VictorJuiz/thesis huggingface dataset:
Attenuation of Circadian Dysfunction Improves Sleep, Mood and Neuropsychometric Performance
Keywords: Circadian Rhythms
Sleep Physiology/Medicine
Neuroendocrinology
Mood and Cognition

Mood and cognition, along with numerous other physiological processes, are under circadian regulation. The synthesis and secretion rhythm of the pineal hormone melatonin is under the direct regulation of the central circadian pacemaker and the secretion rhythm of melatonin can be used to assess circadian alterations. In this thesis, it was demonstrated that low levels of endogenous nocturnal melatonin was associated with subsyndromal depression and alterations in sleep architecture. Studies in individuals with endogenous circadian rhythm disorder, with and without comorbid depressive symptoms, revealed that individuals with depressive symptoms had a greater phase delay in melatonin profiles as compared to individuals without depressive symptoms. Furthermore, in the same study, exogenous melatonin administered to induce phase advances significantly improved depression scores and sleep initiation. In addition to endogenous circadian disruption, circadian rhythms can also be disrupted by repeated atypical alterations in environmental time cues. In mammals, light is the strongest environmental cue that can modulate circadian rhythms. Recent studies suggest that circadian response to photic stimuli is preferentially sensitive to short wavelengths in the range of 450-480 nm. Using an animal model it was demonstrated that filtering a 10 nm bandwidth between 470-480 nm from polychromatic white light prevents nocturnal light exposure induced disruptions in melatonin and corticosterone secretion as well as central and peripheral clock gene expression. These findings were further investigated in humans and revealed that filtering short wavelengths below 480 nm attenuates 12 h nocturnal light exposure induced suppression of melatonin secretion, increased cortisol secretion and disrupted peripheral clock gene expression. Furthermore, attenuation of these changes was associated with improvements in mood, alertness and vigilance at a time close to the endogenous circadian wake drive. However, filtering short wavelengths below 460 nm or reducing the optical transmission by up to 30% below 480 nm did not attenuate the disruptive effects of nocturnal light exposure on physiological and behavioural variables. Overall, the results presented in this thesis support the role of circadian dysfunction in neuropsychometric impairment and presents evidence supporting spectral modulation as a promising approach to attenuate light-mediated chronodisruption.
Controlling the Emergence of Hematopoietic Progenitor Cells from Pluripotent Stem Cells
Keywords: embryonic stem cells
hematopoiesis
hypoxia
serum-free
BMP4
VEGF
mouse

Embryogenesis occurs within a complex and dynamic cellular environment that influences cell fate decisions. Pluripotent stem cells (PSCs) are a valuable tool for research into disease models as well as a resource for cell therapy due to their capacity to self-renew and differentiate into all cell types. Mimicking aspects of the embryonic microenvironment in vitro impacts the resultant functional cells. The aim of this work was to develop a controlled and scaleable process for the generation of hematopoietic progenitor cells (HPCs) from embryonic stem cells (ESCs). We demonstrated with bioreactor-grown embryoid bodies (EBs) that increased HPC generation can be elicited by decreasing the oxygen tension by a mechanism where vascular endothelial growth factor receptor 2 (VEGFR2) activation is controlled through competition with the ligand decoy VEGFR1. This is important as it demonstrates the inherent responsiveness of the developing hematopoietic system to external forces and influences. We also established a serum-free system that facilitates directed differentiation, determining 5 ng/ml bone morphogenetic protein-4 (BMP4) with 50 ng/ml thrombopoietin (TPO) could generate 292 ± 42 colony forming cells (CFC)/5 x 10^4 cells with early VEGF treatment (25 ng/ml, day 0-5). We also controlled aggregate size influencing relative endogenous and exogenous growth factor signaling and modulating mesodermal differentiation; CFC output was optimal when initialized with 100 cell aggregates. For the first time, we demonstrated efficacy of local growth factor delivery by producing HPCs with gelatin microparticles (MP). Overall, these design components generate HPCs in a controlled and reproducible manner using a serum-free bioprocess that couples size controlled aggregates containing gelatin MPs for localized growth factor release of BMP4 and TPO with hypoxia to induce endogenous VEGF production. These strategies provide a tunable platform for developing cell therapies and high density growth, within a bioreactor system, can be facilitated by hydrogel encapsulation of the aggregates.
Digestive Tracts: Early Modern Discourses of Digestion
Keywords: digestion
early modern
body
gender
economics
colonialism

This project explores early modern conceptualizations of the body, offering a cultural history of the belly. I apply the tools of literary, historico-cultural, and discourse analysis to textual depictions of the digestive organs and the processes of digestion they perform. Concentrating particularly on the nexus of body, culture, and language, and continuously foregrounding the material underpinnings of linguistic expression, I argue that representations of the digestive organs serve to naturalize ideology and that digestion is itself an apt metaphor for the processes by which ideology is internalized. In my first chapter, I argue that the stomach is a central site through which hierarchies of gender are expressed and assimilated. I analyze Shakespeare’s The Taming of the Shrew in the context of early modern cultural metaphors associated with the stomach and in the context of medical theories of digestion, according to which hotter male digestion is superior to colder female digestion. Drawing upon Marx’s economic theory and his less-noted physiological rhetoric, in Chapter Two I trace how increasing commodity exchange and concomitant changes to social relations are reflected in, and promoted by, a paradigm shift in medical interpretations of the physiological functions of the liver. Chapter Three offers a more detailed and literary analysis of this process, demonstrating how Spenser’s allegory of the body in Book Two of The Faerie Queene participates directly in the ideological work necessary for the transition to capitalism by naturalizing the consumption and production of commodities driving it. The focus of Chapter Four is on the use of bodily metaphors of excretion in colonialist propaganda to legitimate the enforced migration of those described as England’s “excrements” to the colonies. Influenced by Norbert Elias’s theory of the “civilizing process,” I read these metaphors in light of altering social attitudes towards literal excrement, and I demonstrate how representations of the body’s excretory organs in Phineas Fletcher’s The Purple Island mirror the social processes of the “civilization” and discipline of self, nation, and Other.
Theories of the Fantastic: Postmodernism, Game Theory, and Modern Physics
Keywords: fantastic
postmodern
game theory
modern physics
quantum theory

ABSTRACT “Theories of the Fantastic: Postmodernism, Game Theory, and Modern Physics” Karen Pike Degree: Doctor of Philosophy (2010) Centre for Comparative Literature University of Toronto This dissertation examines the fantastic mode of narrative as it appears in postmodern texts in a variety of media including literature, television, and film. By analyzing the kinds of changes which the fantastic mode has undergone in order to accommodate postmodern concerns, this project attempts to answer both how and why the fantastic has maintained its popularity and effectiveness. The first chapter seeks to define the fantastic mode by tracing the history of its definition from the early twentieth century up until the present. In doing so, it revisits the contributions of such analysts as Vax, Caillois, Todorov, and Freud. The second chapter discusses the changes to conventions demanded by postmodern discursive strategies, many of which include a back-and-forth movement between equally valid interpretations of the text. A discussion of Armin Ayren’s “Der Brandstifter,” a comparison of a recurring X-Files sub-plot to Bram Stoker’s Dracula, and an analysis of an intentionally self-reflexive episode of The X-Files demonstrate these changes. The third chapter introduces game theory as a way of understanding the back-and-forth movement typical of the fantastic mode. Hanns Heinz Ewers’s “Die Spinne” is used to illustrate the psychoanalytical aspect of this movement. The next chapter compares and contrasts three vampire films, The Addiction, Lair of the White Worm, and Nadja, in order to demonstrate how the degree to which this back-and-forth movement is present is an indicator of how successfully the fantastic effect emerges. The fifth chapter introduces modern physics as another mode for understanding the presence of the fantastic mode in the postmodern era. The analysis of House of Leaves in the final chapter illustrates how postmodern theory, game theory, and physics all work together to explain the fantastic’s effectiveness. This dissertation’s aim is to explain how and why a mode once defined as a specific nineteenth-century phenomenon keeps reinventing itself and re-emerging to continue to frighten and entertain us.
The Theatrical Pendulum: Paths of Innovation in the European Stage
Keywords: European theatre
Modernism
Garcia Lorca, Federico
Bontempelli, Massimo
Capek, Karel
Capek, Josef
Evreinov, Nikolai

This dissertation examines the renovation of the modernist stage, from the beginning of the twentieth century to the late 1930s, via a retrieval of three artistic forms that had marginal importance in the commercial theatre of the nineteenth century. These three paths are the tradition of the commedia dell’arte, puppetry and marionettes, and, finally, what I denominate mysterium, following Elinor Fuch’s terminology in The Death of Character. This dissertation covers the temporal span of the first three decades of the twentieth century and, at the same time, analyzes modernist theatre in connection with the history of Western drama since the consolidation of the bourgeois institution of theatre around the late eighteenth century. The Theatrical Pendulum: Paths of Innovation in the Modernist Stage studies the renovation of the bourgeois institution of theatre by means of the rediscovery of artistic forms previously relegated to a peripheral status in the capitalist system of artistic production and distribution. In their dramatic works, Nikolai Evreinov, Josef and Karel Čapek, Massimo Bontempelli, and Federico García Lorca present fictional actors, playwrights and directors who resist the fact that their work be evaluated as just another commodity. These dramatists collaborate with the commercial stage of their time, instead of adopting the radical stance that characterized avant-garde movements such as Italian futurism and Dadaism. Yet they also question the illusionist fourth wall separating stage and audience in order to denounce the subjection of the modernist artist to the expectations of bourgeois spectators. Jan Mukařovský’s concept of practical function in art is central to understanding the didactic nature of the dramatic texts studied in this dissertation. By claiming the importance of Mukařovský’s phenomenological structuralism, I propose a new reading of the theoretical legacy of the Prague School in conjunction with recent contributions in the field of theatre studies by Elinor Fuchs, Martin Puchner and other scholars whose work will be discussed here.
Poetry and Performance: Listening to a Multi-vocal Canada
Keywords: poetry
performance
multiculturalism
polyphony
sound poetry
listening
adaptation
jazz opera
audience

Performances of poetry constitute significant cultural and literary events that challenge the representational limits and possibilities of transposing written words into live and recorded media. However, there has not been a comprehensive study of Canadian poetry that focuses specifically on performance. This dissertation undertakes a theorizing of performance that foregrounds mediation, audience, and presence (both readerly and writerly). The complex methodology combines theoretical approaches to reading (Linda Hutcheon on adaptation, Wolfgang Iser on the reader, and Roland Barthes on the materiality of writing) with poetics as theorized by Canadian poets (namely bpNichol, Steve McCaffery, Jan Zwicky, Robert Bringhurst) in order to argue that performances of poetry are responsive exchanges between performers and audiences. Importantly, the dissertation argues that performances of poetry call for a re-evaluation of reading as listening, thereby altering the interaction between audience and performance from passive to participatory. Arranged in four chapters, the dissertation examines a range of Canadian poets and performances: The Four Horsemen (Rafael Barreto-Rivera, Paul Dutton, Steve McCaffery, and bpNichol), dance adaptations of Michael Ondaatje’s poems, George Elliott Clarke’s poetic libretti, and Robert Bringhurst’s polyphonic poetry. Following the Introduction’s outlining of the term performance, Chapter One examines processes of recording and adapting avant-garde sound poetry, specifically in the sound and written poetry of Nichol and McCaffery. Chapter Two theorizes adaptation as a responsive reading practice in the context of dance adaptations of Ondaatje’s writing (Bruce McDonald’s Elimination Dance and Veronica Tennant’s Shadow Pleasures). In Chapter Three, Clarke’s jazz opera Québécité, with libretto by Clarke and music composed by D.D. Jackson, foregrounds a central argument of this dissertation: that multi-vocal poetics can, in fact, reconfigure multicultural politics. Chapter Four turns to polyphony as a textual representation of multi-vocality in the poetry of Robert Bringhurst. Through a close-listening to a musical poem by Jan Zwicky, the Conclusion points towards new critical directions in listening to Canadian poetry. Only in understanding how cultural and political performances are recorded, enacted and received both on and off the page can we listen, critically and actively, to our multi-voiced Canadian soundscapes.
The Dramaturgy of Appropriation: How Canadian Playwrights Use and Abuse Shakespeare and Chekhov
Keywords: drama
theatre
dramaturgy
Canadian drama
Canadian theatre
adaptation
Shakespeare
Chekhov
Shakespeare adaptation
Chekhov adaptation
Canadian Shakespeare adaptation
appropriation
Sears, Djanet
O'Brien, Michael
Sherman, Jason
Nutting, Kristine
Mad Boy Chronicle
Harlem Duet
The Three Sisters: A Black Opera in Three Acts
After the Orchard
dramaturgy of adaptation
reception studies
Canonicity

Both theatre and drama were imported to Canada from European colonizing nations, and as such the canonical master-texts of European drama, particularly the works of Shakespeare, have always occupied a prominent place in Canadian theatre. This presents a challenge for living Canadian playwrights, whose most revered role model is also their most dangerous competition, and whose desire to represent the spectrum of contemporary Canadian experience on stage is often at odds with the preferences of many producers and spectators for the “classics.” Since the 1990s, a number of Canadian playwrights have attempted to challenge the role of canonical plays and the values they represent by appropriating and critiquing them in plays of their own, creating a body of work which disturbs conventional distinctions between “adaptations” and “originals.” This study describes and analyzes the adaptive dramaturgies used by recent Canadian playwrights to appropriate canonical plays, question the privileged place they occupy in Canadian culture, expose the exclusionary hierarchies they legitimate, and claim centre stage for Canadian perspectives which have hitherto been waiting in the wings. It examines how playwrights challenge, usurp, or exploit the cultural capital of the canon by “re-citing” old plays in new works, how they or their producers attempt to frame the reception of their plays in order to address cultural biases against adaptation, and how audiences respond. This study draws from and builds upon contemporary theories of adaptation and particularly (Canadian) Shakespeare adaptation, seeking an understanding of adaptation based on the motives, tactics, and efficacy of adaptation. Simultaneously, it challenges the dominance of “Shakespeare,” in critical as well as theatrical practice, by comparing appropriations of Shakespeare to appropriations of Chekhov which exhibit similar tactics and motives.
Fathers, Daughters and Masculinity in Crisis
Keywords: Gender
Family Relationships
Masculinity Studies
Contemporary Fiction

This thesis engages with what has become a ubiquitous term in masculinity studies: “crisis”. I argue that the invocation of “crisis” which implies catastrophe, disaster and trauma, and the favorable reception of this invocation both in academic and popular thinking about men, has resulted in a rush to defend and reauthorize aspects of the masculine ideal. The defense of traditional masculinity risks re-entangling men with masculinity and masculinity with patriarchy. The retying of these categorical knots challenges the deconstruction of gender that feminism and early men’s studies carried out in the second half of the twentieth century in the name of equal rights and in the name of freeing both men and women from having to conform to rigid gender stereotypes – particularly in the home. In recent work by J.M. Coetzee, John Banville and Ian McEwan the male protagonists are fathers who are forced to address a crisis of authority and legitimacy. In the first three chapters I argue that fatherhood in these novels is the site wherein the masculine ideal is least likely to be deconstructed and as such, it is in the context of the relationship between father and daughter that I argue heteromasculinity is most powerfully constructed, maintained and defended. In the fourth chapter I consider Alison Bechdel’s graphic memoir Fun Home which provides a queer take on male crisis and father-daughter relationships and which represents female masculinity as a counter to the pressure to reauthorize heteromasculinity for the next historical turn.
Nature and Function of the Signaling Complex Formed by the M2 Muscarinic Cholinergic Receptor
Keywords: G protein-coupled receptor
Oligomers
Cooperativity
Heterotrimeric G proteins
Signaling

G protein-coupled receptors (GPCRs) are known to exist as oligomers, but there is much uncertainty over the oligomeric size, the number of interacting G proteins and the stability of that interaction. The present approach to these questions has been threefold. Monomers of the M2 muscarinic receptor were purified from Spodoptera frugiperda (Sf9) cells and reconstituted in phospholipid vesicles, where they spontaneously formed tetramers. The size of the reconstituted complex was determined from its electrophoretic mobility after cross-linking and inferred from a quantitative, model-based assessment of cooperative effects in the binding of two muscarinic antagonists: N-methylscopolamine and quinuclidinylbenzilate. Binding of the agonist oxotremorine-M to receptor reconstituted with purified G proteins revealed at least three classes of sites that interconverted from higher to lower affinity upon the addition of guanylylimidotriphosphate (GMP-PNP). The binding properties resemble those of muscarinic receptors in myocardial preparations, thereby implying the existence of tetramers in native tissues. G proteins that copurify with the M2 receptor from cardiac membranes also were found to exist as oligomers, some of which contain both alpha(o) and alpha(i2), and the purified complexes contained receptor and G protein in near-equal amounts. A tetrameric receptor implies a tetramer of G proteins, a conclusion that is supported by the distribution of sites between different states identified in the binding of [35S]GTPgammaS to the purified complex. Covalent adducts of a GPCR fused to a Galpha-subunit provide a model system in which the relationship between receptor and G protein complex is defined with respect to stability and composition. Such a fusion of the M2 receptor and Galpha(i1) underwent a cleavage near the amino terminus of the alpha-subunit, however, flagging the likelihood of similar effects in other such adducts. Truncation of the amino terminus prior to fusion generated a stable product that revealed GMP-PNP-sensitive, biphasic binding of oxotremorine-M and noncompetitive interactions between N-methylscopolamine and quinuclidinylbenzilate. A covalent RG complex therefore exhibits the functional properties of M2 receptors in native systems. These observations are consistent with the notion that signaling through the M2 receptor occurs via cooperative interactions within a stable complex that comprises four receptors and four G proteins.
Structure, Mechanism and Chemical Modulation of the Protein Kinase-nuclease Dual-enzyme IRE1
Keywords: Unfolded Protein Response
ER stress

Perturbations that derail the proper folding and assembly of proteins in the endoplasmic retriculum (ER) cause misfolded protein accrual in the ER – a toxic condition known as ER stress. The Unfolded Protein Response (UPR) is a signaling system evolved to detect and rectify ER stress. The work I present herein pertains to the most ancient member of the ER stress transducers, IRE1. ER stress stimulates IRE1 to activate a UPR-dedicated transcription factor called XBP1 in metazoans (or HAC1 in yeast) to bolster the productive capacity of the ER and purge misfolded proteins from the ER. To activate XBP1/HAC1, IRE1 cleaves XBP1/HAC1 mRNA twice to eliminate an inhibitory intron using a dormant nuclease function in its cytoplasmic effector region (IRE1cyto). My focus was to understand the mechanism of XBP1/HAC1 activation by IRE1, the regulation of IRE1 function and the manipulation of IRE1 signaling output using chemical tools. To better understand IRE1 mechanism, I determined the crystal structure of IRE1cyto bound to ADP. Structural and mutational analyses uncovered a probable novel IRE1 nuclease active site, allowing a catalytic mechanism of RNA cleavage to be inferred. Further genetic and biophysical experiments revealed that the ordered sequence of events: autophosphorylation, nucleotide binding and dimerization; orchestrates the assembly of the IRE1 nuclease active site to potentiate nuclease function. The flavanol quercetin was identified in a chemical screen as a potent stimulator of IRE1 nuclease output. To understand the mechanism of action of quercetin, I determined the crystal structure of IRE1cyto in complex with quercetin and ADP. Quercetin docked to a novel ligand binding site, termed the Q-site, at the interface of IRE1 dimers. Biophysical and genetic analyses revealed that quercetin engagement of the Q-site promotes IRE1 dimerization, thereby enhancing IRE1 nuclease activity. To gain insight on how IRE1 recognizes RNA, I performed bioinformatic analysis to identify a conserved sequence element in XBP1/HAC1 mRNA (termed XBP1mini) that may compose a higher-order structure recognized by IRE1. I developed an RNA production scheme to generate XBP1mini RNA for structural and biophysical studies. Preliminary X-ray diffraction studies indicate that XBP1mini may indeed adopt an ordered crystallizable tertiary structure.