VictorJuiz/thesis huggingface dataset:
Investigating Endocannabinoid Metabolism in Alcohol Use Disorder: a focus on fatty acid amide hydrolase (FAAH)

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for Alcohol Use Disorder (AUD) and psychiatric illnesses. Studies suggest that FAAH regulates alcohol intake/preference, and its impairment increases risk for alcohol use disorder (AUD). This thesis’ main objective was to better characterize the status of FAAH in relation to AUD and AUD risk phenotypes. It was hypothesized that reduced FAAH (in brain or inherited via FAAH C385A polymorphism) is related to increased and more hazardous alcohol use, reduced negative and impairing effects of alcohol in heavy episodic drinking (HED) youth and clinical outcomes in AUD. FAAH levels in brain were quantified using positron emission tomography (PET) with [C-11]CURB in treatment-seeking individuals with AUD in early (3-7 days; n=14) and later (2-4 weeks; n=9) abstinence. FAAH in brain, striatum and PFC was measured in HED youth (n=31) and related to retrospective alcohol consumption and alcohol sensitivity during an intravenous alcohol challenge. FAAH C385A genotype was investigated in heavy-drinking youth (n=302) in relation to drinking motives and alcohol consumption patterns. Brain FAAH levels were reduced in AUD during early abstinence and related to increased alcohol consumption. Peripheral FAAH substrates were significantly elevated. Neither FAAH nor FAAH substrates differed in later abstinence. Lower brain FAAH levels in HED youth were related to increased alcohol-induced craving, reduced negative effects of alcohol and increased negative arousal. FAAH polymorphism was related to increased endorsement of coping motives for alcohol use, alcohol consumption and hazardous drinking. Mediation models in HED youth suggested that the FAAH minor A allele related to more hazardous alcohol consumption, which may be mediated by increased negative reinforcement. This thesis provides the first investigations of FAAH in living brain of humans in relation to hazardous alcohol use and AUD. Reduced FAAH and elevated endocannabinoid tone might be related to increased risk of negative consequences from alcohol including increased hazardous consumption, increased craving and AUD. While it is unclear whether reduced FAAH predates or is a consequence of chronic alcohol use, these findings should be considered if considering FAAH as a therapeutic target for AUD or co-morbid conditions.

Keywords: Alcohol Use Disorder
anandamide
endocannabinoid
fatty acid amide hydrolase
positron emission tomography
Advisor: Boileau, Isabelle
Elucidating the Function of MicroRNAs and Argonautes in Normal Hematopoiesis and Acute Myeloid Leukemia

MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of their target mRNAs. MiRNAs associate with Argonaute (AGO) proteins to mediate repression of their targets in a sequence-dependent manner by inducing destabilization and/or translational repression of the mRNA transcripts. MiRNAs play functional roles in all aspects of cellular activity and their expression is frequently deregulated in cancer. The work presented in this thesis directly addresses several outstanding questions regarding the role of post-transcriptional regulation mediated by miRNAs and AGO proteins in normal hematopoiesis and acute myeloid leukemia (AML). Using chimeric CLIP-seq in hematopoietic stem/progenitor cells (HSPC) from human cord blood, fetal liver and primary AML patient samples, we identify miRNA-target interactions underpinning normal and malignant hematopoiesis. Remarkably, we find that the most abundant miRNAs are nearly identical across the different cell states, however the targets and the gene regulatory networks they control are vastly different. Moreover, by combining small-RNA sequencing in leukemic stem cell (LSC)-enriched AML fractions and CLIP-seq targets, we uncover unique molecular networks controlled by LSC-specific miRNAs. Next, we comprehensively characterize the mechanistic function of miR-130a, a miRNA identified from our in vivo repopulation screen as a regulator of human HSC function. Our findings illustrate the important contribution of miRNAs and their targetomes in HSC function and how their aberrant expression contributes to the pathogenesis of specific AML subtypes driven by distinct genetic abnormalities. Finally, we investigate the functional significance of the four members of the conserved AGO family in HSC function. We identify AGO2 as a regulator HSC function and characterize protein interactomes of AGO1-4. Collectively, our findings provide several unprecedented insights into the type and prevalence of miRNA-target interactions in cell populations making up the normal and leukemic hierarchies and the non-redundant function of AGO1-4 in hematopoiesis.

Keywords: Argonaute
hematopoiesis
leukemia
microRNA
stem cell
Advisor: Dick, John E
An Automated Tabletop Continuous Culturing System with Multicolour Fluorescence Monitoring for Microbial Community Eco-evolutionary Experiments

Microbes provide a great model system for studying ecology and evolution. What makes them well suited as model system is their rapid replication rate, ease of handling large populations, and ability to manipulate/monitor their environmental variables for reproducible experiments. Furthermore, small genomes of the microbes also allow for precise genetic analysis and manipulation. While the study of microbial evolution in monocultures has been well explored previously, the study of microbial evolution in communities has only recently come to the forefront of research. Although coexisting microbes are complex to study, microbes often evolve as part of complex microbial communities in both natural and clinical conditions. Hence, understanding how microbial communities respond to external perturbations over short ecological and long evolutionary timescales is important.To deeply investigate microbial communities, real-time monitoring of gene expression dynamics and population levels across multiple coexisting species is necessary. To this end, in this thesis, I introduce a novel table-top continuous culturing device with a scalable in situ multi-fluorescence monitoring function, which provides a unique combination of attributes that are not offered in any existing devices: stable long term culturing, high temporal resolution fluorescence measurement, customizability, and high sensitivity and high dynamic range fluorescence sensors. We demonstrate the ability of this system to capture the population dynamics of a two-species microbial community, which shows a switch between competitive exclusion and long-term coexistence in response to different nutrient conditions. Besides, gene expression dynamics in response to external perturbations in two synthetic genetic systems: a simple inducible genetic circuit and a bistable toggle switch, are also successfully tracked. With these abilities, we propose a set of experiments to study the bacterial strategy of choosing between different defence mechanisms when challenged by their predatory viruses (phages). Finally, an approach that combines a mathematical model and monitoring of bacterial population dynamics to estimate phage-escape mutation rate will be discussed. Overall, novel experimental and theoretical approaches are introduced in this thesis that will facilitate new experimental microbial eco-evolutionary research in the years to come.

Keywords: continuous culturing device
gene expression dynamics
microbial community dynamics
Advisor: Goyal, Sidhartha
On the Functional Components of Community Assembly

My goal for this thesis was to better understand the mechanisms of community assembly and the processes underlying spatial and temporal patterns of species and functional diversity. By using novel experimental designs, long-term field observations, and unique statistical analyses, I address the following questions in four chapters. Chapter 1: How do deterministic processes, sampling effects, and ecological drift influence patterns of species and functional diversity? Chapter 2: Do distinct disturbances that alter either community trait means or variances have different long-term impacts on species and functional trait diversity? Chapter 3: How does community-wide synchrony vary through time in response to changes in the successional stage, or in competitive interactions under a varying environment? Can we detect community-wide selection for specific functional traits that drive changes in species composition through time? Chapter 4: How does the timing of seedling establishment affect its survival and growth, and do species with different phenological traits show greater sensitivity to timing of seedling establishment? Are the consequences of timing and phenology solely due to seasonal environmental changes, or are they contingent on biotic interactions? My research provides several new insights into how species, and their traits, are distributed. Principal among these are the conclusions that 1) functional diversity differs fundamentally from species diversity in its spatial and temporal patterns and responses to disturbance, and 2) traits structure, and are selected by, the interplay of abiotic conditions and biotic interactions. These insights suggest the current focus in ecology on species diversity as a proxy for functional diversity, is limited for understanding and predicting current and future functional attributes of ecological communities.

Keywords: Community assembly
Functional traits
Advisor: Gilbert, Benjamin
Power Training and Functional Performance in Older Women

Age-related difficulties in activities of daily living (ADL) are more prevalent in women, and might be associated with differences in muscle performance between older men and women (e.g., women demonstrate earlier declines in muscle strength compared to men across the lifespan). Power training (PT) has been shown to be an effective resistance training (RT) strategy for improving muscle performance and functional outcomes in older adults, however, with significant gaps in our understanding of the effects of manipulating training frequency and/or intensity. The current work sought to investigate the effects of PT intensity and weekly frequency on lower body muscle power and functional performance in older women. The first study, a systematic review, provides evidence that PT utilizing light, moderate, or heavy training intensities can all lead to significant improvements in muscle strength, power, and functional performance in older adults. Having demonstrated the longer-term reliability of test-retest muscle power and functional performance in older women (Study 2), the impact of PT frequency (1, 2, and 3 days/week) on these outcomes was investigated in a randomized controlled trial (Study 3). In these older women, PT 1 day/week did not produce significant gains in muscle power, however, all PT frequencies demonstrated improvements in muscle strength and functional performance post-study. Given the variable changes observed in each group after PT, an investigation of the individual responses in muscle power and functional performance was performed (Study 4), where a large variability in response was found for each measure and for each individual across measures. Study 4 demonstrated that every participant improved in at least one measure after PT, supporting the importance of including multiple outcomes when assessing the effectiveness of an exercise program. This work extends previous findings of the benefits of low-intensity PT 3 days/week with support for 1 and 2 sessions/week for improvements in muscle strength and functional capacity, and 2 weekly sessions for gains in muscle power in healthy, older women. The evidence presented herein expands viable training options for a broader range of individuals, including clinical populations, for whom higher training intensities and/or frequencies are not possible or preferable.

Keywords: Functional performance
Muscle power
Muscle strength
Older women
Power training
Training frequency
Advisor: Amara, Catherine E
Revolution in the Red Chamber? The Senate of Canada in the 21st Century

This dissertation investigates the extent and effect of a series of reforms made to the Canadian Senate by the Liberal government of Justin Trudeau beginning in 2015. Previous attempts to reform the Senate have proven almost completely unsuccessful despite widespread and longstanding dissatisfaction with the institution. This failure has largely been the result of an inability to unify the federal and provincial governments behind a particular understanding of the Senate's role in Canadian democracy and federalism. This has led to a corresponding inability to generate the constitutionally required level of support behind any specific reform proposal. In this dissertation, I seek to answer a series of related questions: What institutional changes has this government made to the Senate? How have these changes affected the Senate in the way it carries out its work? And why were these reforms successfully implemented when almost every other attempt at reform failed? I conclude that the reforms were successfully implemented because, when compared to many of the more sweeping changes which have been proposed for the Senate in the past, these reforms are inherently limited. As a result, they did not require provincial consent. At the same time, however, these reforms are the most significant ever made to the Canadian Senate and among the most significant changes ever made to any part of the Canadian Parliament. Furthermore, these reforms entrench a coherent vision of the Senate's role in the Canadian democratic process. These reforms institutionalize and prioritize to an unprecedented degree the enhanced representation of women, Indigenous people, and racialized minorities in the Senate. The reforms are also designed to support the Senate as a complementary chamber of independent second thought. This leads to one last important question: how successful have these reforms been in implementing the Trudeau government's stated goals for the Senate? I find strong evidence of increased descriptive representation for women, Indigenous people, and racialized minorities. Finally, while the reforms have made the Senate a more active complementary legislative chamber, I find mixed evidence of increased senatorial independence.

Keywords: Canada
Parliament
Reform
Senate
Advisor: Cochrane, Christopher
Defect Characterization in a Steel Plate Using AC Magnetic Flux Leakage (AC MFL)

Aboveground Storage Tanks (AST) are usually used to store chemical and petrochemical products in the oil and gas industries. Regular inspection of tank floors is vital in order to detect any threat to the tank integrity and prevent economic and environmental loss. In this thesis, an AC Magnetic Flux Leakage (MFL) system is developed to improve inspection services for nondestructive evaluation of tank floors. Much has been written on analytical models, numerical algorithms, and experimental measurements of DC MFL systems. Therefore, in this thesis DC MFL systems are first examined to be used as a basis for development of an AC MFL system model. The magnetic dipole model is the most widely used mathematical technique to predict the MFL from defects in ferromagnetic materials in DC MFL system. In this thesis, coarse approximations made by researchers using magnetic dipole model are evaluated. A finite element model of an AC MFL system is developed for two common defect shapes located on the far-side of a 1018 steel plate with 6.35 mm thickness used in typical AST floors: lake-shaped and rectangular (slot) defects. A signal processing algorithm based on AC MFL signal skewness is developed to distinguish between lake-shaped and rectangular defects. A two-step algorithm is then proposed to estimate the depth of the rectangular and lake-shaped defects using an AC MFL system. In the first stage, the defect is classified as either “shallow” or “deep” based on the amplitude of the maximum MFL signal. In the second stage, the depth is estimated to within ± 10% of the total plate thickness. To do so, the frequency of the applied magnetic field is increased starting from f=0 (Hz) until the maximum MFL signal is decreased by a percentage P of its maximum value at f=0 (Hz). That frequency (f_P) is an indicator for the depth of the defect. A sensor system with a filter and amplifying stage is designed and manufactured to measure the DC and AC MFL from defects. Experimental verification of both proposed algorithms is then carried out. The experimental results are consistent with the proposed algorithms.

Keywords: AC Magnetic Flux Leakage (MFL)
Defect Characterizations
Finite Element Simuations
Magnetic Dipole Model
Non-Destructive Testing
Sensor Design
Advisor: Sinclair, Anthony
Filleter, Tobin
Inclusion and Representation in Rehabilitation Research and Practice of Adults with Traumatic Brain Injury and Comorbid Depression: A Knowledge Translation Perspective

Background: Depression is highly comorbid with traumatic brain injury (TBI). Adults with TBI and depression experience poorer health outcomes, greater disability, and unmet healthcare needs. Depression commonly precludes individuals from clinical trials; it is unknown how well they are prioritized throughout the evidence-to-practice pathway of knowledge translation (KT). Purpose: The purpose of this dissertation is to examine inclusion and representation of adults with comorbid depression in evidence-based TBI rehabilitation research and practice. Methods: Three studies and one conceptual paper were completed: 1) scoping review of the TBI rehabilitation sciences literature that measured depression to describe the representation of the target group; 2) critical analysis of two Canadian TBI clinical practice guidelines to examine how the target group is included in guideline development, recommendations, and evidence base;3) qualitative descriptive study to understand the target group’s experiences of their TBI rehabilitation; and, 4) conceptual paper to examine how the predominant evidence-based practice (EBP) model applies for the target group. Results: Adults with TBI and depression are underrepresented in the TBI rehabilitation sciences literature and under-included in the TBI clinical practice guidelines given the prevalence rates of post-TBI depression. The 13 qualitative study participants expressed values, preferences, and meaningful outcomes of rehabilitation in response to largely negative healthcare experiences, indicating a lack of patient-centred care. A re-conceptualized zonal EBP model with a lens of inclusion and representation was proposed and illustrated using adults with TBI and depression. Conclusions: Comorbid depression is rarely included and represented throughout the evidence-to-practice pathway. Providing evidence-based rehabilitation for adults with TBI and depression is difficult; patient values and perspectives should be emphasized. The zonal EBP model can be applied to comorbid groups to support clinical and KT approaches that are evidence-based and patient-centred.

Keywords: Comorbidity
Depression
Evidence Based Practice
Knowledge Translation
Qualitative
Traumatic Brain Injury
Advisor: Colquhoun, Heather
Dawson, Deirdre R.
Teacher Perceptions, Practices, and Challenges in Detracked Grade 9 Mathematics

While research has identified a wide range of effective instructional strategies for improving students’ mathematical performance in secondary schools, not all Ontario students are benefitting equally. This study investigates teachers’ perceptions, practices, and challenges in teaching the detracked Grade 9 mathematics course and refines the Ten Dimensions of Mathematics Education framework for detracked secondary mathematics programs. Using a qualitative multiple-case study approach, it investigates the ways in which four mathematics secondary school teachers approach teaching detracked classrooms. The major findings are: (1) believing in the purpose and benefit of detracking practices and the belief that all students can succeed is key to teaching detracked mathematics programs; (2) teacher collaboration and self-directed professional development, which includes learning research-based teaching methods, is an important component of teaching detracked math programming; (3) administrator support and teacher autonomy during the planning process is crucial for a successful implementation; (4) teachers differentiated instruction by using tasks that have open-ended questions and range in complexity to meet students’ individual needs; and (5) assessment practices included gathering multiple sources of evidence and grading students within the Grade 9 level expectations rather than holding them to higher standards based on teacher beliefs. The findings extend our understanding of how we can better support teachers as they implement Grade 9 detracked mathematic courses. An emerging model of the Ten Dimensions of Mathematics Education is presented with recommendations for the mathematics education research community.

Keywords: Detracking
Mathematics education
Secondary education
Teacher beliefs
Teacher challenges
Teacher perceptions
Advisor: McDougall, Douglas E
Rhythm Training for People with Stroke: A Tool to Enhance Neurorehabilitation

Rhythmic auditory stimulation (RAS) is a promising therapy to improve spatiotemporal gait parameters after stroke. However, RAS is not equally effective for everyone; an individual’s response to RAS is likely partially mediated by rhythm abilities, specifically beat perception and production. If rhythm can be trained post-stroke, there is potential to enhance response to RAS among people with poor rhythm, which could make RAS more effective for a wider range of people. Furthermore, there are many stroke therapies implemented using telerehabilitation. If rhythm is important for some of the therapies being conducted online, it is necessary to determine if it is feasible to test and train rhythm abilities online as well. This work aims to answer these queries with three studies. Based on the framework of co-design, Study 1 involved collaborating with relevant stakeholders (i.e., people with stroke, musicians/music therapists/teachers, and physiotherapist specializing in neurorehabilitation) to gain insight on how to develop music programs for people with stroke. Four topics were identified as important to consider when designing music programs for people with stroke including: 1) goals of music in stroke rehabilitation, 2) therapeutic interactions with music, 3) individualizing components of music programs, and 4) logistics of music program development and delivery. Study 2 involved evaluating the feasibility of testing rhythm online with the Beat Alignment Test (BAT), a rhythm assessment often used in the stroke population. Completing the BAT online was more feasible for neurotypical adults than people with stroke. BAT components had poor to good test-retest reliability and there were no learning effects when the BAT was completed three times online. Lastly, Study 3 was a pilot study of a rhythm training program for people with stroke that was delivered in-person and online. Rhythm training was well tolerated regardless of delivery method, with minimal changes in BAT scores pre-post intervention. The lack of consistent pre-post changes in rhythm abilities may explain why there were no changes in immediate gait response to RAS pre-post intervention. Future work is needed to investigate dose of rhythm training required to cause meaningful changes in rhythm abilities after stroke.

Keywords: gait
music therapy
physical therapy
rehabilitation
rhythm
stroke
Advisor: Patterson, Kara K