatory system and the clinical availability of untested stem cell therapies. Brazil has created a small but strong RM program, but needs to address challenges to the field including inconsistent funding, slow importation of materials, and weak linkages between stake-holders. Comparative analysis of the three countries identifies several common elements that support RM, including linkages between stake-holders, government support, infrastructure, human resources, and good governance. RM capacity is clustered in large urban centres, which could exacerbate socio-economic and health disparities unless measures are taken to ensure equitable distribution of benefits. RM does not adhere to classical views of southern innovation, suggesting that new models are needed to describe innovation in emerging technologies, where countries are keeping up instead of catching up.

Keywords: regenerative medicine
innovation systems
stem cells
China
Brazil
India
global health
emerging economies
qualitative analysis
Advisor: Thorsteinsdottir, Halla
Daar, Abdallah
Are Executive Function Difficulties Reported by Parents and Teachers Associated with Elevated Levels of Parenting Stress for Children Diagnosed with Attention-Deficit/Hyperactivity Disorder, with and without Oppositional Defiant Disorder?

Parents raising children with Attention-deficit/hyperactivity disorder (ADHD) experience high levels of parenting stress, especially when ADHD is accompanied by comorbid Oppositional Defiant Disorder (ADHD/ODD). Children with ADHD experience difficulties with their executive functions in such areas as inhibition control, working memory, and emotional regulation. Despite evidence linking ADHD with parenting stress, and ADHD with executive function difficulties (EFDs), there is little research exploring whether EFDs within an ADHD population are associated with parenting stress. This dissertation’s main objective is to determine whether parent-reported and teacher-reported childhood EFDs are associated with elevated levels of parenting stress. A secondary data analysis was completed on a cross-section of parent and teacher completed psychiatric assessment measures for children (n=243) diagnosed with ADHD. Measures included the Behavior Rating Inventory of Executive Function, the Conners’ Parent Rating Scale and the Parenting Stress Index, Long Form. A number of important findings were produced; key of which was the finding that a strong association exists between parent-reported EFDs and Child Domain parenting stress. Consistent with prior ADHD research, difficulties with emotional control and inhibition were found to be potent predictors of Child Domain parenting stress. To a lesser degree, children’s difficulties with initiation and self-monitoring were associated with Child Domain parenting stress, suggesting that daily hassles pose challenges for parents, especially when the child attends a new school. Also important was the finding that parent-reported oppositionality partially mediated the relationship between EFDs with emotional control, inhibition and shift, and Child Domain parenting stress. Despite teachers’ reports that children displayed more severe behaviours than were reported by parents, teacher-reported EFDs were not significantly associated with Child Domain parenting stress, with a few exceptions. Although not a well-explored concept within the literature on ADHD and parenting stress, parental acceptance of the child emerged as source of Child Domain parenting stress and a potential focus for assessment and treatment. Findings from the current study suggest that early identification and intervention with emotional control difficulties and ODD are vital due to their strong association with clinically significant levels of Child Domain parenting stress.

Keywords: Parenting Stress
Attention-Deficit/Hyperactivity Disorder
Executive Function Difficulties
Oppositional Defiant Disorder
Advisor: Mishna, Faye
Constructing Quality in Academic Science: How Basic Scientists Respond to Canadian Market-Oriented Science Policy – A Bourdieusian Approach

Canadian science policy has increasingly linked the value of academic knowledge to its contribution to economic competitiveness. A market vision of scientific quality is embedded in new funding criteria which encourage academic scientists to collaborate with industry, generate intellectual property, and found companies. While the “Mode 2” thesis advanced by Gibbons and Nowotny asserts that quality criteria in science are changing to incorporate economic relevance, there is little empirical evidence to either refute or substantiate this claim. Using Bourdieu’s theory of practice, this study explores the responses of basic health scientists to market-oriented funding criteria. The goal of the study was to understand how scientists, occupying different positions of power in the scientific field, defined “good science” and pursued scientific prestige. Twenty semi-structured interviews were carried out with 11 scientists trained before and 9 trained after the rise of market-oriented science policy. Data derived from Curriculum Vitae and Background Information Forms were used to estimate the type and volume of capital each participant held. Scientific capital, as reflected in peer-reviewed publications and grants, was perceived as the dominant form of recognition of scientific quality. However, “entrepreneurial capital”, as reflected in patents, licenses, industry funding and company spin-offs, functioned as a new form of power in accessing resources. Study participants adopted different positions in a symbolic struggle over competing visions of “good science” and used different strategies to acquire scientific prestige. Some pursued a traditional strategy of accumulation of scientific capital, while others sought to accumulate and convert entrepreneurial capital into scientific capital. Findings suggest that there is no longer a single symbolic order in the scientific field, but that the field is stratified according to a scientific and market logic. Hence, support is provided for both continuity with “Mode 1” and change towards “Mode 2” evaluation of academic quality.

Keywords: Bourdieu
knowledge production
Mode 2
sociology of knowledge
academic quality
science policy
university-industry collaboration
knowledge translation
Advisor: McDonough, Peggy
Edge Effects on the Behaviour and Ecology of Propithecus coquereli in Northwest Madagascar

The energy frugality hypothesis states that in response to Madagascar’s unpredictable habitat, lemurs should adopt strategies of energy optimization. I have applied this hypothesis to lemur behavioural ecology in response to forest edges. I compared two groups of Propithecus coquereli living less than 1-km from a forest edge with two groups living greater than 1-km from the edge in Ampijoroa forest station, Ankarafantsika National Park, NW Madagascar. Edge effects in Ampijoroa penetrated up to 625-m into the forest. Propithecus coquereli were edge avoiders, with 94.54% of sightings of Propithecus coquereli found outside of the area of edge influence. There was no difference between group ranges for density of food trees, however tree diameter at breast height (dbh) and tree height did differ between groups. These habitat differences did not neatly divide edge versus interior groups, but appeared to be more nuanced. I found no differences between groups for activity budgets, food quality, or spatial patterns of plant species/ parts consumed. However, groups nearer to the edge had home ranges that were more than double in size to interior groups. Groups in the interior had higher group-specific densities and more frequent intergroup encounters which may have led groups to adopt smaller ranges to avoid expending energy in intergroup encounters. More evidence of human impact was found in the edge, therefore groups near the edge might also range further to avoid humans. Groups showed differences in the spatial pattern of behaviours, activity by age-sex category, substrate size and vertical location used while traveling, and dietary overlap. However, these differences may not be reflective of distance to the forest edge - all groups avoided the edge - but instead may reflect subtle differences in habitat structure between the four groups.

Keywords: anthropology
primatology
Advisor: Lehman, Shawn M.
Becoming an Educational Developer: A Canadian University Perspective

This study sought to understand how individuals come to be educational developers, specifically, their individual and collective journeys toward entry to the profession, the drivers and conditions that shape developer pathways, a sense of how practitioners characterize their developer role and conceive the field overall, and, finally, the point at which they come to associate with the field and identify with what they do. To explore and examine these questions, a qualitative study was undertaken with a subset of the development community. Eighteen Canadian university educational developers, all formally associated with a campus-wide or discipline-based teaching and learning unit, were invited to share their stories. Drawing upon the metaphor of journey to conceptualize the research and storytelling process, and framing the analysis and discussion from a career development and community of practice perspective, the process of becoming an educational developer was revealed. Two trajectories to educational development were identified: (1) those coming from outside higher education and (2) those transitioning from within their academic institution. Various conditions, situational factors, social encounters, or drivers, often serendipitous in form, influenced their journeys, with some participants experiencing more direct paths to the profession and others encountering more twists and turns. Select types of individuals (gatekeepers, distractors, mentors, enablers) also significantly impacted their pathways. Participants characterized their developer role broadly (facilitator, connector, consultant, champion, change agent) and conceived educational development along service, professional, and academic lines. Commitment to the profession and their role solidified within two to four years upon entry. Currently, the field of educational development operates without any formalized career structures to guide entry to or facilitate advancement within the profession. As the community continues to grow and situate itself within the higher education landscape, identifying what attracts developers to the field, their individual pathways, as well as how and when they come to associate with the profession, especially in the absence of socialization and induction strategies, is crucial. With limited research examining the process of becoming a developer and the attraction of working in the field, this study provides a basis from which to continue to examine questions associated with growing and sustaining an emergent profession.

Keywords: educational development
career progression
Advisor: Acker, Sandra
Experimental Approaches to Sound Variation: a Sociophonetic Study of Labial and Velar Fricatives and Approximants in Argentine Spanish

The alternation between labial and velar fricatives (e.g. [x]uego fuego ‘fire’) and labial and velar approximants (e.g. a[ɣ]uelo abuelo ‘grandfather’) frequently co-occur in disparate Spanish dialects (Colombia, New Mexico, El Salvador, Ecuador, Chile, among others). I hypothesize that these alternations are triggered by the perceptual similarity between such variants in the context of [u] and [w]. I further hypothesize that the spread of these variables to the upper layers of society is prevented by formal education, since orthography can block sound change. Although the labio-velar alternations have been observed before, there are few experimental studies addressing their acoustic and perceptual motivations. Yet, the only way to understand the mechanisms of sound variation and change is to analyze the physical, acoustic and perceptual characteristics of the sounds involved. This dissertation uniquely combines three methodologies of data elicitation in order to achieve a better understanding of the alternations. Vernacular speech was collected through sociolinguistic interviews. Contextually controlled target words were elicited via a picture naming task. Finally, the hypothesis that the alternations were driven by the perceptual similarity between the sounds was tested via an AX discrimination test. The sociolinguistic data was correlated with the results from the perception experiment to determine whether more variation in speech correlates with higher rates of confusion in perception. The results reveal that Education and Following Context are two of the most powerful factor groups that influence the alternations. The alternation is almost exclusively found before the diphthongs [we, wi], and in stressed syllables. Knowing the orthography plays an important role in blocking the diffusion of this perceptually driven variation. The same factors affecting the variation in sociolinguistics interviews were found to be significant in increasing the confusion between [f] ~ [x] and [β] ~ [ɣ] in the perception experiment. The acoustic analysis (centre of gravity and F2 at vowel onset), however, did not support the hypothesis regarding the similarity of labial and velar fricatives and approximants.

Keywords: Spanish
fricatives
approximant
sociolinguistics
acoustic
perception
sociophonetic
phonetics
Advisor: Colantoni, Laura