VictorJuiz/thesis huggingface dataset:
Positive Regulation of PKB/Akt Kinase Activity by the Vacuolar-ATPase in the Canonical Insulin Signaling Pathway: Implications for the Targeted Pharmacotherapy of Cancer
Keywords: Cancer
Insulin Signaling pathway

The canonical PI3K/Akt pathway is activated downstream of numerous receptor tyrosine kinases, including the insulin and insulin-like growth factor receptors, and is a crucial regulator of growth and survival in metazoans. The deregulation of Akt is implicated in the pathogenesis of numerous diseases including cancer, making the identification of modifiers of its activity of high chemotherapeutic interest. In a transheterozygous genetic screen for modifiers of embryonic Akt function in Drosophila, in which the PI3K/Akt signaling pathway is conserved, we identified the A subunit of the vacuolar ATPase (Vha68-2) as a positive regulator of Dakt function. Our characterization of this genetic interaction in the larval stage of development revealed that Vha68-2 mutant phenotypes stereotypically mimicked the growth defects observed in mutants of the Drosophila insulin signaling pathway (ISP). The loss of Vha68-2 function, like Dakt-deficiency, was found to result in organismal and cell-autonomous growth defects, and consistent with its putative role as a positive regulator of Dakt function, both the mutational and pharmacological inhibition of its activity were found to downregulate Akt iv activation. Genetic epistasis experiments in somatic clones of Vha68-2/dPTEN double mutants demonstrated that the loss of Vha68-2 function suppressed the growth defects associated with dPTEN-deficiency, placing Vha68-2 activity downstream of dPTEN in the ISP, while the examination of PI3K activity and PH domain-dependent membrane recruitment in pharmacologically inhibited larval tissues further placed Vha68-2 function downstream of PI3K. These findings were recapitulated in cultured NIH-3T3 cells, whose treatment with bafilomycin A1, a potent and specific inhibitor of V-ATPase, resulted in the downregulation of Akt phosphorylation, particularly in non-cytoplasmic intracellular compartments. Furthermore, cellular subfractionation of bafilomycin-treated NIH-3T3 cells demonstrated a decrease in the localization of Akt to early endocytic structures, and a downregulation in the localization and activation of Akt in the nuclei of both Drosophila and mammalian cells. Finally, the pharmacotherapeutic relevance of V-ATPase inhibition was addressed in two tumor models – multiple myeloma and glioblastoma – and our preliminary findings in these cancers, which are often associated with ectopic PI3K/Akt signaling, showed significant cytotoxic efficacy in vitro, warranting its consideration as a tractable pharmacological option in the treatment of cancer.
Behavioural and Neuronal Correlates of Long-term Contextual Memory for Cocaine: Relevance to Craving and Relapse
Keywords: Addiction
Memory

Relapse is the single greatest barrier to recovery from addiction. Long-term memories for drug experience and associated contextual cues can provoke craving and resumption of drug use, particularly when a reminder of a highly charged context is encountered. In this thesis, three key questions related to the maintenance of long-term memory for drug-associated contexts are addressed: (1) Are Pavlovian conditioned associations between cocaine experience and the context in which it occurred maintained in long-term memory after extended periods of abstinence? (2) Are regions of the mesocorticolimbic circuitry, namely the nucleus accumbens and amygdala, differentially activated by retrieval of Pavlovian conditioned associations as time passes after cocaine experience? (3) Do neurons of the nucleus accumbens and amygdala show changes in dendritic architecture that reflect the impact of chronic cocaine exposure, which may underlie the maintenance of Pavlovian and/or instrumental drug-conditioned associations? Results confirm that Pavlovian conditioned memory for a cocaine-associated context is maintained in the long-term, becoming increasingly resilient over time. However, maintenance of these contextual associations is not accompanied by gross changes in dendritic architecture in neurons of the nucleus accumbens or amygdala within the timeframe examined. Nonetheless, these brain regions, along with the prefrontal cortex, are differentially activated by retrieval of Pavlovian conditioned associations after brief versus extended periods of abstinence. Together, these results emphasize a distinct contribution of Pavlovian memory processes, beyond instrumental and operant drug memory processes, in the long-term maintenance of addiction.
Investigation of Glass Fibre Reinforced Polymer (GFRP) Bars as Internal Reinforcement for Concrete Structures
Keywords: GFRP
Stirrup
Reinforced Concrete
Shear

Glass Fibre Reinforced Polymer (GFRP) internal reinforcing bars are being increasingly considered as a potential corrosion free alternative to regular and stainless steel reinforcing bars. In spite of the availability of code provisions governing both design and certification of the GFRP bars, their use within concrete structures is currently limited to very specific applications unless some behaviour aspects are further investigated. In particular, crack control, ultimate member deformability and the behaviour of the bent GFRP bars are areas in need of such further investigation. An experimental program was conducted consisting of 24 large-scale beams reinforced with various types of GFRP and steel bars complying with CSA certification standards. The results of which show that the stress in the bent bar stirrups at beam failure exceeded minimum code-prescribed values for design (CSA S6, CSA S806, ACI440). An alternative bend-less system of shear reinforcement using straight double headed bars was successful as shear reinforcement but did however result in significant reductions to member deformability. A critical review of the various design provisions incorporating GFRP shear reinforcement, it was found that many of the design codes use conservative shear reinforcement strengths coupled with unconservative values of either the angle of inclination of the compression strut or the concrete contribution to shear resistance. A new relationship for the inclination of the compression strut was proposed for use within the Simplified Modified Compression Field Theory which when combined with the bend/anchor strength of the shear reinforcement correlate well with the experimental results. Also, it was determined that the design strain limits for GFRP shear reinforcement should not be increased until more detailed studies on the long-term performance of the stirrups are conducted. Finally, advanced analysis techniques like layered sectional- and finite element-analysis both gave excellent analytical estimates of the experimental beam response.
Explorations of Wellness and Resilience: A Yoga Intervention for Post-traumatic Stress
Keywords: Post-traumatic stress
Yoga
Resilience

Post-traumatic stress is a highly prevalent mental health condition. Mind-body interventions like yoga are increasingly being utilized in the treatment of PTS, but further research is needed to assess its effectiveness. This present randomized control study was designed to supplement the current field of inquiry with a relatively large group of participants and mixed method analysis of the data. The PTS symptoms and overall well-being of 50 participants enrolled in an eight-week trauma-specific Kundalini yoga (KY) program were examined. The findings demonstrate that KY may impact PTS symptomology, sleep, positive affect, perceived stress, and feelings of resilience. Eight month follow-up data are presented. Participant narratives are discussed corroborating quantitative findings and suggest that participants learnt tools to modulate emotions leading to self-mastery. Study limitations are presented with recommendations for future trauma-related research and practice.
Getting Beyond Equity and Inclusion: Queering Early Childhood Education
Keywords: Queer Theory
Early Childhood

The Canadian early childhood landscape is changing substantially, pushing early childhood from a private family responsibility into the greater public policy discourse. New investments in early childhood services, combined with research that defines the importance of early years learning, requires a careful analysis of the professional preparation of early childhood educators. At the same time typical understandings of family and childhood are being challenged through legal and social policy reforms. Although Canadian demographic changes indicate a growing number of queer families with children, the gap in addressing the interests of queer identified parents and their children is exacerbated by the dominance of a heteronormative perspective in early childhood theory, training and practice. My study demonstrates the disparity between the professional preparation of early childhood educators in Ontario and how queer families are understood in the Canadian context. I draw upon queer theory to deconstruct how educators understand child development patterns and family composition including the newly defined family units that can include single or multiple parents of varying sexual identities that may consist of, but are not limited to lesbian, gay, bisexual, queer and trans parents. Using qualitative methods, the research is grounded in data sources including text analysis of key early childhood texts, focus groups with early childhood educators who have graduated from ECE training programs in Ontario during the last decade and interviews with queer parents with young children enrolled in early childhood programs. I argue that the inherent heteronormative discourse of developmentally appropriate practice silences queer in early childhood training and is embedded in foundational approaches including standards of practice, curriculum frameworks and textbooks commonly used in the training of early childhood educators. Notions of diversity, equity and inclusion structure this silencing. My study also found that early childhood educators have a narrow understanding of how queer parents may be similar or different from other parents. Educators have a limited capacity to support and engage with parents that do not fit the dominant framework of family identity. The queer parents’ narratives consistently present subtle forms of homophobia and transphobia through the silencing of their family in their child’s early childhood program. The results of the study provide an opportunity to reimagine the professional training of early childhood educators embedding a much richer theoretical grounding and teaching practice of diversity and difference that includes queer parents and their children.
Functional Characterization of the MCM Complex Binding Protein, MCM-BP
Keywords: DNA Replication
MCM Complex

Complete and accurate DNA replication is essential to maintain the genetic integrity in all organisms. In eukaryotes, the minichromosome maintenance (MCM) complex forms the catalytic core of the CMG helicase that unwinds DNA at the replication fork. We have previously identified a conserved MCM complex binding protein (MCM-BP) through a proteomic screen in human cells. In chapter two of this thesis, I show that MCM-BP makes an important contribution to nuclear morphology in human cells by affecting centrosome duplication. I also show that MCM-BP depletion results in G2 checkpoint signaling and the induction of replication stress. A recent study in Xenopus egg extracts has suggested that MCM-BP functions to unload the MCM complex from chromatin during S-phase. However, the mechanism of this process remains enigmatic. In chapter three of this thesis, I show that MCM-BP directly binds the de-ubiquitylating enzyme, USP7 and that this interaction is mediated by S158 on MCM-BP and the USP7 TRAF domain. Furthermore, I indicate a novel role for USP7 in DNA replication that involves unloading of the MCM complex during S-phase. Finally, my data suggest that MCM-BP tethers an interaction between the USP7 and the MCM complex to facilitate MCM complex unloading at the end of S-phase.
Attenuating Belief Bias Effects in Syllogistic Reasoning: The Role of Belief-content Conflict
Keywords: belief bias
syllogistic reasoning

A reasoner’s beliefs can compromise or inflate the accuracy of their syllogistic judgments when syllogistic content and structure are incongruent or congruent, respectively. An integrated approach to the study of syllogistic reasoning led to the investigation of premise-based belief-content conflict and its impact on belief bias. The belief-content conflict cue attenuated belief bias in incongruent valid and invalid trials, as well as congruent invalid trials. Its efficacy was found to depend on the difficulty level of the syllogism in which it was embedded and the location of its placement. Reaction time analyses were used to guide interpretations about the relative engagement of Systems 1 and 2. The key findings suggested that belief-content conflict activated System 2 for invalid incongruent trials which would otherwise have been processed using low-cost heuristic means due to their inherent difficulty. In contrast, it appeared that in valid trials the cue led to a redirection of System 2 resources such that specialized analytic strategies were applied in incongruent trials preceded by belief-content conflict compared to those lacking this cue. Finally, belief bias was successfully offset by belief-content conflict even in cases of congruency. In congruent invalid trials without this cue participants’ intuitive awareness of the content-structure match appeared to lead to low-cost, belief-based guesses; yet when presented as the major premise this conflict cue appeared to shift System 1 processing away from content and towards structure. Albeit less diligent than System 2 analysis, the shallow consideration of structural features may have been viewed as a safer bet than any shortcut aiming to capitalize on syllogistic content. This set of findings cannot be fully accounted for by the selective scrutiny, misinterpreted necessity, mental models, verbal reasoning, selective processing, or Receiver Operating Characteristics accounts thereby highlighting the need for considering belief-content conflict in future models of belief bias.
Imaging Performance in Contrast-enhanced Mammography
Keywords: mammography
imaging physics
breast cancer

Breast cancer screening by mammography is recommended based on evidence of reduced mortality. However, mammography can have poor performance in women with radiographically dense breasts where sensitivity can be reduced by: 1) little contrast between normal and malignant tissues; and 2) tissue superposition, which can obscure or mimic lesions. These limitations can be overcome with contrast-enhanced digital mammography (CEDM), which uses iodinated contrast agents to increase attenuation in areas exhibiting tumour angiogenesis and image subtraction to cancel normal tissue signal. Two techniques have shown favourable results in clinical pilot studies; single-energy (SE) and dual-energy (DE) CEDM. However, both approaches suffer from non-specific contrast agent uptake in normal tissues and motion artifacts that contribute to structured image backgrounds, or ‘anatomical noise’, as opposed to the uniform appearance typically assumed in physical models for CEDM development. This study evaluates the importance of anatomical noise in CEDM for lesion detection and characterization and uses this parameter in metrics for quantitative imaging performance analysis and optimization. Correlation was demonstrated between CE computed tomography (CT) signal and vessel permeability in nine rabbit tumours. Simulation of 'thick' CT slices demonstrated that this relationship weakened with increased slice thickness, suggesting that normal tissue enhancement can impede tumour characterization. Anatomical noise was characterized by a power law in 44 SE, and 98 DE CEDM clinical images. A decrease in CEDM anatomical noise was measured compared to DM and these data suggested noise contributions from contrast agent uptake and motion artifact. Simulation of CEDM images with uniform and anatomical backgrounds estimated lesion detection limits to be underestimated by a factor of two or more in a uniform background. An optimization of DE decomposition for the 98 DE CEDM cases predicted lesion detectability could be improved compared to a conventional weighting approach when subject-specific anatomical noise was considered.
Automated Synthetic Feasibility Assessment: A Data-driven Derivation of Computational tools for Medicinal Chemistry
Keywords: Artificial Intelligence
Organic Synthesis Planning

The planning of organic syntheses, a critical problem in chemistry, can be directly modeled as resource- constrained branching plans in a discrete, fully-observable state space. Despite this clear relationship, the full artillery of artificial intelligence has not been brought to bear on this problem due to its inherent complexity and multidisciplinary challenges. In this thesis, I describe a mapping between organic synthesis and heuristic search and build a planner that can solve such problems automatically at the undergraduate level. Along the way, I show the need for powerful heuristic search algorithms and build large databases of synthetic information, which I use to derive a qualitatively new kind of heuristic guidance.
How and Why do Teacher Candidates Struggle?
Keywords: teacher candidates
struggles
teacher education
teacher preparation

The aim of this study is to investigate and understand the types, prevalence, and potential impact of teacher candidates’ struggles, as well as factors and contexts that may relate to the occurrence of struggles. The mixed methods study was carried out in three stages – qualitative, quantitative, qualitative – with teacher candidates and teacher educators from a large Canadian teacher education program as participants. Based on participants’ descriptions and experiences of struggles, I developed a taxonomy of 19 struggles, 10 of which were identified by both teacher candidates and their educators. The struggles included a wide range of behaviours, emotions, skills, and conditions. Teacher candidates also discussed which support systems they use in times of struggles, while instructors explained how they help teacher candidates who struggle. The study positions struggles in a broader and multilayered context that involves teacher candidates, their educators, the preparation program, its structure and elements, policies, social dynamics, and professional norms and expectations. The causes, triggers, consequences, and remediation of struggles are considered in relation to a combination of individual, institutional, and structural factors. The study has implications for teacher education programs, policymakers, and the teaching profession.
Historicizing Anti-racism: UNESCO's Campaigns Against Race Prejudice in the 1950s
Keywords: anti-racism
race
history of the human sciences
transnational history

This dissertation offers a revised historical account of how scientific experts associated with the United Nations Education Scientific and Cultural Organization (UNESCO) in the post-WWII era sought to overcome the legacy of scientific racism. Situating UNESCO’s anti-racism initiatives within the geographic context of the South and North Atlantic and the intellectual context of Latin American, Francophone, and Anglo-American social science this study shows that mid-century discussions of ‘race’ were intertwined with the multiple narratives of modernization and societal change that emerged in tandem with decolonization and the Cold War. Thus, one of this dissertation’s key arguments is that anti-racist projects in the post-war era were often cast as projects of redemption that involved coming to terms with the painful and destructive legacy of scientific racism and the anticipation of an improved and harmonious future where ‘race’ did not figure as a source of conflict and tension. However, because mid-century anti-racist scientists hailed from a variety of cultural, linguistic, and racial backgrounds the question of redemption took on different meanings and involved different stakes. This study examines social science experts’ anti-racist narratives of redemption in the context of four different UNESCO initiatives from the 1950s: 1) in projects of ‘cultural change’ (which were predicated on the anti-racist notion of the inherent educability of all peoples) 2) in UNESCO’s study of race relations in various locations in Brazil 3) in the elaboration of anti-racist approaches to ethnographic observation, and 4) in UNESCO attempts to produce anti-racist handbooks for teachers. These projects reveal how anti-racist experts from the 1950s were very much haunted by ‘race’ and concerned with neutralizing and dampening the affective and political impact of racial conceptions in the geopolitics of post-war era. Thus, this dissertation argues that rather than indicating a definitive retreat from ‘race’ UNESCO’s anti-racism initiatives in the 1950s speak to the persistence and plasticity of ‘race’ and of the fraught attempts to escape its legacy.
Optimization Methods for Patient Positioning in Leksell Gamma Knife Perfexion
Keywords: Industrial Engineering
Operations Research
Optimization
Sphere-packing
Skeletonization
Mixed-integer programming
Linear programming
Quadratic programming
Large-scale Optimization
LP approximation
Radiation therapy
Inverse treatment planning
Medical decision making
Continuous dose delivery
Isocentre selection
Dose optimization
Gamma Knife

We study inverse treatment planning approaches for stereotactic radiosurgery using Leksell Gamma Knife Perfexion (PFX, Elekta, Stockholm, Sweden) to treat brain cancer and tumour patients. PFX is a dedicated head-and-neck radiation delivery device that is commonly used in clinics. In a PFX treatment, the patient lies on a couch and the radiation beams are emitted from eight banks of radioactive sources around the patient's head that are focused at a single spot, called an isocentre. The radiation delivery in PFX follows a step-and-shoot manner, i.e., the couch is stationary while the radiation is delivered at an isocentre location, and only moves when no beam is being emitted. To find a set of well-positioned isocentres in tumour volumes, we explore fast geometry-based algorithms, including skeletonization and hybrid grassfire and sphere-packing approaches. For the selected set of isocentres, the optimal beam durations to deliver a high prescription dose to the tumour are later found using a penalty-based optimization model. We next extend our grassfire and sphere-packing isocentre selection method to treatments with homogenous dose distributions. Dose homogeneity is required in multi-session plans where a larger volume is treated to account for daily setup errors, and thus large overlaps with surrounding healthy tissue may exist. For multi-session plans, we explicitly consider the healthy tissue overlaps in our algorithms and strategically select many isocentres in adjacent volumes to avoid hotspots. There is also interest in treating patients with continuous couch motion to decrease the total treatment session and increase plan quality. We therefore investigate continuous dose delivery treatment plans for PFX. We present various path selection methods along which the dose is delivered using Hamiltonian paths techniques, and develop mixed-integer and linear approximation models to determine the configuration and duration of the radiation time along the paths. We consider several criteria in our optimization models, including machine speed constraints and movement accuracy, preference for single or multiple paths, and smoothness of movement. Our plans in all proposed approaches are tested on seven clinical cases and can meet or exceed clinical guidelines and usually outperform clinical treatments.