VictorJuiz/thesis huggingface dataset:
On the Topology of Collective Integrable Systems

This thesis studies the topological properties of momentum maps of a large family of completely integrable systems called collective completely integrable systems. The first result concerns the topological monodromy of a collective completely integrable system on a product of three two-spheres. This system is called a "Heisenberg spin-chain" for its connection with a quantum integrable system of the same name. The remainder of the thesis is concerned with collective systems that are "constructed by Thimm's trick'' with the "action coordinates of Guillemin and Sternberg.'' We observe that the open dense subset of a symplectic manifold where such systems define a Hamiltonian torus action is connected. This observation was absent from the literature until this point. We also prove that if a system is constructed in this manner from a chain of Lie subalgebras then the image is given by an explicit set of inequalities called branching inequalities. When the symplectic manifold in question is a multiplicity free Hamiltonian U(n)-manifold, the construction of Thimm's trick with the action coordinates of Guillemin and Sternberg yields a completely integrable Hamiltonian torus action on a connected open dense subset. If the momentum map is proper, then we are able to prove lower bounds for the Gromov width of the symplectic manifold from the classification of the connected open dense subset as a non-compact symplectic toric manifold. Convex multiplicity free manifolds of compact Lie groups have been classified by Knop [51] and, accordingly, our lower bounds are given in terms of the combinatorics of the classifying data: the momentum set and a lattice. This result is the first estimate for the Gromov width of general multiplicity free manifolds of a nonabelian group. This result relies crucially on connectedness of the open dense subset and the explicit description of the momentum map image. The proof is a generalization of methods used by Pabiniak [71] to prove lower bounds for the Gromov width of U(n+1) coadjoint orbits, which are an example of multiplicity free U(n)-manifolds.

Keywords: collective
convexity
gromov width
hamiltonian
integrable
thimm
Advisor: Karshon, Yael
Thermosensitive Liposome Formulation of Cisplatin for Cancer Treatment

Cisplatin (CDDP) is a platinum-based antineoplastic drug that is approved by the U.S. Food and Drug Administration (FDA) and Health Canada for treatment of many cancers. However, CDDP is associated with severe toxicities, including nephrotoxicity, gastrointestinal toxicity, and neurological toxicity. A number of advanced drug delivery platforms, including liposomes, have been investigated in order to reduce the systemic toxicity associated with this drug. SPI-77 and LipoplatinTM are liposome formulations of CDDP that have been successfully developed and moved forward into clinical evaluation. These liposome formulations demonstrated significantly increased tumor drug accumulation relative to free drug, yet, there was lack of improvement in therapeutic efficacy over free drug as a result of limited release of drug from carriers at the tumor site. This thesis aims (1) to develop a heat-activated thermosensitive liposome formulation of CDDP (HTLC) to overcome the limited drug release of conventional liposome formulations of CDDP, (2) to assess the therapeutic efficacy of the HTLC formulation in combination with local hyperthermia (HT) in comparison to free drug and LipoplatinTM, (3) to evaluate the impact of tumor microenvironment (TME) of cervical cancer on treatment response to the HTLC formulation to identify potential prognostic markers, and (4) to investigate the short-term (i.e. 24 hr) effect of local HT on tumor morphology, microvessel density (MVD), and innate inflammatory response in non-small-cell lung cancer (NSCLC). Overall, this work demonstrated successful development of the HTLC formulation, which revealed superior therapeutic benefit in combination with local HT relative to free drug and LipoplatinTM in mouse xenograft models of cervical carcinoma and NSCLC, including four distinct patient-derived xenograft (PDX) models. TME parameters, in particular elevated levels of both tumor-associated stroma and hypoxia were shown to be overriding factors that limit drug efficacy in cervical cancer. Furthermore, local HT resulted in a significant change in the TME of NSCLC at 24 hr post-treatment, including widespread necrosis, reduction of MVD, and activation of the innate immune system.

Keywords: Cervical Cancer
Cisplatin
Hyperthermia
Liposome
Lung Cancer
Advisor: Allen, Christine
Determined Consent: Female Choice and the Love Plot in British and American Realist Fiction, 1860-1918

This dissertation explores the representation of women in love in nineteenth-century British and American realist novels to demonstrate how the love plot paradoxically precludes the rational consent required for the marriage contract. While the choice of a lover, and the subsequent consent to marriage, is the most significant action available to a heroine in a nineteenth-century novel, this “choice” is consistently portrayed as a dream-like surrender to larger forces, which render the heroine’s will inconsequential. My dissertation probes at these forces by turning to discourses that influenced the love plot: the genre of the romance, Darwinian sexual selection, and pre- and early-Freudian conceptions of dreams and the unconscious. In the first chapter, I focus on scenes of reading in novels by George Eliot, Virginia Woolf, and William Dean Howells to consider how feminized, identificatory reading practices “prepare” women for the experience of falling in love. The second chapter turns to Darwin’s theory of sexual selection to explore biological arguments for limited female choice in love in George Gissing’s In the Year of Jubilee and Henry James’s The Portrait of a Lady. In the third chapter, I shift focus to consider how the dream, a common trope of the love plot, functions as a potential space for feminist rebellion and revolution in works by Sarah Grand and Kate Chopin. Finally, in the fourth chapter, I discuss nineteenth-century notions of consent and contract and analyse novels by Thomas Hardy and Edith Wharton. In this project, I work towards an understanding of the Anglo-American “myth” of love, to consider how a love characterized by dream-like irrationality and surrender undermines the legitimacy of the heroine’s agency and consent. This suggests that our contemporary problems with delineating and making space for sexual consent may have origins in an unlikely place: the love stories of the nineteenth century.

Advisor: Bolus-Reichert, Christine
Transgenerational Effects of Synthetic Glucocorticoids on Offspring Behaviour and HPA Development in Guinea Pigs

Glucocorticoids are essential for fetal maturation. However, exposure to high levels of glucocorticoids (i.e. maternal stress/anxiety or synthetic glucocorticoid treatment [sGC]) alters the trajectory of development and increases the risk for chronic diseases later in life. Approximately 10% of pregnant women are at risk for delivering prematurely and receive treatment with sGC to reduce neonatal morbidity and mortality. Studies in children and animals demonstrated that single- and multiple-course sGC program alterations in hypothalamic-pituitary-adrenal (HPA) function and stress-associated behaviours in first generation (F1) offspring. Emerging studies in animals determined that sGC results in transmission of HPA and behavioural effects to the next generation (F2) of offspring, but no study has investigated transmission to the third generation (F3). We hypothesized that prenatal treatment with sGC results in maternal and paternal transmission of altered HPA activity and stress-related behaviours to three generations of guinea pig offspring. Prenatal treatment with either single- or multiple-course sGC resulted in transmission of effects to F2, but there were fewer effects with single-course treatment. Prenatal treatment with multiple-course sGC resulted in maternal transmission to F3. The strongest effects of sGC occurred in juvenile females from the paternal line; increased HPA response to stress, hyperactivity, impaired attention. Molecular analyses in the brains of these animals revealed that sGC programs large changes in gene expression that dissipate across generations. DAVID pathway analysis identified significant changes in the expression of genes associated with the HPA and behavioural phenotypes. This is the first study to demonstrate transgenerational programming to F3 of HPA activity and behaviours resulting from prenatal sGC transmitted. Paternal transmission to F3 strongly implicates epigenetic mechanisms. Transgenerational programming by sGC is a hallmark of in utero sGC exposure irrespective of current or past dosing regimens. These studies highlight the importance of developing new treatment approaches that maximize therapeutic efficacy while minimizing long-term adverse outcomes.

Keywords: Brain
Epigenetics
Gene regulation
Glucocorticoids
Guinea pig
Transgenerational
Advisor: Matthews, Stephen G
An Unexpected Journey: A Medicinal Chemistry Exploration through the Realm of Protein Tyrosine Phosphatases, Signal Transducers, and Receptor Tyrosine Kinases

This thesis details the medicinal chemistry research undertaken from the perspective of three drug targets; protein tyrosine phosphatase 1B (PTP-1B), signal transducer and activator of transcription 3 (STAT3), and the proto-oncogene receptor tyrosine kinase (ROS1). Concerning PTP-1B, initial library screening and follow-up biological evaluation of a library of compounds led to a series of salicylic acid-based inhibitors. Additionally, absorption spectroscopy enzymatic assays intended for the evaluation of novel compounds, revealed aggregation based inhibition of PTP-1B by an inhibitor with an ene-rhodanine core, linked to pan assay interference compounds (PAINS). In the work concerning STAT3, the potential electrophilic character of the pentafluorobenzene sulfonamide functional group in SH-4-054 was hypothesized, and subsequently proven, a metabolic liability. Discussed is the chemical evaluation of the kinetic reactivity profile for the nucleophilic aromatic substation (SNAr) substrate and initial evaluations of its potential protein modification of Cys-based nucleophiles. Continuing the STAT3 focused research concerning protein alkylators, is the exploration of the reactivity of the small molecule inhibitor S3I-201, shown to be a non-specific chemical modifier of STAT3 through tosyl mediated substitution. Finally, progress towards inhibition of ROS1 is described. Where initial attempts were aimed at expanding the research of cabozantinib, an FDA-approved drug known to overcome a clinically significant ROS1 mutation. We describe the computational chemistry, cellular, and biophysical analysis of this compound and several structural derivatives. Furthermore, the screening of a focused library of low molecular weight compounds used to identify potential hit molecules as starting points for chemically novel ROS1 inhibitors as future research is described.

Keywords: biological chemistry
drug discovery
medicinal chemistry
molecular recognition
small-molecular inhibition
Advisor: Gunning, Patrick T
Expression and Function of Kir2.1 and Kv1.3 Channels in Cytokine-induced Activation of Rat and Mouse Microglia: A Tale of Two Rodents

After acute CNS damage, microglia undergo complex molecular and functional changes. Pro-inflammatory (M1) activation can exacerbate tissue damage, while multiple anti-inflammatory (M2) states can help resolve inflammation and promote tissue repair. Potassium (K+) channels are potential targets for modulating inflammation, but their expression and roles in activated microglia are poorly understood. Also, whether rat and mouse microglia respond the same is unclear. This thesis presents two studies: 1) expression and roles of Kir2.1 in rat microglial migration and proliferation in unstimulated (CTL) and two M2 states, M2a and M2c; and 2) a comparative analysis of the molecular (gene expression) and functional (K+ channel activity, migration) responses between rat and mouse microglia in M1, M2a and M2c states. Study 1: Kir2.1 channels are necessary for microglial Ca2+ signaling and migration but weakly inhibit proliferation under CTL, M2a and M2c states. Microglial Kir2.1 expression (transcript, currents) were comparable in CTL, M2a and M2c states. Kir2.1 blockers (Ba2+ or ML133) increased proliferation slightly in CTL or M2a (but not M2c) microglia. While M2 states increased migration and chemotaxis, blocking Kir2.1 reduced both. In all three states, ML133 reduced Ca2+ influx through Ca2+-release-activated Ca2+ channels. Study 2: This collaborative project showed that pro-inflammatory genes increased only in the M1 state, but genes associated with the M2a state were not consistent between species and/or were induced in multiple activation states. Gene expression for several Kir2 and Kv1 family members was detected in both species, but the currents were mainly Kir2.1 and Kv1.3, and depended on the activation state and species. Migration was affected similarly in both species by the activation state (reduced in M1, increased in M2a or M2c), and by channel blockers (reduced by Kir2.1 block, increased by Kv1.3 block). Thus, caution is recommended in generalizing microglial responses to activating stimuli between species.

Keywords: Central Nervous System
Inflammation
Ion Channels
Microglia
Migration
Proliferation
Advisor: Schlichter, Lyanne C
The Choteadora's Body in Performance: Carmelita Tropicana and the Intersectional Strategy of Choteo

This dissertation undertakes an analysis of Carmelita Tropicana’s body in performance as it enacts “self” across the representational strategy of choteo. Carmelita Tropicana is the performance persona of Cuban-American, queer performer Alina Troyano. Choteo is a representational strategy that irreverently subverts the context and content of its referent. This doctoral study proposes that Carmelita’s work activates choteo in an intersectional and disidentificatory manner that opens up a site of negotiation, wherein the politics of representation are queried, and identity is revealed as an eventness. Specifically, by outlining choteo as an intersectional, disidentificatory strategy, I formulate choteo as an act that mobilizes through and against the complex process of identification across intersectional axes. Drawing on performance scholar José Esteban Muñoz’s suggestion of applying choteo as an optic for reading Carmelita Tropicana’s performance work, I map out the terms of this practice of “critical Cubanía,” foregrounding the intersectional and disidentificatory potential of this representational strategy. Utilizing this methodological groundwork, the project analyzes two performances—Memorias de la Revolución/ Memories of the Revolution and Milk of Amnesia/ Leche de Amnesia. My analysis of Carmelita’s body in performance and its embodiment of choteo hopes to make visible the problematics of representation and the alternative modes of self-enactment that this choteadora’s body negotiates in theatrical space. The act of choteo subverts site, memory, and identity, as Carmelita’s body in performance enacts stereotypical iconography, and simultaneously resists this reductive process of identification through excessively self-ascribing it. Moreover, the choteo within these works finally turns its bite on itself, enacting a choteo of choteo, which subverts its own framework, reckoning with the limitations of representation. My application of the intersectional, disidentificatory hermeneutic onto Carmelita Tropicana’s body in performance is rooted in a commitment to engaging and elaborating on critical scholarship and spectatorship, and querying its own framework.

Keywords: Carmelita
choteo
performance
politics
representation
Tropicana
Advisor: Johnson, Stephen
Synthesis and Applications of 3- and 5-Membered Azacycles: Natural Product Synthesis, Boron Heterocycles, and Molecular Probes

Nitrogen-containing heterocycles (azacycles) are ubiquitous in nature and are essential for the existence of life. This dissertation explores the synthesis and applications of azacycles in natural product synthesis, exploratory fundamental chemistry, materials science, and medicinal chemistry. After an introduction to azacycles and amphoteric molecules (Chapter 1), the following three chapters explore the applications of amphoteric molecules developed in the Yudin lab. Chapter 2 outlines a three-component Petasis borono-Mannich (PBM) reaction of aziridine aldehyde dimers to furnish syn-diamines. The chiral scaffolds were applied to ring-opening studies where an intriguing case of anchimeric assistance was found to govern regioselectivity. Chapter 3 discusses further application of the syn-diamines in the total synthesis of a 6-hydroxyceramide natural product found in the human epidermis. This was accomplished via a Meisenheimer rearrangement, a Lewis acid-catalyzed regioselective aziridine ring-opening, and a selective N-O bond cleavage. A number of unnatural 6-hydroxyceramide analogues were prepared, which were found to be non-toxic to yeast. Chapter 4 details the synthesis and applications of α-boryl aldoximes derived from amphoteric α-boryl aldehydes. Borylated oxadiazoles and isoxazoles were prepared via nitrile oxide chemistry, as well as a number of β-boryl-hydroxylamine derivatives en route to the synthesis of an unprecedented boron-containing azacycle. The final two chapters outline collaborative projects. Chapter 5 details a comparative study of triaryl-substituted boratriazaroles and their carbon-based analogues, and explores the role of the B-aryl substituent on photophysical properties. With p-CN substitution on the B-phenyl ring, a large Stokes shift was observed, which exhibited positive solvatochromism. Finally, Chapter 6 outlines a medicinal chemistry project utilizing fragment-based drug design. Triazole-containing small molecules were found to bind in an N-acetyllysine binding region of epigenetic protein SETDB1. Synthetic efforts towards molecular optimization of various regions of a triazole-containing biaryl system enabled the understanding of the steric and electronic requirements of this unexplored binding region.

Keywords: amphoteric molecules
boron heterocycles
materials science
medicinal chemistry
total synthesis
Advisor: Yudin, Andrei K
Consent to Rape? The Ambiguation of Sexual Consent in Contemporary World Literature

This dissertation studies that which divides rape from sex: the unstable line formed by the concept of sexual consent. It combines an exploration of the promises, paradoxes and problems associated with locating the liberal subject’s sexual consent at the heart of rape law with an analysis of contested representations of consent and nonconsent in several key literary texts about rape. These texts include the paradigmatic rape novel of the eighteenth century, Samuel Richardson’s Clarissa, and four twentieth century novels from Africa and North America: J. M. Coetzee’s Disgrace, Gayl Jones’s Corregidora, Assia Djebar’s Fantasia: An Algerian Cavalcade, and Tayeb Salih’s Season of Migration to the North. This interdisciplinary and transnational work connecting law and literature draws on the theoretical perspectives of feminism, postcolonialism and trauma theory to fill an important gap in literary analysis of what is constituted as the grey zone of sexual experience between rape and consensual sex. To explore this critical space, I attend to heterosexual representations of sexual violence that cannot be categorized as rape because nonconsent is ambiguous, and to representations that meet definitions of rape, but that critical and cultural commentary identifies as ambiguously consensual sex. Racial, sexual, colonial and national discourses among others overdetermine the female characters whose consent is at stake in these representations, obscuring their nonconsent to sex. An exploration of the problematics of the female subject’s sexual consent reveals that the liberal subject premised by rape law is an unattainable ideal compared to which actual individuals are found to be lacking. What emerges from my analysis is not just the power of rape myths, the rhetoric of seduction, and the denial of female sexual autonomy and desire, but the ambiguating force of narrative itself. The problem of representing rape is not encapsulated by a dialectic of speech and silence. Rather rape appears most indeterminable when it is represented in narrative as a sequence of events over time, for the female subject is treated as though she exists in a state of perpetual consent, and so nonconsent can only ever be a temporary action of no duration and little force.

Keywords: consent
law
postcolonial
rape
sexual violence
transnational
Advisor: Quayson, Ato
Slave, Hero, Victim: The Child Soldier Narrative in Context

This dissertation interrogates the newly prominent figure of the child soldier in African literature. I examine a number of recent texts narrating the child soldier experience, both memoir (Ishmael Beah, Emmanuel Jal, China Keitetsi, Senait Mehari, Grace Akallo, Tchicaya Missamou, Niromi de Soyza) and fiction (Uzodinma Iweala, Ahmadou Kourouma, Emmanuel Dongala, Chris Abani). The anthropologist David Rosen argues that the contemporary Western humanitarian narrative often makes an automatic assumption of innocence based on age that is not necessarily applicable in non-Western cultures. The danger of imposing such Western frameworks on non-Western cultures is that it risks engaging in the same colonial tropes of paternalism towards the native â childâ that were used to maintain dominance over colonized populations. Yet the hunger for narratives that portray the child soldier as an innocent victim who eventually is rescued and rehabilitated, as well as the fact that child soldier narratives are almost purely an African genre (even though there are substantial numbers of child soldiers in Asia, South America and the Middle East) suggests the kind of Orientalism that Edward Said warned us against: a desire to see Africa specifically as a place of violence and lost innocence that can be redeemed through Western intervention. This study takes a comparative approach, contextualizing the current literary trope of depicting the child soldier as lost innocent by comparing these contemporary narratives to a range of other texts. Chapter One examines the striking parallels between child soldier narratives and antebellum American slave narratives. Chapter Two juxtaposes child soldier narratives to the very different portrayal of South African youth involved in the militarized anti-apartheid movement. Chapter Three compares child soldier narratives to three texts narrating the experiences of young adult soldiers in the Zimbabwean war of liberation. Chapter Four questions why the child soldier is almost invariably imagined as African, while analyzing the one real exception to this rule, Niromi de Soyza's Tamil Tigress. Ultimately, through its examination of literary representations, my dissertation exposes the category of (African) child soldiers as highly problematic, allowing us to reconsider implicit myths of childhood and human rights.

Keywords: Africa
African literature
childhood
child soldiers
human rights
war
Advisor: ten Kortenaar, Neil