VictorJuiz/thesis huggingface dataset:
Marshall Plan Metropolises: The Transatlantic City in Postwar American Fiction
Keywords: Twentieth-Century American Literature
Transnational American Studies
Cold War Studies

This dissertation explores Cold War U.S. fiction’s complex engagement with a nascent culture of state-based foreign aid inaugurated by the Marshall Plan. Marshall Plan funds exceeded all previous U.S. overseas aid combined, establishing a precedent for subsequent Cold War foreign assistance projects like Truman’s Point Four program. The authors treated in my project—Joseph Heller, William Faulkner, James Baldwin, and Paule Marshall—reformulate the unique affective and social technology of Cold War compassion associated with Marshall Plan aid to postwar Europe. In their texts, the Marshall Plan subtly configures imaginings of distant, needy others on the part of an affluent America but also reveals the tolls of conditional giving—the exactions made by foreign aid that arrives with twinned humanitarian and geopolitical, expressly anticommunist aims. However, the Marshall Plan, by framing a unique relationship between U.S. money and destroyed European cities in these texts, also acts as a fulcrum upon which American authors imagine U.S. urban decline through the war-torn cityscapes of Western Europe. Marshall Plan Metropolises thus also revises scholarly accounts of Cold War U.S. culture by arguing that the literature of America’s postwar “urban crisis” can only be fully understood when read against European wartime urban annihilation. By intertwining programs of U.S. governmental support for urban restructuring on both sides of the Atlantic, the dissertation reimagines both money-saturated scenes of compassion in U.S. Cold War fiction and literary depictions of “urban renewal” of the time. Chapter one argues that Joseph Heller’s Catch-22 conceives of “reconstruction” across both time and space, linking the shattered infrastructure and political community of World War II Rome to the fraying seams of U.S. Cold War urbanity. Chapter two asserts that William Faulkner’s post-WWII corpus locates at the heart of Cold War political-discursive formations a complex relationship between geography, architecture, and sound, disclosing strategies for imagining political collectivities in spaces of ruin. Chapter three musters an unconventional reading of James Baldwin’s Giovanni’s Room as a text that meditates upon the singular affective, ethical, and geopolitical complexities of American tourism during the high Cold War. Finally, chapter four explores how Paule Marshall’s Brown Girl, Brownstones elaborates a triangulated spatial sphere encompassing America, war-wracked Europe, and “third world” Barbados, staging a distinctly Cold War mode of bildungsroman that critiques U.S. rhetorics of “freedom” and “modernization.”
Transcriptional Priming for Intrathymic Dendritic Cell Development
Keywords: thymic dendritic cells
development
Delta-Notch signaling
transcription factors
thymocyte precursors
chemokines

It has been conclusively shown that conventional dendritic cell (DC)-restricted precursors are generated in the bone marrow and migrate through the blood to the spleen and lymph nodes. However, the origins and developmental programs of thymic DC subsets remain obscure. Here, I have established unique transcriptional profiles for splenic and thymic DC subsets and I have used this information to identify candidate precursors in the thymus that are transcriptionally primed towards the DC lineages. I have also shown that DCs can develop in the presence of moderate levels of Delta-like-4 (Dll4)-Notch signaling, consistent with development of these cells within the thymic medulla, and that these levels of Dll4 are restrictive for myeloid development. The addition of Fms-like tyrosine kinase 3 ligand (Flt3L), exclusively, to DC cultures enables greater DC development in the presence of medium or high levels of Delta-like-1 (Dll1) or Dll4 ligand. Similarly, transient overexpression of inhibitor of DNA binding 2 (Id2) can enhance DC development in vivo from thymocyte precursors without significantly perturbing T cell development. Thymic DC populations are severely disrupted in recombination activation gene (RAG)-deficient mice, which lack medulla, and interleukin 7 receptor α (IL-7Rα)-deficient mice, which have reduced cellularity, indicating that a properly structured thymus and developing T cell pool are required for optimal thymic DC development or maintenance. Finally, I have demonstrated that early T cell progenitor (ETP), double negative 1 d (DN1d) and DN1e subsets have the capacity to generate thymic DCs in vivo in the context of a fully structured thymus. Our data supports a model in which the expression of chemokine (C-C motif) receptor 7 (CCR7) and chemokine (C-C motif) receptor 4 (CCR4) on DC-lineage primed ETP, DN1d and DN1e thymocyte subsets allow them to preferentially migrate to the medulla after entering the thymus, where they are exposed to a microenvironment that favors DC development.
Role of VHL in DNA double-strand break repair and genomic instability in renal cell carcinoma
Keywords: DNA repair
VHL
cancer
SOCS1

DNA repair is essential for maintaining genomic stability and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is characterized by high genomic instability. However, the molecular mechanisms underlying the association between loss of VHL and genomic instability remain unclear. Here, we show that suppressor of cytokine signalling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. We further demonstrate that the 30kDa and 19kDa isoforms of VHL have opposing roles in the DDR. Upon induction of DSBs, VHL30 activates the DDR, while VHL19 attenuates this response and is actively degraded through the proteasome to alleviate its inhibitory effect. Finally, we show that VHL30 binds heterochromatin protein 1 alpha (HP1 alpha) in the presence of DSBs and this interaction is required for the full activation of the DDR. VHL binding to HP1 alpha transiently releases it from chromatin to induce chromatin relaxation, which is predicted to allow for the access of DNA repair proteins. Remarkably, the DDR defect in VHL-null and VHL mutant cells deficient for HP1 alpha binding could be rescued in the presence of a histone deacetylase inhibitor (HDACI), suggesting that VHL activates the DDR by inducing chromatin decondensation to promote the recruitment of DNA repair factors to the lesion. Collectively, these results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.
Body National in Motion: The Biopolitics of Dance in Twentieth-Century Iran
Keywords: Iran
biopolitics
dance
20th century

This transdisciplinary historiographical dissertation elucidates the ways in which dancing bodies have provided evidence for competing representations of modernity, urbanity, and Islam throughout the twentieth century. Linking the sociopolitical discourses on performance with the staged public dancer, this study interrogates the formation of dominant categories of “modern,” “high,” and “artistic,” and the subsequent “othering” of cultural realms that were discursively peripheralized from the “national” stage. Through utilizing and probing a wide variety of textual and visual sources, this inquiry offers a history of corporeality centered on the transformation of the staged dancing body, its space of performance, and its spectatorial cultural ideology. The process of gender modernity in early twentieth-century Iran led to the heteronormalization of theatrical space and the emergence of a public female performer of the genre “national dance” (raqs-i milli). Often depicted as an angel or a princess, this ideal female construct enacted the narratives of the nation on the prestigious “national” stage of the Pahlavi period (1926–79). Her contrasting counterpart was the provocative “cabaret dancer” (raqqas) who rose to prominence in the then expanding private-sector entertainment industry. The cabaret dancer’s “enticing” presence prompted the wide circulation of social narratives that identified her with prostitution and led to the construction of a widely depicted dancer-prostitute character type in Iranian pre-revolutionary cinema. Symbolizing “degeneration” (ibtazil) and “eroticism” (shahvat) in the revolutionary discourse, she became an emblem of the “social ills” under the Pahlavi regime. The 1979 Revolution eliminated all forms of dance from the public stage until the genre “rhythmic movements” (harikat-i mawzun) introduced a chaste theatrical dancing subject. Purged from the corporeal characteristics of the pre-revolutionary cabaret dancer that signified degeneration and eroticism, the performer of rhythmic movements has been enacting the narratives of Islam and the state on the post-revolutionary stage.
Performative Language and Social Status in Shakespeare's Plays
Keywords: Shakespeare
drama
performative language
social status
speech act theory

This dissertation attempts to clarify some aspects of the operation of speech acts as they relate to power, authority, status, and rank in Shakespeare’s plays. At its core, it consists of three arguments. The first is that the ultimate index of power is the ability to have one’s words felt. That power then may translate – in terms that are neither simple nor fixed – into authority, rank, and status. The second is that such assertions or deployments of power (unless authorized by broad cultural consensus) are almost always met with resistance, and that consequently the assertions most likely to succeed are those that are least visible. The third point brings the first two together. If speech acts are often a means of asserting and exercising power, then paradoxically those speech acts that are least overt will be those most likely to succeed in that assertion: speech acts that are indirect, off-record, ambiguous, or perlocutionary. Bearing these arguments in mind, I will consider the operation and either the frustration or fruition of social ambition in Shakespeare’s plays, particularly his comedies. The plays bear out the pattern that speakers who make subtle, incremental assertions of status, by means of exploiting expectations of speech acts and genres, can then consolidate those incremental assertions into more enduring changes in status.
The Role of TRAF1 in Signaling Downstream of 4-1BB on CD8 T Cells
Keywords: TRAF1
4-1BB

4-1BB is a T cell costimulatory member of the TNFR superfamily known to regulate T cell responses. Engagement of 4-1BB contributes to T cell proliferation, cytokine production, and cell survival. Elucidating how 4-1BB induces these responses in T cells is crucial for understanding how these responses can be manipulated for immunotherapy. Upon engagement with its ligand, 4-1BB recruits TRAF1 and TRAF2 to its intracellular domain to induce downstream signaling pathways that influence the T cell's biology. 4-1BB had previously been shown to require TRAF2 to activate the canonical NF-kappaB pathway. I extended these findings to show that TRAF1 was also required, as well as either cIAP1 or cIAP2, to activate the canonical NF-kappaB pathway. I also showed that 4-1BB is capable of inducing TRAF3 degradation to induce activation of the non-canonical NF-kappaB pathway. T cells activated in the absence of costimulation do not show activation of the non-canonical NF-kappaB pathway. However, I showed that loss of TRAF1 or cIAP1 results in the unrestrained activation of the non-canonical NF-kappaB pathway, even in the absence of costimulation, resulting in hyperproliferation and excess cytokine production that normally requires costimulation. I also showed that TRAF1 expression was required in activated T cells during 4-1BB signaling in nutrient stressed T cells to stabilize TRAF2 expression. This suggests a mechanism of limiting 4-1BB costimulation only to activated T cells that are responding under optimal conditions. I conclude with a current model of the signaling that occurs downstream of 4-1BB to induce its biological effects on T cells.
The Irish Diaspora in Comparative Perspective: St. John's, Newfoundland, Halifax, Nova Scotia, and Portland, Maine, 1880-1923
Keywords: Irish
Diaspora
Ethnicity
Identity
Canada
United States
Newfoundland
Nova Scotia
Maine
New England

Whether they settled in Great Britain, the United States, Canada, Australia, or elsewhere, there was no common experience for the Irish abroad. Emigrants from Ireland and their descendants reshaped their ethnic identities in response to circumstances in both the old world and the new. A comparative study of three Irish-Catholic communities in different stages of development reveals the extent to which Irish ethnicity varied over time and space. In St. John’s, Newfoundland, and Halifax, Nova Scotia, immigration from Ireland was a largely early-nineteenth century, pre-famine phenomenon, so by the 1880s the Irish-Catholic communities were long-established, overwhelmingly native-born, and had achieved relative political and economic independence. Those of Irish descent in St. John’s formed a majority of the city’s population, while in Halifax they were a strong minority. The Irish in Portland, Maine, by contrast, arrived during and after the potato famine of the 1840s, and were a smaller minority in a mostly Yankee-Protestant milieu. This comparative study of three port cities tests how varying new world contexts affected expressions of Irish ethnicity over several generations. Was a sense of “Irishness” transmitted generationally? How, and to what extent, could a sense of ethnic community be maintained? How did relations with other ethnoreligious groups influence identity? What was the role of religion, gender, and class? How did local and external forces combine to influence expressions and understandings of Irishness? By examining associational life, the Catholic Church, education, politics, and Irish nationalism, this study argues that Irish-Catholic communities cannot be understood in isolation. Identities were created and sustained by the complex interaction of local, regional, national, and transnational networks. Through such mechanisms as ethnic, benevolent, and nationalist associations, for example, Catholics of Irish birth or descent constructed their understandings of Irishness from outside sources, but the day-to-day expression of these identities was inherently local. At the same time, religion, class, and gender influenced how ethnicity was conceived and articulated, and these processes varied considerably both within and between these three cities. Together, the comparative study reveals how Irish ethnic identity varied from place to place and over time, and how three different Catholic communities on the prow of northeastern North America remained part of an interconnected, transnational Irish diaspora until well into the twentieth century.
Investigating the Cytotoxic Mechanisms of Hepatotoxicity Induced by Xenobiotics and their Metabolites
Keywords: Toxicology

Xenobiotics or their metabolite(s) can be electrophilic or free radicals that elicit a variety of chemical reactions either directly or indirectly effecting the biochemistry of a cell, resulting in oxidative stress and/or cell death. Because drug-induced liver injury (DILI) is the leading cause of death from acute liver failure and the most common cause of drug withdrawals from the market, understanding and identifying hepatotoxic mechanisms have become a major focus area with drug and environmental regulatory agencies. In the following chapters, the in vitro cytotoxic mechanisms of known hepatotoxins were investigated using the ‘Accelerated Cytotoxicity Mechanism Screening’ (ACMS) technique. The following hypothesis was formulated: the ACMS technique can be utilized as a basic toxicological screening model to assess xenobiotic-induced hepatocyte toxicity. Using this technique, the following investigation provides support for the validity of an inflammatory model using glucose and glucose oxidase to generate hydrogen peroxide (H2O2) and its effects on known hepatotoxins, including nitroaromatic drugs (nimesulide, nilutamide, flutamide), aromatic amine drugs (clozapine, thioridazine), ethanol and its metabolite acetaldehyde. Using this inflammatory model, cytotoxicity increased with all examined compounds. This thesis also examined the hepatotoxicity of chlorpromazine (CPZ) and its reactive metabolites. Toxic CPZ metabolites were generated by cytochrome P450 (CYP) or peroxidase/H2O2-catalysed oxidation of CPZ resulting in loss of hepatocyte viability, collapse in mitochondrial membrane potential (MMP) and increased glutathione (GSH) oxidation. Finally, this thesis investigated the molecular targets of acrolein and chloroacetaldehyde (CAA), reactive metabolites of anticancer agents cyclophosphamide/ifosfamide, and the subsequent protective capacities of various protecting agents in both cell- and cell-free models. This study could provide a better understanding into the therapeutic value of protective agents currently being prescribed and agents not currently being used, but which have demonstrated protecting effects against acrolein, CAA or other toxic aldehydes. There are needs for basic toxicology screening models to assess and categorize the hepatotoxic risks associated with xenobiotics, including drugs and environmental toxins. The ACMS technique may be such a model and have a valuable application that may be 1) adaptable for high-throughput screening, 2) useful for supplementing existing in vitro screening techniques as a means to accelerate the pre-clinical screening process and 3) result in a better understanding of environmental pollutants.
Discovering Genes Responsible for Kidney Diseases
Keywords: gene
kidney disease
mouse model
ENU mutagenesis

Discovering genes responsible for kidney diseases. Joseph Ly, Doctor of Philosophy, Department of Medicine, University of Toronto, 2013. With the completion of the human genome project, researchers are now poised to discover new functions of the numerous genes identified. This is particularly important to our understanding of their role in maintaining normal physiology and in disease states, thereby guiding the discovery of novel therapeutic targets. Method: In collaboration with the Center for Modeling Human Disease, forward genetics using N-ethyl-N-nitrosourea mutagenesis was undertaken. A mutant with renal glucosuria and cystic kidneys was found on a dominant screen and further characterized. Genome-wide association was performed using a which was followed by whole-exome next-generation re-sequencing, for identification of causative mutation(s). Results I: A novel nonsense mutation in the Slc5a2 gene, leading to the loss of normal functioning Sglt2 proteins, the major sodium glucose co-transporter in the renal tubules, is causative to the renal glucosuria observed. Homozygous mutants with induced diabetes exhibit better overall glycemic control, but have an exaggerated mortality rate (70% in homozygous mutants versus 10% in wild-type controls at 20 weeks of diabetes). Results II: We have identified a point mutation in Samd9l that causes cystic kidney phenotype. Homozygous mutants do not survive beyond P0. Glomerulocysts are present in most of the P0 homozygous mutants. They also manifest “kinked” tail and disoriented inner ear hair cells, phenotypes suggestive of planar cell polarity defects. Immunoprecipitation reveals potential interaction with E3 ubiquitin ligase Stub1, whose substrate is P53. Surprisingly, we observe lower protein levels of P53 and its downstream effector P21 in whole kidney lysates from homozygous mutants compared to their wild-type littermates. Summary: Taken together, two new mouse models of kidney diseases are generated by ENU mutagenesis. The first mouse model has deficient sglt2 expression. The second mouse model of cystic kidney phenotype suggests the involvement of ubiquitination of cell cycle proteins in the pathogenesis of cystic kidney diseases, a novel pathway in cystogenesis.
Charity and the Economy of Power: The Ospedale di Santa Maria della Scala and Siena's Network of Charity in the Sixteenth Century
Keywords: Siena
Charity
Santa Maria della Scala
Renaissance State

This study examines charitable institutions as a source of power through an analysis of Siena’s largest and most prominent hospital, the Ospedale di Santa Maria della Scala. This analysis is accomplished by situating Santa Maria della Scala in the context of relationships between Siena and its surrounding territory before and after Siena’s loss of independence in 1555. From its eleventh century origins, Santa Maria della Scala developed social, religious, and political power within Siena, serving as the city’s central source of charity and playing a key role in civic rituals and devotions. Additionally, through its vast network of farms and small hospitals, Santa Maria della Scala exercised economic power and influence across the Sienese state. Through the early sixteenth century, Siena’s government drew as needed on the social, religious, and economic power of the hospital to reinforce ties with both the urban population and subject communities. However, internal political strife, increasing foreign involvement in local affairs, and a war at mid-century upset the distribution of power and strained relations between Santa Maria della Scala and the city government. After Siena’s loss of independence in 1557 and subsequent governance by Cosimo de’ Medici, competition for control of the hospital between local elite and the Medici of Florence resulted in a process of negotiation which demonstrates the ability of hospitals to function simultaneously as local power centres and as arms of the territorial state. Thus, an analysis of Santa Maria della Scala and Siena in the sixteenth century not only highlights the complex power dynamics that comprised the Grand Duchy of Tuscany, but also contributes to debates surrounding the transition in Italy from medieval communes to early modern states, and the distribution of power within those states.