VictorJuiz/thesis huggingface dataset:
Mutation Evolution and Genomic Patterns of Recurrence in Ewing Sarcoma and Leiomyosarcoma
Keywords: Cancer
Genomics
Mutational Signatures
Next-Generation Sequencing
Sarcoma

Sarcomas are a highly heterogeneous group of tumours of the bone and soft tissue whose mutation evolution has been unexplored in the majority of subtypes. From a molecular perspective, sarcomas are sub-classified in two categories: (1) those with disease-defining genetic alterations (commonly translocation-associated gene fusions) and overall quiet genomes and (2) those with no disease-defining alterations and numerous other genetic changes. The work in this thesis centered on a representative sarcoma from each category. First, the genomes of Ewing sarcoma (ES), the second most frequent bone cancer of childhood, were explored. ES represents a prototypical fusion-driven sarcoma as it is characterized and driven by the EWSR1-ETS fusion. Secondly, leiomyosarcoma (LMS), an adult soft-tissue cancer, was examined. LMS is a malignant neoplasm that affects smooth muscle tissue and has a high risk of metastatic relapse. The aim of this research was to advance our knowledge of the basic biology of these two sarcoma subtypes, including the initiating events of sarcomagenesis, the subsequent order of mutations, and the ongoing mutagenic processes in primary, relapse and metastatic ES and LMS. Chapter 1 provides a comprehensive background on the current knowledge of cancer genomics and an introduction to general sarcoma biology, followed by an overview of the clinical and genomic intricacies of ES and LMS. Chapter 2 provides a synthesis of the informatics tools and approaches developed to detect and characterize mutations in the cancer genome. Chapter 3 describes the patterns of mutations in ES tumours. This chapter reports that in several sarcomas, canonical fusions frequently emerge from rearrangement bursts, also called ‘chromoplexy’, creating complex genomic loops and disrupting additional genes. The transcriptional heterogeneity and cellular lineages of LMS molecular subtypes are presented in Chapter 4. Additionally, the genomic mutation signatures and the mutation dynamics contributing to relapse and metastatic spread are described. Lastly, Chapter 5 examines future directions for ES and LMS genomics research. Overall, this thesis highlights recent advances in ES and LMS genomics and provides the molecular framework for future work in patient stratification and early cancer detection in these subtypes.
Structural and Functional Manipulation of the Eukaryotic Ubiquitination System by Pathogenic Bacteria
Keywords: Effector proteins
Gram-negative bacteria
Host-pathogen interaction
Pathogenesis
Structural biology
Ubiquitination

The pathogenic strategy of many Gram-negative bacteria involves the translocation of arsenals of proteins, termed effectors, directly into the eukaryotic host cell. These effectors control and manipulate the host cell to inhibit host defenses and promote bacterial infection. A primary target of many effectors is the eukaryotic ubiquitination system, a conserved eukaryotic signalling cascade culminating in the attachment of one or multiple copies of a small protein called ubiquitin to a target protein, leading to specific regulation of the target protein. Bacteria lack ubiquitination, yet pathogens have evolved many effectors to manipulate this process, which act to either impede ubiquitination machinery or mimic the ubiquitin protein ligases to hijack the ubiquitination system for the pathogens’ benefit. How many of these effectors function remains an open question. To better understand these mechanisms by which pathogens manipulate host ubiquitination, I aimed to characterise poorly understood effectors that interface with the ubiquitination system. This dissertation details that effort, describing the characterisation of two previously poorly characterised effector families, the NleG family from the dangerous enterohaemorrhagic Escherichia coli O157:H7, and a pair of paralogous effectors from the pneumonia-causing Legionella pneumophila, MavC and MvcA. With 14 NleG effector homologs they represent the largest effector family in E. coli O157:H7. I was able to determine the N-terminal domain of NleG effectors represents a structurally unique effector fold. This N-terminal domain allows NleGs to bind human proteins and, in conjunction with their C-terminal U-box ubiquitin ligase domain, use ubiquitination to mark those human proteins for degradation during E. coli infection. By solving the crystal structures of the effectors MavC and MvcA from L. pneumophila, I was able to determine that MavC and MvcA are unique ubiquitin-deamidating effectors. In addition, MavC uses this catalytic activity and an additional unique binding domain to inhibit the E2 ubiquitin conjugating enzyme UBE2N and suppress NF-κB by limiting Lys63 ubiquitination. This dissertation expands our knowledge of bacterial pathogenesis by revealing new effector biology that allows these effectors to interface with host ubiquitination to disrupt signalling and further emphasizes ubiquitination as a key intracellular battleground during bacterial infection.
Understanding Critical Parameters Affecting the Dissolution of Amorphous Solid Dispersions
Keywords: Amorphous Solid Dispersions
Crystallization
Dissolution
Mechanism of Drug Release
Phase Separation

Amorphous solid dispersion (ASD) is one of the formulation techniques that attempts to address the delivery challenges associated with poorly water-soluble drugs. ASDs generate supersaturation in solution and often lead to increased absorption. However, the high energy nature of this strategy leads to phase separation and crystallization, which diminish the effectiveness of ASDs. The work presented in this thesis aim to further our understanding of how the effect of extent and rate of supersaturation as well as phase separation processes during dissolution of amorphous solid dispersion impact critical design parameters. The first part of the study focuses on the concept of critical supersaturation as defined by the supersaturation at which the induction time is equal to the observation time period. Below this critical supersaturation, increasing the degree of supersaturation leads to increased in vitro AUC, as higher supersaturation is maintained for that the observation period. Above the critical supersaturation, the induction time decreases rapidly as supersaturation is increased. Thus, for immediate release ASDs, the maximum in vitro AUC occurs at an intermediate dose, which corresponds to this critical supersaturation upon dissolution. In the second part, critical loading level of ASDs transitioning from polymer and drug congruent to incongruent release was studied through matched rotating disk dissolution and imaging of the ASD surface post-dissolution by confocal fluorescence imaging. Upon hydration, the model ASD system underwent moisture induced phase separation and, at a critical drug loading level, the drug rich regions were observed to transition from discrete to continuous domains. Further, spinodal decomposition was identified as the mechanism of phase separation based on the confocal fluorescence images and the water-drug-polymer ternary phase diagram. Examination of the phase diagram and the position of the locus of binodal provided insights into the critical moisture content where phase separation is thermodynamically favorable. Kinetic aspects were also examined by assessing the competition between the rate of phase separation in the gel phase and rate of release from ASDs. Overall, the kinetic and thermodynamic understandings obtained from this work should contribute to improving the dissolution performance of amorphous solid dispersions.
Against Arcadia: Rereading Pastoral in Contemporary Poetry in Canada
Keywords: Canadian Literature
Contemporary Poetry
Ecocriticism
Environmental Humanities
Pastoral
Poetics

“Against Arcadia” argues that the pastoral persists in Canadian poetry, often redeployed to address the ongoing manifestations of settler-colonialism and the ever-accelerating environmental crisis. I read this emergent critical pastoral in the context of governmental tactics aimed at the material dispossession of land, health, and life, linking neoliberalism and the attendant fraying of social relations to intensifying ecological degradation. The logic of neoliberal capital privileges a particular mode of relationality that underlies what Eric Cazdyn and Imre Szeman name a “common sense” that naturalizes the political and economic status quo. Against this neoliberal common sense, the redistributed pastoral invokes a “sense of the common,” my critical shorthand for a reorganization of ways of being and relating in the Anthropocene that might open onto a more equitable and just “common world.” I begin with two texts that borrow explicitly from pastoral predecessors: Lisa Robertson’s XEclogue (1993) and Erin Moure’s Sheep’s Vigil by a Fervent Person (2001). In Robertson’s appropriation of Virgil and Moure’s “transelations” of Portuguese bucolics, I find two, related models for contemporary engagement with the pastoral: the seed bomber and the terraformer. My second and third chapters, focusing on Jordan Abel, Rachel Zolf, and George Elliott Clarke, complicate the “common” by foregrounding the pastoral’s correspondence with both settler colonialism’s dispossession of Indigenous land and what Christina Sharpe identifies as the historical and ongoing “climate of antiblackness.” Together, these chapters demonstrate the necessity of approaching both the Anthropocene concept and the pastoral in Canada through the lens of settler colonialism. In the fourth chapter I turn to the oil sands poetry of Stephen Collis and Rita Wong, arguing that their “petropastoral” poetry positions extractivism as a contemporary manifestation of settler-colonial appropriation, one carried out at the expense of the health and livelihood of predominantly Indigenous, racialized, and poor communities. Responding to the entanglements of neoliberalism, global capital, settler colonialism, and extractivism, “Against Arcadia” offers the contemporary pastoral as one particular mode through which to approach the question of how to think and write poetry in Canada under the sign of the Anthropocene.
Step Right Up: (Re)imagining the Freak Show in Contemporary Performance and Disability Theory
Keywords: anatomy theatre
contemporary performance
disability
freak show
freakery
monstrous

The latter half of the twentieth and early twenty-first century has seen both an exponential increase in the visibility of exceptional bodies on stage and screen, and a renewed interest in the aesthetics and history of the freak show as a performance practice. This dissertation is part of a growing field of scholarship that seeks to examine the freak show and anatomy theatre as not only a performance practice, but also as a site that has shaped contemporary notions of what constitutes “disabled,” “healthy,” “freakish,” and “normal.” The chapters in this dissertation are comprised of five case studies from contemporary visual and popular culture. The first half of this dissertation begins with the exploration of three distinct but related case studies: the 2015 production of Bernard Pomerance’s The Elephant Man, von Hagens’s Body Worlds: Pulse, and the 2016 BBC documentary Obesity: The Post Mortem. As I argue, these three sites are exemplary of what Rachel Adams describes as the freak show’s “tireless ability for reinvention” (11). My examination of these sites is two-pronged. Firstly, I consider how these sites call upon the aesthetics and dramaturgy of the freak show and medical theatre. Secondly, I consider these three sites as modern-day freak shows in so far that these sites are part and parcel in shaping and promulgating contemporary notions of what constitutes “normal” and “abnormal.” The second half of this dissertation explores the works of two contemporary artists who self-identify as disabled and freakish: Mat Fraser and jes sachse. As I argue, both artists deliberately utilize the spectacle of the freak show (and the voyeurism and curiosity associated with this spectacle) as a means of framing their own self-representation. Unlike the case studies in chapters one and two, the works of sachse and Fraser deliberately invoke the gaze as a means of not only subverting and challenging the ableist stereotypes and narratives that have emerged from the freak shows of past and present, but to reclaim and celebrate the identity of “freak.”
The Eocene Sulfur Cycle
Keywords: barite
Eocene
Paleocene-Eocene Thermal Maximum
sulfate
sulfur cycle
sulfur isotope

The Earth system experiences a climatic transition from a greenhouse state to the start of an icehouse state over the Eocene. Such significant fluctuations have exerted influence on sea levels, ocean chemistry, and biogeochemical cycles. To provide better constraints on the Eocene sulfur cycle, I redefine sulfur and oxygen isotope ratios of seawater sulfate (δ34S and δ18Oso4) derived from marine barite between 60 and 30 Ma. Specifically, I investigate the sulfur cycle for the Paleocene-Eocene Thermal Maximum (PETM; ~55 Ma) event, the best representative of the IPCC RCP8.5 emission scenario. Increased temperature and nutrient supply may have caused large-scale oxygen loss from the PETM ocean. In the absence of oxygen, sulfate reduction replaces oxic respiration as the main mode of organic matter remineralization in seawater, producing hydrogen sulfide inside an oxygen minimum zone (OMZ). This process results in the buildup of a transient ocean internal reservoir of reduced sulfur, which can jeopardize marine ecosystems. Advection and diffusion transport hydrogen sulfide towards the upper and lower boundaries of the OMZ, where sulfide is reoxidized to sulfate. Globally intensified sulfate reduction and sulfide reoxidation affect both δ34S and δ18Oso4 values, which can in turn be used as tracers to evaluate the effects of ocean deoxygenation. Quantitative interpretation suggests that the OMZ has expanded to 10-20% of the global ocean volume during the PETM, which is sufficiently large to hold and release approximately 8×10^16 mol of reduced sulfur within 100,000 years. The short-term gross sulfate reduction flux is ~4×10^14 mol/yr, exceeding that in the present-day ocean by one order of magnitude. These findings paint a much more dynamic picture of sulfur cycling, where a transient sulfur reservoir like an OMZ leaves almost no record in rocks and sediments but does affect seawater sulfate δ34S by 1‰ and δ18Oso4 by 1.5‰ on timescales orders of magnitude shorter than its residence time. This unequivocally demonstrates that the ocean may no longer be well mixed for sulfate during such events. Given the similarities between the PETM and the projected anthropogenic carbon emission, this thesis outlines a framework for understanding global warming and future oxygen loss.
Health Need, Demand And Cost Burden Of Type 1 Diabetes Health Technologies On Families
Keywords: Cost burden
Health policy
Health technologies
Nursing
Paediatrics
Type 1 diabetes

Insulin pump therapy and continuous glucose monitoring (CGM) can benefit children living with type 1 diabetes (T1D) and their families. Families can accrue costs for these, despite public and private funding sources. The impact of a government program in the province of Ontario, the Assistive Devices Program (ADP) for insulin pump therapy, is not well understood in the context of the paediatric population’s T1D health needs, family’s cost burden or diabetes nurse educator’s (DNE) role. The first aim of the study was to better understand the paediatric population’s type 1 diabetes health needs and families’ cost burden in the context of the ADP. The second was to expand understanding of the diabetes nurse educator’s role and impact in the context of the ADP, and helping families’ access T1D health technologies. An explanatory sequential mixed methods design comprised of a cross-sectional, web-based survey of parents and semi-structured interviews with DNEs were conducted. Survey data analysis involved descriptive statistics, and a cost analysis of parents direct and indirect costs including sensitivity analyses on select outcomes. An inductive content analysis of qualitative survey and interview data was conducted, before interpreting the study results. Annual expenditures for insulin pump therapy generally exceeded the $2,400/year ADP grant. Parents of a child requiring a multiple daily injection regime accrued slightly more expenditures on average over 12 months ($3,605.25) compared to insulin pump therapy ($3,447.72), when accounting for both direct and indirect costs as well as repayments by government programs and third-party payers. Parents and DNEs perceived benefits and barriers (e.g., cost) of pump therapy and CGM. Diabetes nurse educators helped families access the ADP, and worked with them and other diabetes team members to ensure children maintained program eligibility. Study results could help influence the Ontario government’s decision-making related to future health technology funding for T1D management and diabetes programs. Findings also provide greater clarity about the DNE’s role in the context of government programs such as the ADP, and highlight recommendations for nursing scope of practice, and broader health policy.
Multi-scale Remote Assessment of Phenology of Photosynthesis and Productivity of Northern Forests
Keywords: Carotenoids
Chlorophyll fluorescence
Deciduous forest
Evergreen forest
Photosynthesis
Spectral reflectance

Northern trees undergo seasonal regulation of photosynthetic activity in response to environmental conditions. Remote sensing provides a powerful tool to assess photosynthetic phenology at the global scale. However, traditional “greenness” based vegetation indices, like the normalized difference vegetation index (NDVI) which is sensitive to chlorophyll content, are often limited in monitoring the phenology of evergreen conifers due to the retention of green foliage year-round. Therefore, the main goal of my thesis is to evaluate the ability of carotenoid sensitive vegetation indices, photochemical reflectance index (PRI) and chlorophyll/carotenoid index (CCI), for monitoring the phenology of photosynthesis in evergreen conifers and deciduous trees. This study was conducted at two long-term carbon monitoring forest stands at the Turkey Point Observatory in Ontario, Canada, representing an evergreen forest and a mixed deciduous forest. First, I characterized the energy partitioning of photochemical and photoprotective processes and photosynthetic pigment composition in eastern white pine, red maple and white oak to understand the photosynthetic mechanisms reflected by NDVI, PRI and CCI at the leaf-scale. In deciduous trees, NDVI adequately reflected seasonal variation of photosynthetic activity and pigments. In pine, NDVI was unable to represent phenology. In contrast, PRI and CCI reflected seasonal variation in carotenoid pigments to represent photosynthetic phenology in both deciduous and evergreen trees. I then further evaluated NDVI, PRI and CCI as proxies of photosynthetic parameters at the canopy-scale and validated using leaf-scale measurements. NDVI and PRI were confirmed to be good indicators of the fraction of absorbed photosynthetically active radiation (ƒAPAR) and photosynthetic efficiency (ɛ), respectively. CCI was revealed to be a good indicator of both photosynthesis and ɛ. Finally, I parameterized a light-use efficiency (LUE) model with PRI and CCI as proxies of ɛ and compared model performance with a meteorological-based LUE model and a land surface model. The PRI- and CCI-LUE models demonstrated improved performance for reflecting the timing of phenology of GPP. Together, these results show that PRI and CCI reflect seasonal variation of carotenoid pigments and photoprotection in both evergreen and deciduous trees and are good proxies of photosynthetic activity for parameterizing LUE models to improve the monitoring of photosynthetic phenology.
A Novel Approach for Landing Gear Far-field Noise Prediction Using Multiple Two-dimensional Simulations
Keywords: aeroacoustics
far-field noise
FW-H
landing gear
multiple two-dimensional
two-dimensional

During the design stage, a quick tool is desirable to estimate the far-field noise generated due to flow past a landing gear (LG). In this research, a new approach is proposed to predict the far-field noise using near-field flow data obtained from multiple two-dimensional (2D) simulations. The three-dimensional (3D) LG model is divided into multiple 2D cross-sections (C-Ss) representing different configurations. The C-Ss locations are selected based on the number of components, sizes, and geometric complexities. The 2D Computational Fluid Dynamics (CFD) analysis for each C-S is carried out first to obtain the acoustic source data using the Large Eddy Simulation (LES) turbulence model. The far-field noise is then computed utilizing the Ffowcs Williams and Hawkings (FW-H) acoustic analogy. To compensate for the missing flow data in the third dimension, a source correlation length (SCL) is assumed based on a perfectly correlated flow. The overall noise of the LG is calculated as the incoherent sum of the predicted noise from all C-Ss. Flow over a single circular cylinder and tandem circular cylinders are chosen benchmark problems to examine the 2D simulations accuracy in predicting the far-field noise. Two distinct 3D LG models such as a two-wheel nose landing gear (2-NLG) and a four-wheel main landing gear (MLG) available in literature are considered. First, the proposed method is applied to 2-NLG to validate the model. Then, more numerical investigations are carried out to account for the presence of the wheel’s inner-cavities (In-Cs). After that, the reliability of the proposed method is assessed by increasing the structural complexity from 2-NLG to 4-MLG. Two different scenarios are molded to examine the effect of the LG installation under the wing. The effect of acoustic source and receiver locations on the far-field noise signature are investigated. For 2-NLG a better agreement with the experimental tone is obtained when the quadrupole sources generated around the wheels-axle C-S are included. Overall, the results are in good agreement with the experimental and 3D numerical data using low computational cost. Therefore, the proposed method has the potential to be used as an effective framework for assessing different LG designs.