VictorJuiz/thesis huggingface dataset:
Computational Methods for Learning and Predicting the DNA binding Specificities of Transcription Factors

The protein-DNA interactions between Transcription Factors (TFs) and Transcription Factor Binding Sites (TFBSs) are the key activities in gene regulation. Considerable efforts have been spent on elucidating their binding mechanisms in the past twenty years. In this thesis, I propose and describe three methods to learn and predict the DNA binding specificities of TFs.The first method named kmerHMM is a sequence pattern recognition method to discover the sequence patterns of TFBSs from protein binding microarray (PBM) data. The novelty of kmerHMM lies in two aspects. First, it has a competitive edge over the existing methods in using Hidden Markov Models (HMMs) to derive an HMM model to represent PBM data. Secondly, kmerHMM incorporates N-Max-Product algorithm and can derive multiple motif matrix models to represent PBM data. The second method named SNPdryad is a classification method to predict the deleterious effect of amino acid substitutions on proteins (including TFs). Comprehensive performance comparisons are conducted on benchmark datasets, reflecting that SNPdryad has the performance comparable to the best of the other methods. SNPdryad has been run on the complete human proteome, generating prediction scores for all the possible amino acid substitutions. In particular, case studies are conducted to show that SNPdryad can help identify the deleterious effect on TFs if a DNA-binding residue is mutated to others.The third method is a computational framework to learn specificity-determining pair-wise residue and nucleotide interactions between TFs and TFBSs. Its novelty lies in the fact that the existing methods usually focus on learning DNA-binding residues on the protein side (TF) only, ignoring the DNA side (TFBS). In contrast, our novel framework aims at learning the interactions between both sides. The proposed method is compared to state-of-the-art methods comprehensively, demonstrating its competitive performance. We also describe case studies showing how our method can be applied to reveal meaningful biological insights into protein-DNA interactions across different DNA-binding families.

Keywords: Data Mining
DNA Binding Site
Gene Regulation
Machine Learning
Sequence Analysis
Transcription Factor
Advisor: Zhang, Zhaolei
Variation in Nicotine and Nitrosamine Pharmacology Genes and Smoking-associated Lung Cancer

Lung cancer is the leading cause of death from cancer in North America. While the vast majority of lung cancer cases are attributable to cigarette smoke exposure, among smokers there are substantial differences in the risk for lung cancer even taking into account cigarettes per day and years of smoking. Identifying and characterizing genetic factors that influence the relationship between smoking and lung cancer continues to be a priority. Among the thousands of chemicals in cigarette smoke, nicotine is critical in establishing and maintaining smoking behaviours, while nitrosamines are an important class of carcinogens that require metabolic processing by the body to exert their full carcinogenicity. Owing to the structural similarities between nicotine and nitrosamines, these chemicals interact with many of the same enzymes and receptors in the body. We demonstrate that genetic variation in the nicotine/nitrosamine metabolizing genes,

Advisor: Tyndale, Rachel F
Disruption of Lymphatic Function following Lymph Node Excision and Irradiation: Integrating Natural Compensatory Responses with Potential Therapeutic Approaches to Facilitate Lymph Flow Restoration

Introduction: The removal or irradiation of one or more lymph nodes during cancer surgery appears to be a significant causative factor in lymphedema development. In the studies outlined in this thesis our first objective was to define the lymph transport deficit caused by nodal excision and/or the application of radiation to a single node. The second objective was to examine two potential methods to restore function after node removal, autologous node transplantation and the introduction of lymphangiogenic factors into the nodal excision site. Methods: In both sheep and rabbits, popliteal nodes were removed and/or subjected to radiation. Animals received one of two potential therapies at the excision site; lymph node transplantation or growth factor therapy (VEGF-C and Ang-2). Following surgery/treatment, a tracer was injected into a prenodal vessel and the system’s ability to transport this tracer to plasma was used as a measure of lymphatic functionality. Fluoroscopic and histological examination provided supporting data. Edema was quantified from the circumferential measurement or bioimpedance of the hind limbs. Results: Following insult to the popliteal node lymphatic function was reduced significantly in comparison to control limbs. Additionally, in the case of radiation, the pressure-flow relationships differed from controls in a way that indicated enhanced resistance to flow (possibly caused by fibrosis and the thickening of the nodal capsules and trabeculae). Fluoroscopy and studies with Evans blue dye revealed new lymphatic vessel growth and occasionally, these vessels had anastomosed with local veins. Left untreated, limbs undergoing insults regained some lymphatic functionality but did not reach control levels. Both treatments increased lymphatic functionality in comparison to non-treated limbs. Edema was almost completely resolved in animals with successful node transplants, and significantly reduced in those receiving growth factor therapies. Conclusions: Damage to and/or removal of the lymph node as a result of cancer treatment can significantly impair the lymph drainage in limbs. Regeneration of lymph vessels, the formation of collateral pathways and lymph-venous anastomoses act as natural compensatory mechanisms, although usually only to a limited extent. However, therapies such as autologous lymph node transplantation or growth factor therapy have the ability to restore lymphatic functionality and decrease edema.

Keywords: Lymphedema
Breast Cancer
Lymphatics
Radiation Therapy
Lymph node
Advisor: Johnston, Miles
Safety and School Travel: How Does the Built Environment Relate to Correlates of Safety, Mode of Travel and Physical Activity Levels to and from School

Many children do not meet the physical activity targets necessary to accrue health benefits. Declines in active school travel over the past half century are one example of how opportunities for daily physical activity for children have been lost. Adult safety concerns may partially relate to the recent decreases in active school travel. This dissertation examines the connection between safety, the built environment and school travel behaviour. A mixed methods study design explores the links between safety, the environment, physical activity and school transport. Findings from the first results chapter suggest that safety in general is a concern for both parents and children but safety concerns are not uniform. Both parents and children were worried about strangers, while children identified additional concerns such as dogs and bullies. Traffic safety concerns related to street crossings, incomplete sidewalks and traffic around the school. Further analysis determined that objective measures of the environment such as street crossings, sidewalk, traffic and parking relate to mode of travel. Perceptions regarding the presence of strangers, street crossings and living in a safe neighbourhood, were also important factors. Differences were observed across the to/from school models, with more environmental features influencing mode choice during the trip to school. Concerning children’s health, findings suggest that the environment may relate to healthier body weights along with encouraging walking and minutes of physical activity. Longer distances, mode of travel and traffic calming features along the route to school related to an increase the number of minutes of activity before school. There is evidence that safety is an important factor in determining travel behaviour and features of the built environment may influence these decisions. Current policies aimed at curbing bullying at both the school and provincial level should continue and be expanded. Further work should look at reducing the number of vehicles around the school to increase walking rates. More time walking translates into more physical activity and may assist children in achieving daily physical activity targets.

Keywords: School Travel
Pedestrian Safety
Physical activity
Advisor: Buliung, Ron
Hess, Paul
A Risk Stratification Model for Adult Patients with Obstructive Sleep Apnea: Development and Evaluation

Despite emerging evidence that obstructive sleep apnea (OSA) may cause cardio-metabolic disturbances independently of known risk factors, the strength and significance of this association remains unclear. This thesis is comprised of three studies assessing the long term-consequences of OSA, and specifically the prognostic value of OSA-related variables for cardiovascular (CV) events, all-cause mortality and incident diabetes. Methods: The first study is a systematic review of longitudinal studies, from 1999 to 2011. Quality was assessed using published guidelines. Studies two and three linked a clinical sleep database to Ontario health administrative databases for the period of 1991 to 2011 to examine the relationship between OSA variables and a composite CV outcome and incident diabetes. For the latter, we assembled a cohort free of diabetes at baseline, as defined by health administrative data. Cox regression models were used to investigate the association between of OSA-related predictors and outcomes of interest, controlling for potential confounders. Study one identified significant relationships between OSA and all-cause mortality and composite CV outcome in men; associations with other outcomes remain uncertain. Among OSA-related variables, only apnea-hypopnea index (AHI) was a consistent predictor. Limitations of the clinically-based studies were small numbers of events, weak definitions of outcomes, and inconsistency in polysomnographic scoring criteria over time. Study two found that 1,172 (11.5%) of 10,149 participants experienced our composite CV event over a median follow-up of 68 months. In a fully adjusted model, the following OSA-related variables were significant independent predictors: time spent with oxygen saturation (SaO2) < 90%, sleep time, awakenings, periodic leg movements, heart rate, and presence of daytime sleepiness. In study three, of 8,678 cohort participants without diabetes at baseline, 1,017 (11.7%) developed incident diabetes over a median follow-up of 67 months. In fully-adjusted models, patients with AHI > 30 had a 30% higher hazard of developing diabetes than those with AHI < 5. Among other OSA-related variables, REM-AHI, and SaO2<90%, heart rate and neck circumference were associated with incident diabetes. Conclusions: Based on these studies, we demonstrated that OSA-related predictors significantly and independently contribute to the risk for occurrence of composite CV outcome and incidence diabetes.

Keywords: clinical epidemiology
Sleep-Disordered Breathing
long-term adverse outcomes
predictive modelling
Advisor: Tomlinson, George
Semantic-aware Anomaly Detection in Distributed Storage Systems

As distributed storage systems become central to business operations, increasing their reliability becomes an essential requirement. Towards this goal, distributed storage systems come equipped with various monitoring probes. As a result, they generate massive amounts of monitoring data. The amount and complexity of such monitoring data surpasses the human ability to detect anomalies in this data. Our thesis is that, in order to obtain a practical solution to the reliability issues posed by modern distributed storage systems, the semantics of these systems must be incorporated into the anomaly detection process. Our semantic-aware approach enables digesting large amounts of monitoring data, through statistical methods, into a few human understandable patterns. These selected unusual patterns provide intuitive pinpointing towards the possible root causes of an anomaly; they can be leveraged by the human in the loop for root-cause anomaly analysis and related investigations. Our strengths lie in the lightweight, minimal overhead of our techniques, as well as their sensitivity to detect even subtle and localized unusual patterns. In this dissertation, we introduce three semantic-aware anomaly detection techniques: i) anomaly detection based on validation of high-level invariants, ii) stage-aware anomaly detection through runtime tracking of execution flows inferred from existing log statements in the code, and iii) a composite anomaly detection model using cross-component correlations. We studied our methods in two realistic environments: networked multi-tier storage systems used in enterprise settings, and a variety of scalable distributed storage platforms used in large data centers, i.e., HBase, HDFS and Cassandra. Our evaluation shows that our methods are lightweight, introducing negligible overhead, and detect anomalies in real-time.

Keywords: Storage Systems
Anomaly Detection
Advisor: Cristiana, Amza
Comparison between the Helen Iron Formation (Algoma-type) and the Sokoman Iron Formation (Superior-type)

The Sokoman Iron Formation with an age of 1.88 Ga in the Labrador Trough and the Archean Helen Iron Formation in Wawa, Ontario (2.75 Ga) are examples of shallow and deep water iron formations respectively, which are of a low metamorphic grade. The two iron formations vary greatly in their mineralogy and geochemistry. The deep water Helen Iron Formation is dominated by siderite and quartz and provides an example of a direct precipitate from seawater which had a strong but distal hydrothermal component as indicated by the lack of Cu, Pb and Zn enrichment. It has a thickness of 100m. The first 20 meters are dominated by input of detrital material of both basaltic and felsic sources before deepening of the basin led to purely chemical sedimentation. Iron in the Helen Iron Formation occurs predominantly as Fe2+, indicating that oxygen played no role in the deposition of this iron formation. Negative carbon isotope excursions close to organic rich horizons in the Helen Iron Formation are the result of dissimilatory iron reduction. In contrast, the mineralogy of the Sokoman Iron Formation is dominated by magnetite, hematite and quartz and has a thickness of 180m. The depositional environment was variable and ranged from a fairly deep, reducing basin to shallow, oxidizing water. The original mineralogy probably consisted of a silica-iron hydroxide gel which was precipitated due to oxidation of Fe2+to Fe3+. The source of the Fe2+ was probably a distal hydrothermal input. Anoxic deep water allowed the transport of Fe2+over long distances to the site of iron formation deposition. When this deep, anoxic water mass came into contact with shallow water, which was enriched in oxygen due to the photosynthetic activity of cyanobacteria, a silica-iron hydroxide gel precipitated. Dewatering of this gel during burial caused the strong diagenetic overprint preserved in the section in which the original mineralogy is obscured. The high degree of diagenesis also explains the present low organic matter content of the Sokoman Iron Formation as well as the presence of Fe2+ minerals, since organic matter may have reacted as an electron acceptor reducing Fe3+ to Fe2+.

Keywords: iron formation
geochemistry
petrology
REE
carbon isotopes
geology
Precambrian
Advisor: Spooner, Edward T.C.
Task-based Imaging Performance in 3D X-Ray Tomography: Noise, Detectability, and Implications for System Design

Quantifying imaging performance is an important aspect in the development, optimization, and assessment of medical imaging systems. This thesis addresses new challenges in the characterization of imaging performance for advanced x-ray tomographic imaging technologies. Central to the work is a task-based cascaded systems analysis framework that encompasses aspects of system geometry, x-ray beam characteristics, dose, detector design, background anatomy, model observers, and the imaging task. The metrology throughout includes Fourier domain descriptors of spatial resolution (modulation transfer function, MTF), noise (noise-power spectrum, NPS), noise-equivalent quanta (NEQ), and task-based detectability. Central elements and advances of the work include: a task-based model for 3D imaging performance in tomosynthesis and cone-beam CT (CBCT); generalization of imaging performance metrics to include the influence of anatomical background clutter; validation of the model in comparison to human observer performance; extension to dual-energy (DE) tomographic imaging; analysis of non-stationary (i.e., spatially varying) signal and noise characteristics; and extension to model-based statistical image reconstruction. In each case, the analytical framework demonstrates the importance of task-based assessment and the capability for system optimization in a fairly broad scope of clinical applications ranging from breast to abdominal and musculoskeletal imaging. The validity of the framework in describing “local” signal and noise characteristics is demonstrated under conditions of strong nonstationarity, ranging from simple phantoms to complex anthropomorphic scenes. In addition to providing a framework for system design and optimization, the analysis opens potential new opportunities in task-based imaging and statistical reconstruction, with examples demonstrated in the design of optimal regularization in iterative reconstruction.

Keywords: Image quality
Computed tomography
Detectability
Noise power spectrum
Modulation transfer function
Model observer
Advisor: Siewerdsen, Jeffrey
The Integration of Safety Engineered Needles in Acute Care Hospitals: Opportunities and Challenges of Regulated Change

Needlestick injuries have been identified as an important modifiable risk factor associated with the transmission of bloodborne pathogens between patients and healthcare workers. A number of jurisdictions, including the province of Ontario, turned to regulation to accelerate the adoption of safety-engineered needles (SENs) for the prevention of needlestick injuries. Available surveillance data demonstrates that needlestick injuries captured in work-related emergency department records and workers’ compensation claims have not declined substantially in Ontario. Drawing on organizational change and implementation science theory, a qualitative instrumental case study design was used to examine the implementation of SENs in three acute care hospitals in Ontario. Program documents were reviewed and interviews were carried out with staff across the three hospitals. While all three hospitals responded to the regulatory requirements with integrity, there was evidence of inconsistent processes and outcomes, which may have been due to variation in the types of SENs that had been integrated, the organization’s readiness for change, and the implementation practices that were adopted. During the initial implementation phase some front-line workers developed strategies to avoid using the SENs. There was a conflict between the values healthcare workers placed on performance and patient care and the learning curve associated with the initial transition to SENs. Explanations as to why needlestick injuries continue to occur were organized under two themes: the importance of staff compliance and "being more careful" and the inevitability of injury as a consequence of the work environment. While further progress will be challenged by competing health and safety priorities, a renewed interested in this injury issue among front-line workers and health and safety professionals may produce better outcomes as there appear to be a number of opportunities to advance prevention efforts to further reduce ongoing needlestick injuries.

Keywords: Needlestick
Regulation
Qualitative
Evaluation
Advisor: Mustard, Cameron
The Impact of Neighbourhood Context on Work-Family Conflict and Psychological Distress

Does neighbourhood context influence work-family conflict (WFC) and its mental health consequences? If so, how do these associations unfold? And do these processes differ for men and women? My dissertation research addresses these significant and timely questions. Recent changes in work and family domains have led to unprecedented levels of WFC. However, theories and research on the topic to date remain limited, because they emphasize individual-level antecedents to the exclusion of broader contexts, including individuals’ neighbourhood of residence. My study is among the first to effectively examine the impact of neighbourhood context on WFC and mental health consequences. I outline three overarching mechanisms through which neighbourhood influences WFC, including (a) the social composition of the neighbourhood, (b) processes of neighbourhood structural amplification; and, (c) the objective and perceived presence of community resources. I test my hypotheses using data from Toronto, Canada, compiled from a variety of sources, including individuals, the Canadian census, and municipal data on community resources. I use Hierarchical Linear Modeling (HLM) techniques for all analyses to appropriately distinguish individual and neighbourhood-level variations. Collectively, the results from my dissertation research contribute to a more advanced framework of the antecedents of WFC and its mental health consequences compared to previous approaches—one that incorporates the importance of place.

Keywords: neighbourhood effects
work-family conflict
psychological distress
mental health
Advisor: Wheaton, Blair
Characterization of Phosphatidylinositol 4-kinase IIIα During Drosophila Development

Phosphoinositides regulate diverse cellular processes such as actin organization, membrane trafficking, and signal transduction. However, the mechanisms by which phosphoinositides contribute to formation and patterning of tissue during development are not well understood. I have used Drosophila melanogaster to examine the role of phosphatidylinositol (PI) 4-kinase type IIIα (PI4KIIIα) during development. I generated a deletion in PI4KIIIα and discovered that this gene is essential and is required in multiple cell types for signaling during oogenesis. In the germline, PI4KIIIα is required for production of plasma membrane (PM) PI4P and its metabolic derivative, PI 4,5-bisphosphate (PIP2). PI4KIIIα is important for actin organization, membrane addition, and oocyte polarity. Moreover, PI4KIIIα orchestrates these processes through its cellular effectors, Moesin and the exocyst complex, by regulating phosphorylation and localization of Moesin, as well as PM recruitment of the exocyst. These effects are unique to PI4KIIIα, as egg chambers from flies mutant for either of the other Drosophila PI4Ks, fwd or PI4KII, show Golgi but not PM phenotypes. In addition, PI4KIIIα is required for axis specification and localization of the germ cell determinant Oskar, establishing an essential role for PI4KIIIα in egg chamber development. In follicle cells, PI4KIIIα is required for maintenance of epithelial architecture and Notch signaling during the stage 6-7 mitotic-to-endocycle switch, when follicle cells stop dividing and start endoreplicating their DNA. PI4KIIIα mutant posterior follicle cells show sustained Cut expression, continue to proliferate, and are impaired in their ability to induce oocyte axis specification. Thus, PI4KIIIα regulates Notch signaling and cell-cell communication. Finally, PI4KIIIα is also required for germline stem cell maintenance in the ovarian germline niche. PI4KIIIα mutant stem cells are unable to compete for niche occupancy and are soon expelled. Together, my results uncover essential roles for PI4KIIIα in developmental signaling and provide models in which to study the underlying molecular mechanisms of these pathways.

Keywords: Drosophila
oogenesis
phosphoinositides
germline stem cells
Notch
phosphatidylinositol 4-phosphate
Advisor: Brill, Julie A.