VictorJuiz/thesis huggingface dataset:
A New Religious Language for a Secular Age: Canadian Poetry of the Long 1960s and Secularism in Canada

This dissertation examines the work of Canadian poets of the long 1960s who conceptualize their poetry as a new form of religious language for a secular age. I argue that these poets both imagine that certain forms of religion are no longer available in modernity and resist a secular conception of the world. They therefore create poetic languages that blur the boundaries between the religious and the secular. In pursuing this argument, I aim to complicate the longstanding account of secularization as the decline of religion in modernity. Scholars such as Charles Taylor and Talal Asad have challenged this narrative in light of its failure to account for important features of the modern West, such as the rise of religious fundamentalism. As these and other scholars demonstrate, secularity can be more accurately understood as involving the creation of new discourses and practices that reshape the ways in which religion is understood and experienced. Bringing this approach to bear on the poets I study, I read their poetry in the context of the long 1960s as a key period for the emergence of the secular imaginary in Canada. Chapter One examines Dennis Lee’s nationalist response to the secular imaginary: namely, his claim that poetry can maintain a balance between the material and the spiritual that he deems essential to national development. Chapter Two demonstrates that bpNichol registers debates about divine inspiration as he develops a poetics that is open to the sacred but that refuses to confine it within language. Chapter Three explores Leonard Cohen’s foregrounding of a Jewish perspective on secularity that informs his efforts to translate religious experiences into languages that will resonate in secular Canada. Chapter Four argues that Gwendolyn MacEwen critiques alternative spirituality as she frames her poetry as a journey to her inner depths that paradoxically gives her access to a universal reality. Moving beyond the narrative of religious decline, I show that these poets were responding to changing constructions of the religious and the secular in Canadian society as they framed their poetry as a new form of religious expression for a secular age.

Keywords: Canadian Poetry
Postsecular Studies
Religion and Literature
Secularism
Advisor: Mount, Nick
Sympathy and Authority in Seventeenth-century Poetry and Philosophy

When historians of the Renaissance talk about sympathy, they tend to focus on its “occult” associations. This project asks how such an occult concept could have become a key term for the rationalist discourse of eighteenth-century moral and political philosophy. The usual story is that sympathy reemerges in sixteenth- and seventeenth-century natural philosophy as a way to explain mysterious phenomena like magnetism or electricity. Then gradually it migrates inward and becomes a psychological principle that governs human social and political relations. The assumption is that modern science leaves no room for mystical explanations of natural phenomena, and so sympathy loses its cosmic significance and becomes strictly emotional. Through readings of John Milton’s epic Paradise Lost, Katherine Philips’s friendship poetry, work by the Cambridge Platonists including Anne Conway, and commentaries by three prominent Scottish Calvinist divines, I offer two counterclaims. First, sympathy was always-already a psychological concept, even if it also bore associations with metaphysics, magic, and religion. The notion that sympathy just changes into a moral concept is too simple. Second, sympathy becomes a pillar of eighteenth-century moral philosophy precisely because it was understood to be both an internal and an external law of attraction. When moral philosophers like Shaftesbury, Hutcheson, Smith, or Hume try to explain what ultimately binds free citizens together, they all invoke sympathy as a way to describe a type of political association that would be governed less by the state’s external laws and dictates than by the subject’s deepest, most natural desire to be connected with others. Sympathy’s odd status in sixteenth- and seventeenth-century natural philosophy as both an external force and a personal feeling made it the ideal foundation for a new form of political authority whose laws, as Rousseau said, would not be “graven on tablets of marble and brass, but on the hearts of citizens.” Defined both as a feeling in the bosom of nature that draws all things to their proper place, and as an impulse rooted in personal human desires, “sympathy” suggests that creatures are determined by the order of things, while allowing room for human freedom and creativity.

Keywords: Authority
Embodiment
Subjectivity
Sympathy
Advisor: Nyquist, Mary
Solid Dispersions in Medium-Insoluble Hydrogels for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs

Formulating poorly water-soluble drugs into Amorphous Solid Dispersions (ASDs) based on medium-insoluble hydrogels is an emerging approach showing promise for tackling solubility related oral bioavailability problems. However, critical parameters important to the design of these ASDs have not been fully elucidated. Thus, the first part of the present study examines design factors for ASDs based on Poly(2-Hydroxyethyl methacrylate) (PHEMA) hydrogel beads. Here, it is shown that one can obtain a more sustained supersaturation either through increasing the particle size of medium-insoluble hydrogels to reduce the rate of supersaturation generation or by lowering the total dose under non-sink dissolution conditions. The results of the second part demonstrate that the interplay of particle size, total dose and the swelling capacity is an essential aspect to be considered when tailoring the supersaturation generation from these ASDs. Generally, the higher the swelling capacity of the medium-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to associated drug precipitation. Furthermore, a large drug partitioning effect between the polymer carrier and dissolution medium has been found to limit the extent of drug supersaturation buildup from these ASDs. The subsequent third part of the study highlights the benefit of defining the Sink Index (SI) as when one simply changes the volume of the dissolution medium or its scale; the resulting kinetic solubility profiles can still remain similar as long as SI is kept constant. It also reveals the difficulty in predicting in vivo performance due to the impact of changing the media buffer composition on the kinetic solubility profiles of amorphous pharmaceuticals. The results of the fourth and the last part of the study serve as a proof of concept exercise for the combined effects of supersaturation rate and dose approach in rats. Here, the head-to-head in vivo comparison of ASDs in water-insoluble and soluble carriers coupled with the Physiologically based Biopharmaceutics Modeling using GastroPlus® demonstrates that these test carriers can provide similar oral absorption enhancement. Further optimization of ASDs in water-insoluble carriers is still required before they can be employed as alternative strategies for bioavailability enhancement.

Keywords: Amorphous Solid Dispersions
Enabling Formulations
In vivo Evaluation
Kinetic Solubility
Non-sink Dissolution
Supersaturation
Advisor: Lee, Ping I
Regulation of a Downstream Effector (DIAPH1, 2 and DIAPH3) of RhoA Signaling in Ciliogenesis and Maintenance of the Primary Cilia

The primary cilium works as a sensory structure by localizing receptors of various signaling pathways such as Sonic Hedgehog, Wnt and PDGF. Genetic defects that compromise ciliogenesis or cilia maintenance cause a spectrum of disorders referred to as ciliopathies. Previously, RhoA signaling had been implicated in ciliogenesis, but the involvement of pathways downstream of RhoA in cilia are unclear. One class of RhoA effectors are the DIAPHs (Diaphanous-related formin) family of formins that promote actin polymerization and also stabilize microtubules in an adenomatous polyposis coli (APC) and EB1-dependent manner. However, the role of DIAPHs in cilia function is unknown. EB1 and EB3 have previously been implicated in cilia biogenesis by centrosome-related mechanisms. Intriguingly, APC mutations in Gardner’s syndrome result in cilia-like defects, suggesting that APC might also have a role in cilia. Interestingly, APC was found to associate with the septins (SEPTs), which are also found in cilia, but the implication of this interaction for cilia is unclear. My objectives of this thesis are (a) to understand the role that DIAPHs protein play in ciliogenesis and cilia maintenance and (b) to investigate the function of the APC-SEPT interaction in cilia. My results revealed the localization of DIAPH isoforms(DIAPH1, DIAPH2 of DIAPH3) at the base of cilia, and their depletion resulted in the reduction of cilia length and ciliogenesis. Also, basal body targeted-DIAPH1-3 proteins caused cilia elongation and the formation of the bulb at the distal tip of the axoneme. Interestingly, DIAPH1-3 proteins regulate cilia maintenance by controlling vesicular trafficking to the ciliary base. Intriguingly, expression of DIAPH1 mutants associated with human deafness and microcephaly impaired ciliation and caused cilia elongation and bulb formation. Both actin and microtubule functions of DIAPH1 are needed for their roles in cilia. Interestingly the interaction of APC with SEPTs regulates cilia length, possibly by affecting vesicle traffic via changes to the cytoskeleton through their interaction with DIAPHs-EB1. Together, these studies have identified downstream effectors of RhoA, specifically DIAPHs and APC, that function in primary cilia and may shed light on the mechanisms of cilia related disorders.

Advisor: Trimble, William
Dúngal: A Study of his Life and Works

This study provides the first comprehensive treatment of the life and works of Dúngal, cleric and scholar active on the European continent during the ninth century. This dissertation has two main aims. First, it seeks to clarify what we can know about Dúngal based on an examination of the texts and manuscripts. It establishes a corpus of texts that can be attributed to Dúngal, and reassesses the palaeographic evidence of the manuscripts associated with him. Second, this dissertation provides a study of Dúngal in order to investigate broader questions about Carolingian intellectual history in the ninth century: what texts were they reading, what questions were they asking, or how were manuscripts being constructed, used, and reused? In sum, it examines Dúngal in order to contribute to our understanding of Carolingian intellectual culture in the ninth century.

Keywords: Carolingian
Dungal
Early Medieval
Intellectual History
Latin
Palaeography
Advisor: Magee, John
Herren, Michael
Roles for Novel Modulators of the Genome-reorganizing Retrotransposon

Genomes across species are filled with copious amounts of repetitive DNA sequences that contribute to diversity in genome size and structure. Examples of such repeats include transposable elements (TEs) that move around within the genome through a copy-and-paste (retrotransposons) or cut-and-paste (DNA transposons) mechanism. Retrotransposons account for about 45% of the human genome and their dysregulation has been linked to various diseases. An emerging mechanism linked to retrotransposition involves potentially DNA damaging RNA-DNA hybrid structures called R-loops. In the budding yeast, Saccharomyces cerevisiae, mutants that accumulate R-loops at Ty1 retroelements show elevated levels of retromobility through an unknown mechanism. Our work has uncovered a role for the evolutionary conserved RNA-binding protein and R-loop suppressor Pbp1 (orthologue of mammalian Ataxin-2) in the control of Ty1-LTR retromobility. Our findings point to a model in which alterations in retromobility may be involved in the pathogenesis of Ataxin-2-related diseases. Additionally, we uncovered that hybrid accumulation at Ty1 cDNA exists as one of two forms, either as a duplex structure or part of a triplex nucleic acid stricture, that promote retromobility via Rad52-dependent or -independent mechanisms respectively.

Advisor: Mekhail, Karim
DNA Secondary Structures and Cytogenetic Fragility of the C9orf72 (GGGGCC)n Repeat Expansion, Associated with ALS/FTD

Expansion of the C9orf72 repeat (GGGGCC)n is the most common cause of amyotrophic lateral sclerosis and fronto-temporal dementia. Here I characterize the unusual structures formed by the C9orf72 repeat in vitro, the effect of DNA methylation on these structures, and explore the effects of structure and methylation on protein interactions. With this foundation, we can begin to unravel therapeutic targets for ALS/FTD-targeted treatments that could arrest or even reverse disease progression such as structure-specific compounds that could be used to induce contractions or halt somatic expansion in affected tissues. Furthermore, I show that the C9orf72 expansion is in fact a cytogenetic folate-sensitive chromosomal fragile site (FSFS), similar to the ten cloned FSFS that each have been mapped to (CGG)n expansions, including FRAXA, the cause of fragile X syndrome (FXS) and a plethora of other diseases. Like other FSFS, C9orf72 repeat expansions predispose to chromosome breaks, gaps, elongated under-condensed regions, aberrant CpG methylation, unusual DNA structures, micronuclei, double-strand breaks, sister-chromatid exchanges, and lead to aberrant chromatin packaging. That the C9orf72 expansion is a fragile site now broadens the repeat sequences associated with FSFS, and sheds light on the varied genetic alterations, variable manifestations and multiple modes of pathogeneses that can arise at the C9orf72 locus, as observed with FXS.

Keywords: C9orf72-ALS/FTD
cytogenetic fragility
DNA methylation
DNA secondary structures
genome instability
repeat expansion disease
Advisor: Pearson, Christopher E
Identifying MYC-dependent Vulnerabilities in Breast Cancer

MYC is deregulated in the majority of human cancers making it an ideal candidate for therapeutic inhibition. However, targeting MYC directly with small molecule inhibitors is difficult and so alternative approaches are needed. One promising strategy is to identify and exploit non-oncogene addictions (NOA) that arise in MYC-transformed tumours. Targeting NOAs therapeutically can result in synthetic lethality and so we refer to these vulnerabilities as MYC synthetic lethal interactions (MYC-SLIs). Our working assumption is that MYC-SLIs are targetable and are likely to have little to no side-effects in normal tissues. NOAs are usually identified by comparing a wildtype cell line to one expressing a knockout or mutant gene. However, as MYC is essential for growth and rarely mutated, we instead developed an isogenic model that was transformed solely by deregulated MYC, thereby creating a tumour and normal cell pair in which NOAs could be identified. This model is dependent on MYC and can recapitulate human disease at both the pathological and molecular levels in vivo. Using this model, we were able to identify TOP1 as a MYC-SLI. Knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation when compared to control cells, demonstrating synthetic lethality. Furthermore, knock-down of TOP1 in a MYC-driven xenograft model was sufficient to reduce tumour volume. TOP1 relieves torsional stress in DNA during transcription and prevents R-loop formation. Interestingly, we identified other R-loop regulators as MYC-SLIs, suggesting that MYC imposes an increased burden onto this regulatory system. Finally, we examined the effect of cell-culture context on MYC protein:protein interactions (PPIs) and MYC-SLIs by comparing traditional adherent and mammosphere cultures. We identified unique MYC-PPIs and MYC-SLIs that are only observed in MYC-driven mammosphere culture, including components of epigenetic regulatory complexes. These data suggest that certain vulnerabilities and protein-interactions will only appear in specific contexts. As mammosphere cultures better reflect phenotypes observed in vivo, vulnerabilities identified using these methods may better translate clinically. Together, using a novel MYC-dependent transformation model, I identified novel and targetable MYC-SLIs and highlighted context-dependent changes to MYC-SLIs and MYC-PPIs.

Keywords: Cancer
Modelling
MYC
Oncogene
Synthetic Lethality
Topoisomerase
Advisor: Penn, Linda Z
Flowable Approach for the Formation of Biomaterial Sheets

Nature routinely uses a bottom – up approach for the organization of materials arounds us. This unique structural and hierarchical organization spans seven orders of magnitude in length scale: from molecular (~ nm) to organ dimensions (~ cm) is a hallmark of many organs. The variation in the structural organization imparts different functionalities and macroscopic properties such as elasticity, permeability, and optical transparency to tissues. Tissue – engineering routinely uses several promising strategies to engineer tissues that mimic the complex architecture and functionality of native tissues. However, some of their limitations include the inability to recapitulate the hierarchical assembly of materials, tunability of nanoscale properties, lack of scalability, and time – consuming fabrication methods. In this thesis, we have developed two microfluidics – enabled approaches for the scalable formation of fibrillar and polysaccharide – based hierarchical soft materials with precise control over the material composition, geometric and mechanical properties, cellular response, and structural assembly. In the first approach, we adopted a microfluidic strategy for the continuous formation of centimeter – wide, ultrathin collagen sheets. Application of shear via hydrodynamic flow – focusing through a geometric constriction and strain – induced pulling by a rotating mandrel, and the osmotic and evaporation – induced removal of water resulted in anisotropically aligned and compacted sheets with ultimate tensile strengths of 0.5 – 2.5 MPa and elastic moduli of 3 – 36 MPa. We used multi – lamellar collagen sheets to produce tissue – engineered vascular grafts with biomechanical properties similar to native vessels. The collagen sheets were also used as transwell – membranes for drug screening purposes. Human bronchial epithelial cells showed a high trans – epithelial resistance of 1900Ω x cm2. F508del – CFTR cells showed a three – fold increase in chloride conductance when treated with Cystic Fibrosis Trans –Regulator corrector, lumacaftor (VX – 809). The second microfluidic strategy allowed the continuous preparation, and processing of meter – long, roll – to – roll processed biomaterial sheets with control over thickness, morphology, and elastic properties. 3D structures with deterministic and stochastic voids were produced using layer – by – layer folding and stacking techniques. The approaches presented here find application in areas such as tissue engineering, regenerative medicine, drug – screening, and biohybrid devices.

Keywords: aligned collagen
anisotropic biomaterial sheets
biomanufacturing
microfluidics
molecular alignment
roll-to-roll processing
Advisor: Guenther, Axel
Mutation Evolution and Genomic Patterns of Recurrence in Ewing Sarcoma and Leiomyosarcoma

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.

Keywords: Cancer
Genomics
Mutational Signatures
Next-Generation Sequencing
Sarcoma
Advisor: Shlien, Adam