VictorJuiz/thesis huggingface dataset:
Towards an Ethics of Reading: The Canadian Documentary Long Poem

This dissertation explores the ethical reading strategies at play in and impelled by the Canadian documentary long poem. I consider the ways in which poets encode and engage with the ethical problematics occasioned by their reconstruction of historical figures and events, arguing that documentary long poems encourage the reader to undertake a similar engagement—one that may result in the reader reaching drastically different conclusions than those apparently posited by a given work. Questions pertaining to appropriation, representation, and poetic license abound—questions that rarely, if ever, have stable answers. I contend that this indeterminacy is key to the ethical dimensions of the documentary long poem, as it generates open-ended dialogue regarding the recuperative work and potential harm that can result from the genre’s interrogative approach to historiography. In Chapter One I consider how Stephen Scobie’s McAlmon’s Chinese Opera invites the very ethical scrutiny that it thematizes via its representation of an historical subject who did not want aspects of his personal life transformed into literature. Chapter Two examines the documentary long poem’s capacity to offer the reader a dubious sense of historical veracity by looking to Patricia Young’s All I Ever Needed was a Beautiful Room and Douglas Burnett Smith’s Sister Prometheus, two works that link this capacity to the genre’s utilization of conventions associated with auto/biography. In Chapter Three I address the paucity of attention paid to Indigenous oral histories in critical engagements with the genre, reading Colin Morton’s The Hundred Cuts and Louise Bernice Halfe’s Blue Marrow as works that explore the damage wrought by a broader privileging of material evidence in historiographic considerations of Indigenous Peoples. Chapter Four reads Phinder Dulai’s dream / arteries and Jordan Abel’s Un/inhabited as works that outline different strategies by which archival holdings may be used to seek redress from the institutions and nation-states typically responsible for their maintenance. Throughout this dissertation, I frame the historiographic interventions of documentary poets as acts that invite scrutiny of not merely the contexts surrounding the production of historical records but also the uses to which such records are put by the poets themselves.

Keywords: Canadian Literature
Canadian Poetry
Documentary
Ethics
Historiography
Advisor: McGill, Robert
Characterizing Social Determinants of Nutrition among Late Adolescent Girls in Rural Pakistan

Although recognition of the importance of the adolescent period to both current and future health and well-being has increased, there is an acknowledged need internationally for more data to fully understand the complexities around growth and nutrition during this sensitive life stage. In Pakistan, adolescent girls are considered to be at greater risk for poor nutrition between their increased physiologic demands to support maturation, general poor dietary intake, and potential vulnerability given cultural and social norms; yet, limited data exists. Understanding the social determinants of nutritional status could serve to further elucidate where inequalities occur and shape the development of interventions. This dissertation aimed to describe the nutritional status of non-pregnant, late adolescent girls enrolled in the Matiari Empowerment and Preconception Supplementation (MaPPS) Trial, regardless of marital status, using cross-sectional data collected at enrolment. To characterize nutritional status, multiple measures were employed, including anthropometrics (n = 25,447; height, weight, and middle-upper arm circumference); dietary intake (n = 390; dietary diversity score from three repeats of a 24-hour recall); and biochemical markers (n = 3,461; hemoglobin, ferritin, retinol, and 25(OH)D concentration). A conceptual framework of social determinants of health was used to guide the development of hierarchical models for the respective nutritional status outcomes. Nearly half of participants were found to have a divergent body mass index (underweight: 36.9%, overweight: 7.9%, obese: 2.3%) and 9.2% were stunted. Only 13.5% achieved minimum dietary diversity. The overall prevalence of anemia was high at 53.6%, and, after adjustment for inflammation, 65.9% of participants were iron deficient and 38.0% had iron deficiency anemia; vitamin A and D deficiency affected 31.8% and 81.1%, respectively. At least one micronutrient deficiency was experienced by 91.0% of participants. Within the hierarchical models, variables related to poverty were more likely to lend to the greatest inequalities in nutritional status. In this population, reducing the observed triple burden of malnutrition and addressing the underlying factors that lead to nutritional inequalities will be critical. Collectively, the findings demonstrate that late adolescent girls in Pakistan would benefit from the implementation of evidence-based direct and indirect interventions to improve nutritional status and reduce poverty.

Keywords: adolescent
diet
empowerment
micronutrient deficiencies
social determinants of health
undernutrition
Advisor: Bhutta, Zulfiqar A
Tail-anchored Triphosphate Tunnel Metalloenzymes in Arabidopsis thaliana: An Investigation into the Molecular Mechanisms underlying their Biological Functions

The Triphosphate Tunnel Metalloenzymes (TTMs) superfamily is a group of proteins that contain a tunnel-shaped β-barrel structure, called a TTM domain. They exist in all domains of life where they act on a range of triphosphate substrates. However, the biological function of most TTM proteins is not well understood. The Arabidopsis genome encodes three TTM proteins named TTM1, 2, and 3. Our research group previously found that both TTM1 and TTM2 are involved in different types of programmed cell death (PCD), dark-induced senescence and immunity, respectively. It was concluded that this functional differentiation was governed by their transcriptional regulation. In this thesis, I show that the knockout mutant of TTM1 (ttm1) also displays delayed natural and ABA-induced senescence, indicating its universal role as a positive regulator of senescence-related PCD. I further found that TTM1 undergoes multiple phosphorylation events at three major sites upon perception of senescence cues (i.e. ABA or dark treatment). One of the sites, S437, shows a strong increase in phosphorylation after dark treatment and I have shown that phosphorylation at S437 is crucial for TTM1's function in senescence. Our extensive in vitro kinase assays identified two MAP kinases that phosphorylate TTM1 at S437, connecting these kinases to senescence via TTM1. I also identified a set of MAP kinases that phosphorylate TTM1 at two additional sites, S10 and S490. My data suggest that phosphorylation of these additional sites regulates TTM1 protein turnover via the 26S proteasome. These data provided the first mechanistic evidence connecting the mitochondrial outer membrane-localized protein TTM1 with ABA and leaf senescence. Further, to understand the transcriptional regulation which determines the biological functions of TTM1 and TTM2, a combination of a yeast one-hybrid assay and various in silico analyses were performed. Based on my analyses, I propose fivet ranscription factors that potentially regulate TTM1 expression during senescence and two transcription factors that likely contribute to the transcriptional down-regulation of TTM2 upon pathogen infection. In summary, my thesis work describes a mechanism for the post-translational regulation of plant TTM1 and also identifies possible transcriptional regulators of TTM1 and TTM2 for future study.

Keywords: ABA
MAP kinase
Programmed cell death
Senescence
TTM
Advisor: Yoshioka, Keiko
Diversification of Riverine Cichlids: Phylogenomic, Locomotor and Habitat Patterns using Natural History Collections

Documenting biodiversity and uncovering the adaptive and non-adaptive mechanisms involved in its generation are major goals in evolutionary biology. Insular oceanic island and lake environments have long been the focus of diversification studies, especially from the perspective of adaptive radiation. However, most of life’s diversity originated and diversified across broader continental scales, where large geographic areas and coexistence of various unrelated taxa complicate niche availability and diversification opportunities. Macroevolutionary studies in mainland taxa are therefore also needed to achieve a more general understanding of how adaptive and non-adaptive processes contribute to the formation of biodiversity. Cichlid fishes are an ideal system in which to study continental diversification, as the family is species rich, ecologically and phenotypically diverse, and inhabits multiple large continental areas. In this thesis I use several sources of data from museum collections and emerging molecular, phylogenetic and comparative approaches to investigate the evolution of functional locomotor phenotypes across cichlid fishes, with a focus on continentally distributed riverine lineages in the Neotropics and Africa. I develop robust higher level phylogenetic hypotheses for African cichlids, which have posed several longstanding taxonomic challenges, and for the whole family. Riverine cichlids exhibit diverse locomotor phenotypes and this diversity arose through selective constraints towards multiple distinct adaptive optima, consistent with adaptations to diverse diets and habitats. Shifts to new adaptive optima occurred early in some clades, such that early bursts consistent with adaptive radiation are detected for African Great Lake cichlids and two riverine tribes, the Neotropical Geophagini and African Chromidotilapiini. For other riverine clades, evolutionary patterns are instead consistent with allopatric or constrained diversification. Evolutionary patterns also vary between the Neotropics and Africa, and between continentally distributed riverine and lacustrine groups, indicating local influences on the evolutionary trajectory of these lineages. Using a novel transformation approach to extract ecological data from archived field notes I provide evidence for an association between locomotor phenotypes and habitat use, thereby supporting habitat as one ecological driver of cichlid locomotor diversity. Overall, this thesis reveals that riverine cichlid diversity was shaped by a mosaic of adaptive, non-adaptive and contingent evolutionary processes.

Keywords: Comparative Phylogenetics
Ecological Opportunity
Fishes
Macroevolution
Museum Studies
Phylogenomics
Advisor: López-Fernández, Hernán
Claramunt, Santiago
Regulation of Biological Timekeeping and Secretory Trafficking by the N-recognin UBR4/POE

Most organisms possess circadian clocks that allow them to anticipate and accordingly respond to daily cycles in the natural and ecological environment. This endogenous timekeeping machinery is driven by numerous clock proteins, whose interaction generates daily rhythms in gene expression. At the core, ubiquitin ligase enzymes contribute immensely to the molecular clock by controlling the degradation of core clock proteins, which in turn serves to govern the speed and resetting properties of the central circadian clock. However, few studies have addressed their potential to regulate other cellular events within clock neurons beyond clock protein turnover. Here, I report that the ubiquitin ligase, UBR4/POE, strengthens the central pacemaker by facilitating neuropeptide trafficking in clock neurons and promoting network synchrony. Ubr4-deficient mice are resistant to jet lag and prone to constant light-induced arrhythmicity, whereas poe knockdown flies become arrhythmic under constant dark conditions. These behaviors are reflective of the reduced axonal trafficking of circadian neuropeptides induced by the loss of ubr4/poe in clock neurons. In addition to impaired neuropeptide transport, the loss of ubr4/poe also perturbs the expression of the core clock protein, PERIOD in both mouse and fly clock neurons. However, it appears that the in vivo behaviors are best explained by the neuropeptide transport deficit, which led me to pursue this phenotype further. The biosynthetic secretory pathway is responsible for the synthesis and trafficking of membrane and secretory proteins, including neuropeptides. Within this pathway, I found that UBR4 ablation leads to altered Golgi morphology and impedes the export of secreted proteins from the Golgi apparatus by reducing the expression of Coronin 7, a protein essential for the budding of Golgi-derived transport vesicles. In summary, this work reveals a conserved and unexpected role of UBR4/POE in vesicular trafficking of neuropeptides, a function that has important implications for circadian clock synchrony and circuit-level signal processing.

Keywords: Central pacemaker
Circadian rhythms
Golgi
Neuropeptide
UBR4
Vesicular trafficking
Advisor: Cheng, Hai-Ying Mary
Levine, Joel
The Multifaceted Roles of Fragile X Mental Retardation Protein in Developmental Plasticity at a Central Synapse

During their critical period of sensory development, postsynaptic glutamatergic receptors, namely AMPA receptors (AMPARs) and NMDA receptors (NMDARs), undergo rapid remodeling in abundance and composition to enable fast neurotransmission. Dysregulation of this process can lead to neurodevelopmental disorders such as Fragile X Syndrome (FXS) which shares several mental retardation-associated features of Autism Spectrum Disorders (ASD). This is caused by a loss of Fragile X Mental Retardation Protein (FMRP), a critical translational repressor at the synapse recently implicated in ion channel modulation. To investigate the roles of FMRP in synaptic remodeling of glutamatergic receptors, I have established developmental profiles at the calyx of Held-MNTB synapse in the auditory brainstem by measuring whole-cell electrophysiological synaptic responses from pre-ear canal opening (post-natal day 6-9) and after-hearing onset (post-natal day 16-19) synapses in wild-type and the FMR1-/- mouse model of human FXS. My results indicate the loss of FMRP causes early maturation of AMPARs by accelerating the developmental switch from the slower-gating GluA1-dominant to faster-gating GluA4-dominant subunit composition of AMPARs, consistent with the canonical role of FMRP as an mRNA translational repressor. In contrast, developmental downregulation of NMDARs is not only stunted in FMR1-/- synapses, but also resistant to activity-dependent downregulation. This defect can be acutely rescued by intracellular delivery of the protein binding N-terminus fragment of FMRP during whole-cell patch clamp recordings, suggesting FMRPN-terminal is sufficient for mediating activity-dependent plasticity of NMDARs. Importantly, pulldown of the NMDAR subunit GluN1 and mGluR5 by FMRP in co-immunoprecipitation experiments provides evidence of FMRP binding to mGluR5-NMDAR complexes. This raises the possibility that a protein-protein interaction involving FMRP is engaged in the developmental downregulation of NMDARs. Based on these novel findings, I propose a model whereby activity induced increases in intracellular calcium triggers a two-pronged biochemical cascade through which FMRP differentially regulates two glutamatergic receptors within the same cell type. Altogether, FMRP functions as a canonical translational repressor to regulate AMPAR subunit expression, as well as as a non-canonical signaling molecule to mediate activity-dependent downregulation of NMDARs. These deficits in developmental synaptic remodeling provide mechanistic insights into the sensory hypersensitivity and cognitive impairments in FXS and ASD.

Keywords: AMPA-R
developmental plasticity
Fragile X Mental Retardation Protein
Fragile X Syndrom
NMDA-R
synapse
Advisor: Wang, Lu-Yang
Trimble, William S
The Brain Complex: Indeterminacy in a neuroscience laboratory

This dissertation is an ethnographic study of how notions of the human and scientific practices in a neuroscience laboratory transform under the contemporary condition of complexity. I focus on a group of researchers working in a neuroscience laboratory in Ottawa, Canada, and who have close ties with researchers in China and Taiwan. Rejecting especially deterministic and reductionist approaches, these researchers take up a notion of the human brain—the “most complex” scientific object, that is embodied, embedded in the surrounds, and emplaced in time, but also active on its own, and thus what they see as a living brain, an especially lively and active one. Captivated by the lively activity of the brain, the scientists bring dynamic, temporalized, noisy, and processual matters and methods into their scientific practices of imaging, experimenting, measuring, and modelling brains, what I term the brain complex. With the brain complex, the scientists revision the brain less as a thing, and more as a verb, a process or a doing, and captured in the term ‘activity’ that was the focus of study and materialized through dynamic interactivity. This dissertation argues that, with this revision, the scientists’ efforts to study the lively brain involve incorporating indeterminacy in their scientific practices and doing so challenges notions of science as reductive, deterministic and as a fixed practice itself, studying static scientific objects with stabilized technical apparatuses. Indeterminacy in practice instead acknowledges the change and transformation of this science, as well as the complex anthropological notions with which the brain is conjoined, namely the human, the body, and life. By following how scientific practices take up indeterminacy in this neuroscience laboratory, this dissertation challenges taken for granted understandings of the neuroscientific human as not just fixed but also dynamic, and, even further, how this dynamic human, still latent in anthropology as well, can (re)produce an uneven politics of knowledge.

Keywords: Complexity
Indeterminacy
Advisor: Bamford, Sandra
SHP2 Inhibition as a Therapeutic Strategy to Target High-risk Neuroblastoma

Survival for high-risk neuroblastoma (NB) remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of NB tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (ALK) gene. However, at NB recurrence more frequent mutations in genes in the RAS-MAPK pathway have been detected. The PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and we and others have shown that pharmacologic inhibition of SHP2 suppresses the growth of various tumor types harboring KRAS mutations such as pancreatic and lung cancers. Here, we report inhibition of growth and downstream RAS-MAPK signaling in NB cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, NSC-87877, and RMC-4550. Furthermore, our findings provide a rationale for the molecular and clinical potential of SHP2 inhibition in the treatment of ALK mutated NB, the most commonly mutated gene in NB tumors. Conversely, we showed that NB cell lines harboring endogenous NRASQ61K mutation (which is commonly detected at relapse) or isogenic NB cells engineered to overexpress NRASQ61K are distinctly resistant to SHP2 inhibitors. We further show that combinations of SHP2 inhibitors with other RAS-MAPK pathway inhibitors, such as the MEK inhibitor trametinib, RAF inhibitor vemurafenib and ERK inhibitor ulixertinib, are synergistic and reverse NRASQ61K-associated resistance to SHP2 inhibition in NB. Moreover, we demonstrate that combinatorial treatment with SHP2 and ALK inhibitors sensitize ALK-mutant and other MAPK-activated NB cells to ALK tyrosine kinase inhibitors and synergize in vitro. Finally, our pre-clinical studies in NB xenografts have provided evidence of the synergistic anti-tumor effects of SHP099 plus trametinib or ulixertinib treatments and showed that anti-SHP2/MAPK combinations led to an overall reduction in RAS signaling and alleviation of RTK feedback signaling in vivo. Together, these results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS-MAPK pathway may be effective against conventional therapy-resistant relapsed NB including those that have acquired NRAS mutations.

Keywords: combination therapy
neuroblastoma
NRAS
pediatric cancer
RAS-MAPK pathway
SHP2 inhibitor
Advisor: Irwin, Meredith S
Ohh, Michael
Navigating the Labyrinth: Women, Work and Career Coping

The present study sought to examine the life-career experiences of women in senior corporate leadership with a specific focus on career coping. This study was in response to gender discrepancy in executive leadership and focused on the minority of women who have attained high-ranking corporate positions. Using a qualitative approach to data collection, in-depth interviews were conducted with fifteen senior female leaders in Toronto, Canada. The goal of the study was to gain insight into their lived experience including their perspectives on career advancement and progression. A qualitative approach consistent with constructivist grounded theory yielded rich narratives and personal reflections that formulated underlying themes based on principles of theoretical sufficiency. The findings of data analysis validated a multidimensional approach to career navigation based on a combination of psychological, behavioural and contextual factors. The model presented in this study, illustrates each of these components on a “Career Triflex,” or a triangle, as means of highlighting the process of continually traversing between psychological, behavioural and contextual factors at various points throughout one’s career. Importantly, contained within each point on the “Career Triflex” were various career supportive items as endorsed by high ranking female executives. The psychological and behavioural components described action-oriented concepts that were directly applicable and within their locus of control. Meanwhile, the contextual component considered the role that organizations, stakeholders and/or other individuals play in supporting gender parity. This study provides nuanced conceptualizations and perspectives towards a greater understanding of how participants navigated their careers and coped with difficulty and challenge. This research addresses the lack of female representation within career theory and career counselling literature and presents a model of career coping as endorsed by a niche population of women in corporate business.

Advisor: Chen, Charles P.
Cross-species Multi-platform Screens to Characterize Novel Targetable Pathways in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is an invariably fatal brain tumour. Despite advances in surgical techniques, radiation therapy, and chemotherapy, the prognosis of patients with glioblastoma remains grim. The median survival in adults following diagnosis with GBM is only 14 months, and most patients succumb to their disease within two years. Our failure to offer a meaningful therapy to these patients has driven scientific studies towards increasing our understanding of the biology of these tumours, and in the process, identifying new targets for therapy. We propose that an integrated therapeutic approach which targets the pathways involved in regulating the hyperproliferative signaling, replicative immortality and cancer stem cell subpopulation, and the migration and invasion potential of the tumour cells is needed to achieve remission and prevent recurrence of GBM. Here, we performed multiplatform in silico and in vivo cross-species screens to identify novel therapeutic targets in GBM. Using these approaches, we have identified 25 different targets from the KRAS/PTEN, Rho-GTPase, and SOX2 signaling pathways. These studies may prove helpful in understanding the utility of targeting tumours in preclinical models, and potentially lead to novel therapeutic avenues for treating patients with GBM.

Keywords: brain tumours
C elegans
cancer therapy
glioblastoma
RNAi screens
SOX2
Advisor: Rutka, James T
Das, Sunit