VictorJuiz/thesis huggingface dataset:
Chromatin Regulators of MYC Oncoprotein Activity in Cancer

The MYC oncoprotein is a key contributor to the development of virtually all cancer types. MYC is known as a global regulator of transcription that controls diverse physiological and oncogenic functions. Though there are 35 yearsâ worth of research on this protein, mechanistic understanding and therapeutic targeting of MYC are still needed. We hypothesize that chromatin interactors are critical for MYC to achieve transcriptional control and biological outcomes. Our proteomic study of the MYC interactome yielded chromatin complexes and epigenetic regulators. In this thesis, we investigated two MYC-interacting complexes and defined the chromatin landscape of the MYC interactome. We characterized the novel interaction of MYC and the G9a histone methyltransferase and demonstrated their coordinated regulation of genome-wide transcriptional repression. This interaction and their resulting gene expression output support breast cancer growth, which is impaired with G9a inhibition. This study underscores the crucial role of epigenetics and epigenetic regulators in modulating MYC activity; this serves as the basis for a compelling strategy to target oncogenic MYC. We also interrogated the interaction of MYC and the SWI/SNF chromatin remodeling complex, whose many components are inactivated in a multitude of cancer types. We specifically showed the direct interaction of MYC and the INI1 subunit and their antagonistic relationship in regulating transcription and biological functions. Combining our proteomic approach with genome-wide resources, we established the chromatin landscape of the MYC interactome, defining chromatin profiles and target gene networks of known and novel MYC interactors. Collectively, these studies brought new insights to the understanding of MYC through the identification of novel chromatin interactors of MYC, their coordinated roles in regulating transcriptional activation and repression, their contributions to MYC-driven oncogenesis, and their therapeutic potential.

Keywords: Cancer
Epigenetics
G9a
MYC
SWI/SNF
Transcription
Advisor: Penn, Linda Z
Within-host Diversification of Pseudomonas aeruginosa in the Cystic Fibrosis Airways and its Effects on Antimicrobial Resistance

The opportunistic bacterial pathogen Pseudomonas aeruginosa causes fatal pulmonary infections in patients with the genetic disease cystic fibrosis (CF). Phenotypic and genetic diversity are prominent features of P. aeruginosa populations adapting to changes in the lung microenvironment during chronic infection. However, little is known about how this diversity impacts factors such as antimicrobial resistance and patient clinical outcome. Here, we characterized diversity within a P. aeruginosa population from a chronically infected CF patient to identify the extent of phenotypic and genetic change over time. Significant heterogeneity was observed in 34 phenotypes tested among 233 sputum cultured P. aeruginosa isolates from a single study patient, making predictions of an isolate’s phenotypic properties by colony morphology alone difficult. Fluctuations in susceptibility profiles for β-lactam antibiotics over a 350 day period coincided with the emergence of three variant alleles of the penicillin binding protein 3 gene (pbpB). Distinct allele-specific susceptibility patterns for different types of β-lactam antibiotics were not associated with other common mechanisms of resistance. Multiple variant alleles of pbpB carrying novel non-synonymous mutations were common among other P. aeruginosa isolated from CF patients with a history of β-lactam treatment. The work described in this thesis demonstrates that P. aeruginosa can behave somewhat unpredictably to antimicrobials in CF infections due to high levels of phenotypic and genetic diversity, and identifies that antibiotic target modification, in the form of penicillin binding protein 3, is a common adaptation among β-lactam exposed P. aeruginosa and may be clinically relevant.

Keywords: antibiotic resistance
cystic fibrosis
Pseudomonas aeruginosa
Advisor: Hwang, David M
Guttman, David S
The role of RNF168 in PML-NB recruitment to DNA damage and maintenance of genetic stability under oxia and hypoxia conditions

The repair of DNA damage, such as DNA double strand breaks (DSBs) is dependent on a choreographed DNA damage response (DDR) to maintain genetic fidelity and to prevent genetic instability. While the roles of the ubiquitin E3 ligase RNF168 in DDR signaling and DNA pathway selection are being elucidated, little is known about the interaction between ubiquitin E3 ligase RNF168 and nuclear components, such as PML, at the DNA double strand breaks (DSBs). In addition, it is not known if RNF168 activity differs under oxic versus hypoxic conditions to alter DNA repair and genetic stability, which is the basis of the oxygen enhancement ratio in radiotherapy. In this thesis, I have shown that PML-NB is actively recruited to DSBs and juxtaposes to open chromatin with residual DDR activity at the DSB and this recruitment is dependent on an ubiquitin-mediated recruitment process (Chapter 2). Using a RNF168 isogenic system (RIDDLE cells), I discovered that PML-NB recruitment to DSB is abolished in the RNF168-deficient RIDDLE cells, leading to increases in chromosomal and centrosomal aberrations de novo and post-IR. These defects can be restored with the complementation of human RNF168. Thus, I show that RNF168-mediated PML-NB recruitment to DSB is critical to the maintenance of genetic stability (Chapter 3). Surprisingly, I discovered that hypoxia did not synergize with RNF168-deficiency to produce greater residual DSBs. This is likely attributed to an OER of 1 at 0.2% O2 and OER of 1.86 at 0% O2 in the RIDDLE cells. As a result, hypoxia only slightly increases chromosomal and centrosomal aberrations (Chapter 4). These findings may have important implications in personalized medicine and molecular targeting of RNF168 loss or mutations in subsets of human tumors. However, I acknowledge that addition work is required to augment my data, since preexisting genetic instability in RIDDLE cells may be a confounding factor in my results. Thus, I proposed an inducible system using CRISPR-Cas9 knockout and knockin technologies to interrogate functional domains that are critical for RNF168 activity and PML-NB recruitment, and suggested improvements to live cell imaging to observe DNA repair events across longer (e.g. 4-24h) periods to corroborate our results (Chapter 5)

Keywords: DNA repair
genetic instability
hypoxia
PML
RNF168
Advisor: Bristow, Robert G
Defining Politics: On History and Political Thought in Homer's Iliad, with a Focus on Books 1-9

The Iliad is a work of great literary complexity that contains profound insights and a wide-ranging account of the human condition. Some of the most important recent scholarly work on the poem has also emphasized the political dimension of Homer’s account. In this dissertation, I aim to contribute to our understanding of the Iliad as a work of political thought. Focusing on books 1 through 9 of the Iliad, I will try to show how we can discover in it a consistent chronological or historical account, even though at many points that history is not presented in a linear way, in the poem itself. Through various references we are able to discern an historical account of the entire cosmic order. Homer focuses on the newly established Olympian gods and, therewith, their need to enforce the crucial separation between themselves and human beings: that is, between their own status as immortals, and our condition as mortals. Homer’s history of the Trojan War, in turn, conveys crucial lessons about politics and the human condition. The dissertation traces the history of the war as it emerged from a private struggle and developed into a public war. That historical narrative arc allows Homer’s readers to compare regimes that exhibit varying degrees of political phenomena. The dissertation shows that, as the Iliad’s history of the Trojan War unfolds it clarifies how politics stands in relation to the other spheres of human existence – that Homer’s poem provides us with a fundamental account of politics, of justice, of the promise and limits of human virtue, and of how the political and other aspects of existence serve to define one another. Further, the sphere of politics is shown to illuminate other, sometimes more pressing or more important, spheres of human existence - not least, those of family and friendship. Through considering these elements of Homer’s poem, the dissertation brings to sight a number of vital discoveries about politics and the human situation.

Keywords: Achilles
Ancient Greek Religion
Homer
Honor
Politics
Virtue
Advisor: Balot, Ryan K
Julia Kristeva's 'Culture of Revolt' and (Post) Modern Religious Subjectivity

This study offers a close reading of Julia Kristeva’s theories of ‘intimate revolt’ and ‘revolt culture’ and applies them to discussions of religious subjectivity. Decidedly non-militaristic, intimate revolt is reconceived in psychoanalytic and literary terms to mean an ongoing process of introspection and interrogation. The notion is derived from a multi-faceted and dynamic view of the mind, which, I submit, can broaden our conceptualization of religious subjectivity in popular discourse and vis-à-vis other psychoanalytic interpretations of religion. Indeed, Kristeva’s seemingly ambiguous treatment of Christianity is better understood in light of her theory of intimate revolt, which accepts and encourages working through competing ideas. Taking seriously the socio-political implications of intimate revolt, the overarching questions of this project are whether or not religion can fit into Kristeva’s vision of revolt culture, and, if so, what it might look like. I argue that, while she privileges aesthetic and psychoanalytic forms of revolt, Kristeva leaves open the possibility of intimate revolt in religion, particularly through her discussions of ‘the sacred’ and Christian mysticism. Finally, I survey progressive Christianity and John Caputo’s postmodern religion to identify potential examples of religious subjects who contribute to a culture of revolt. I conclude that – to the degree that it may be possible – intimate revolt should be promoted in religion today.

Keywords: Intimate Revolt
Kristeva
Psychoanalysis
Advisor: DiCenso, James
Are there perks to being a Twitter wallflower? Peripheral participants in a Twitter-enabled learning space in public relations and higher education

Despite widespread perceptions of the “digital native” generation, the majority of college- and university-age young people,18-plus, do not engage Twitter as a “learning technology”. Students’ reluctance to use Twitter within educational and professional contexts catalyzed this mixed-methods investigation of students’ engagement with #Humberpr, the online community of practice for public relations (PR) students at Humber College, a Canadian post-secondary institution. Despite the fact that industry expects PR graduates to be knowledgeable in the professional use of Twitter, during my seven years teaching undergraduate and post-graduate social media courses at Humber College, the majority of PR students were observed to engage only peripherally within the requisite Twitter learning environment. There is scant research on the peripheral participant in social media networks, and even less on student-practitioner interactions. To explore these understudied areas, my three research foci were: students’ perceptions of Twitter use; experiences using Twitter in education; and Twitter’s influence on the learning experience of peripherally-participating students. Building on situated learning theory (Lave Wenger, 1991), students’ differential engagement within #Humberpr was investigated using mixed-methods (survey, focus groups, and interviews). Tracking #Humberpr use over four months, students were categorized as peripheral or active users. My research findings reveal that peripheral participation (traditionally identified as “lurking”) warrants understandings and recognition not only as a legitimate but as a complex and rich learning modality. To recognize the “Twitter wallflower” as a peripheral participant and not merely a “lurking,” silent, and disengaged non-participant, allows for nuanced understandings of technology-enhanced learning not adequately captured by most relevant contemporary scholarship. This study offers voice to a misunderstood majority of students who struggle with the transition between personal and professional use of educational and social media networks. Many described their choice to remain on the “periphery,” as resulting from feeling they have “nothing to say”. Contributing to educational and situated learning theories, and to online learning and digital media studies, my quantitative and qualitative findings demonstrate the critical importance of expanding conceptions and analyses of learning communities and technology-enhanced education. This study highlights the need to develop flexible learning spaces that best prepare young people with the digital literacies required for technologically-mediated communications, particularly in contexts of professional education.

Keywords: community of practice
digital native
hashtag
Lave and Wenger
peripheral participant
Twitter
Advisor: Boler, Megan
Recombinase in Trio (RIT) Elements in Bacterial Genomes: Assessing the Distribution and Mobility of a Novel yet Widespread Set of Mobile Genes

The research performed over the course of my doctorate training outlines the environmental distribution, mobility, expression and potential role of a newly described family of mobile elements as well as providing valuable information on the challenges and potential benefits of environmental metagenomics. Sequencing technologies have evolved considerably over the course of this work, and evaluating the limitations and opportunities provided by these evolving technologies has formed a significant portion of my thesis work. The remainder of the work has been dedicated to understanding the distribution and mechanisms of Recombinase in Trio (RIT) elements, a previously underappreciated mobile element found in a large diversity of strains, but predominantly in non-pathogenic bacteria. Recombinase in Trio (RIT) elements contain three tyrosine-based site-specific recombinases and display a characteristic gene order and repeat architecture that is conserved across 7 bacterial phyla (Van Houdt et al. 2006; Van Houdt et al. 2012; Ricker et al. 2013). RIT elements have been postulated to be mobile due to the occurrence of multiple identical copies within individual genomes, and are commonly found on plasmids and in genomic islands, including plant symbiosis and catabolic islands. The ability of RIT elements to excise and relocate themselves was tested using a variety of mating experiments. Although the determination of a potential target site sequence was initially elusive, this was overcome and RIT element mobility was observed during conjugation. The transformants analyzed subsequently provided some insight into the mechanism of recombination. Finally, environmental sampling was performed on Southern Ontario streams in order to develop a methodology for evaluating the mobilome community of bacterial communities.

Keywords: bacterial communities
genome assembly
mobile genetic elements
next generation sequencing
RIT element
tyrosine recombinase
Advisor: Fulthorpe, Roberta
Reception and Adaptation: Magic Tricks, Mysteries, Con Games

This study of the reception and adaptation of magic tricks, murder mysteries, and con games calls for magic adaptations that create critical imaginative geographies (Said) and writerly spectators (Barthes). Its argument begins in the cave of the magician, Alicandre, where a mystical incantation is heard: "Not in this life, but in the next." These words, and the scene from which they come in Tony Kushner's

Keywords: adaptation theory
Borges
con games
magic
magicians
Mamet
Advisor: Jagoe, Eva-Lynn
Deciphering Pleiotropic Effects: A Molecular Characterisation of the Foraging Gene in Drosophila melanogaster

Pleiotropy is defined as the manifold effects of a gene at the phenotypic level. Understanding the mechanisms of manifold gene action has important implications for many fields of biology ranging from evolution and to medicine. The foraging gene, in Drosophila melanogaster, has long been a pivotal example of a single gene with natural variants that affect feeding-related phenotypes. One possible mode of action for foraging’s pleiotropy is through independent regulation of its gene products. Characterization of the foraging gene revealed 4 distinct promoters that produce 21 transcripts, and 9 ORFs. A foraging null mutant of the locus was generated using Ends-out gene targetting. foraging null mutants had reduced foraging behaviour, reduced food intake behaviour, and increased lipid levels. A recombineered full genomic rescue of the gene rescued the effects of the null mutation. By comparing the effects of the null mutant with those of the natural variants, I showed that these feeding-related phenotypes were differentially regulated. A promoter manipulation strategy identified diverse, and non-overlapping expression patterns associated with the 4 foraging promoters. Expression was seen in the nervous and gastric systems of the larva and adult fly, as well as the reproductive systems of adult fly. This expression suggests potential new roles for the foraging gene in the larva and adult fly. Characterizing the regulation of foraging's gene products will further our understanding of its role in behaviour, and shed light on the evolutionary origins of natural variants of the foraging. Not only will this study further our understanding of this gene's conserved function across taxa, but it will also help elucidate the role for differential transcriptional regulation in achieving multiple functions of a gene. This could further serve as fodder for investigations intro the roles of neo-functionalization versus escape from adaptive constraint.

Advisor: Sokolowski, Marla B
The Verb in the Amarna Letters from Canaan

The present dissertation is devoted to the Amarna letters from Canaan. This corpus of letters, directed to the pharaoh from Canaanite kinglets, dates to the fourteenth century B.C.E. and is inscribed on clay tablets in cuneiform writing. The dissertation focuses on the nature of the linguistic system of the letters and on their verbal system, its morphology and semantics. The language of the letters is a second language learners' interlanguage developed through time by the Canaanite scribes who failed to acquire normative Akkadian language in local schools because of the lack of access to proper educational materials and native speakers of the target language. Two linguistic mechanisms contributed to the formation of the Amarna interlanguage: the fossilization of linguistic knowledge on a level lower than the previous generation and the transfer of Canaanite features which affected the verbal system in a systemic manner. The resulting verbal system exhibits mixed verbal morphology: Akkadian forms used as lexical bases with added Canaanite morphemes. The morphology of the mixed forms is characterized by a great deal of variation which depends mostly on the place of the origin of letters and reflects the habits of individual scribes acquired during their scribal training. The semantics of the verbal system is characterized by the opposition between the perfective (yaqtul and qatal) and imperfective (yaqtulu) forms. These aspectual forms receive a default temporal interpretation in the past (yaqtul and qatal) and in the present-future (yaqtulu). Within the qatal paradigm, two forms are to be distinguished: the perfective verbal qatal and the nominal predicative qatal of the lexically stative verbs. The verbal syntax has a sequential nature: verbs have implications which are carried over sentence boundaries and guide the interpretation of the forms that follow in the same verbal sequence. The sequential nature of the verbal system is apparent in the modal sequence triggered by a directive-volitive form. This sequence may use the yaqtula form which is both modal and subordinated. This verbal system is used in Canaan, with the exception of the letters from Tyre which apparently emulate Akkadian morphology and semantics.

Keywords: Akkadian Language
Amarna Letters
Canaanite Languages
Verbal Morphology and Semantics
Advisor: Beaulieu, Paul-Alain
Abubakr bin Tufayl's Hayy bin Yaqzan and its Reception in Early Modern England

This study of Abubakr bin Tufayl's Hayy bin Yaqzan and its reception in early modern England aims to determine the extent and nature of John Milton's, John Locke's and Daniel Defoe's engagement of Hayy. I begin with historical research that offers the interpretative contexts upon which my comparative analyses rely. The dissertation begins with a study of seventeenth-century England where Hayy was received and twelfth-century Morocco where it was written, correcting misunderstandings in recent studies of the meaning and role of Hayy. In Chapter Two, I argue that Milton's representation of Adam's awakening in Book VIII of Milton's Paradise Lost may have been influenced by Hayy. I further suggest considering whether Milton had access to other medieval Islamic sources, particularly Islamic stories of ascent. The shared elements suggest considering these stories part of a common cycle. As for John Locke, my analysis corrects earlier suggestions that his Essay Concerning Humane Understanding and Hayy are in agreement. I show that Locke in fact disagreed with the claims made in Hayy. In Book II of his Essay, Locke closely examines the arguments made in Hayy in order to point to epistemological errors. Finally, Chapter Four discusses the importance of Daniel Defoe's reliance on Hayy in conceiving the relationship between Friday and Crusoe in the Crusoe trilogy. Defoe mimics the Hayy-Asal relationship in Hayy to develop the religious or spiritual aspects of Crusoe's character, whose religiosity is in some ways complicit with the colonial project. However, the development of Crusoe's character through his relationship with Friday allows Defoe to reveal the violence of colonial practice and to critique the moral and political philosophies that underpinned colonialism. The comparative analyses of Milton's, Locke's and Defoe's engagement of Hayy rely on viewing these texts as mediating between different historical worlds. The three English writers found Hayy attractive because it offered new ways of imagining and thinking. They imitated some of Hayy's major aspects but responded in original ways to their own contemporaneous English world. I conclude by suggesting further research on the extent of seventeenth-century English knowledge of medieval North African history.

Advisor: Nyquist, Mary
The Ethics of Enmity: Partiality’s Negative Analogue

At the outset of the Republic, Polemarchus advances the bold thesis that “justice is the art which gives benefit to friends and injury to enemies”. He quickly rejects the hypothesis, and what follows is a long tradition of neglecting the ethics of enmity. The parallel issue of how friendship (and other positive relationships) affects the moral sphere has contrastingly been greatly illuminated by discussions both ancient and contemporary. My work bridges this existing work with the less explored topic of the normative significance of our negative relationships.

Keywords: Enemies
Ethics
Friendship
Partiality
Wrongdoing
Wronging
Advisor: Hurka, Thomas