VictorJuiz/thesis huggingface dataset:
Narratives of Amelioration: Mental Slavery and the New World Slave Society in the Eighteenth-century Didactic Imagination

This dissertation examines the remarkable preoccupation with enslavement in the British didactic imagination throughout the long eighteenth century. Drawing on a range of reformist narratives and writings, I suggest that the representational tendencies surrounding slavery and education in eighteenth-century reform literature can best be understood through what I call the “Protestant utopianism” that informs the didactic imagination of the Georgian era. This study thus examines a specific current of intellectual thought animating representations of colonial slavery—a tradition that was both independent of (and often in tension with) colonialist attempts to naturalize and legitimate the racial ideologies upon which the system of Atlantic chattel slavery depended. In contrast to current critical approaches, which continue to rely heavily upon the lens of imperial race ideology or “colonial discourse” to read slavery in Georgian literature, I examine the ways in which slave societies were engaged as universal landscapes—allegorical and emblematic spaces in which a variety of social process relating to the reform of civil society were enacted. These narratives of amelioration, I argue, continually depict the reform of slave societies not to establish a clear self-other dialectic based on discrete racial or geographical differences, but rather to identify Britain’s own unfinished reformation—the everyday forms of mental slavery and social violence which proliferated at home no less than in the far-flung world of the colonies. The reformed slave society emerges in these works not as the enslaved “other” to a triumphalist fantasy of a free and sovereign Britain, but as the model by which an unregenerate England can one day realize its national destiny of becoming a spiritual and secular Zion—a vision of a regenerate Protestant future purged of mental slavery. Paradoxically, these works present the reformed slave society as a universal ideal and utopian pattern for social and cultural reform at home. In the first chapter, I focus on representations of colonial slavery in Daniel Defoe’s The Family Instructor. Chapters two and three continue this examination in the work of Edward Kimber and Maria Edgeworth, respectively. I conclude by investigating amelioration-era black writing in the U.S. and Caribbean.

Advisor: Bewell, Alan
Differentiating Questions from Statements: The Role of Intonation

The most salient cues to yes/no questions and statements are rising and falling terminal pitch contours. Because young children readily differentiate rising from falling pitch contours, the presumption is that they can discern speakers’ questioning or declarative intentions from intonation alone. This thesis examined developmental changes in the use of intonation to identify questions and statements. In the first of three studies, participants from 5 years of age judged naturally produced utterances and low-pass filtered versions as questions or statements. Children correctly identified utterance type above chance levels and achieved adult accuracy levels at 9 years of age, highlighting younger children’s confusion about the links between intonation contours and pragmatic intentions. In the second study, participants from 8 years of age judged utterances with graded manipulations of terminal contours as questions or statements. Children’s question/statement judgments shifted more gradually than those of adults, reflecting greater uncertainty, but the location of the category shift was comparable across age. Adults' discrimination of utterance pairs was best for the pair that crossed the category shift, implying categorical perception of the intonation contours. In the final study, participants from 7 years of age judged the statement or question status of child- and adult-directed utterances in a gating task with words added incrementally. After limited exposure to the speaker’s voice, adults and children from 9 years of age correctly identified questions and statements from the initial word, demonstrating for the first time that English-speaking adults and children perceive pre-terminal cues to these utterance types. Identification was more accurate for child-directed than for adult-directed utterances, indicating that the former speech register exaggerates the distinctions between question and statements. Collectively, the findings reveal a protracted course of development for the questioning and declarative intentions signalled by intonation patterns and, more generally, for the pragmatic functions of intonation.

Keywords: development
intonation
perception
prosody
question
speech
Advisor: Trehub, Sandra E
Schellenberg, Glenn
Characterizing the Motor Deficits in Children with Specific Language Impairment

The objective of this dissertation was to characterize the motor deficits in children with specific language impairment (SLI). This research was motivated by the hypothesis that the motor deficits provide a window into the underlying cause of SLI, which is currently unknown. The motor abilities of children with and without SLI were explored through a broad range of tasks across three experimental studies. The first study examined childrenâ s gross, fine, oral motor and speech motor skills. The second study investigated childrenâ s motor sequence planning and execution, adaptation and retention abilities. And the last study explored temporal aspects of the manual communicative gesture productions of children with SLI. The results of these studies revealed that children with SLI had significant difficulties with novel balance, fine limb and speech motor skills. At the processing level, children with SLI exhibited impaired fine motor sequence planning and execution, while adaptation and retention appeared to be unaffected. These procedural measures were also significantly correlated with performance on grammar and vocabulary measures. Finally, the temporal relationship between speech and communicative gesture was comparable between children with and without SLI. This profile of motor impairment in SLI and its association with language ability may be best explained by deficits in procedural learning. Future studies should examine whether procedural motor measures can supplement current diagnostic protocols of SLI and whether treatment approaches that target procedural learning capacity are more effective at treating the language, motor and cognitive deficits in SLI.

Keywords: Developmental disorders
Language development
Motor learning
Procedural memory
School-aged children
Specific language impairment
Advisor: Mainela-Arnold, Elina
Temporal Transferability of Model Components within an Activity-Based Travel Demand Modelling Approach

Temporal transferability is one of the key and implicit conditions of developing travel behaviour models as these are developed for forecasting future levels of transport demand. Current travel demand modelling practices are focusing on the development of advanced models that better explain current behaviour rather than an emphasis on the ability of these models in forecasting. The importance of producing high temporal transferability of models should not be neglected as these models are used by planners and policy-makers to test policy decisions and to estimate future demands, which are critical inputs for infrastructure planning and maintenance. This research presents an investigation of the temporal transferability of activity generation process, scheduling process, and mode choice models. Three repeated cross-sectional household travel survey datasets collected in the greater Toronto and Hamilton area (GTHA) are used for the investigation. A multiple discrete-continuous extreme value model is used to develop an activity-travel generation model, and separate models are estimated for non-workers and workers. A Random utility maximization (RUM) based dynamic activity scheduling model is utilized to develop an activity-travel scheduling model for non-workers and workers separately. Heteroskedastic GEV model (HET-GEV) and HET-GEV model with scale parameter parameterized as a function of entropy are developed for commuting mode choice trips. Models are developed for individual years and then for the pooled data set of three cross-sectional years to develop a Meta model for each component. Individual year-specific models are used to increase knowledge about the temporal stability of different parameters of the model so that the Meta model could capture the non-linear evolution of some key parameters of the model. Different transferability indices are used to test temporal transferability of cross-sectional year-specific models and the Meta model. Results demonstrate an approach of effectively using multiple repeated cross-sectional datasets as pseudo panel data to develop Meta models to improve the temporal transferability of activity-based travel demand models.

Keywords: Activity-based models
Econometrics
Temporal transferability
Travel behaviour
Advisor: Nurul Habib, Khandker M
Non-confidential Clinical Prediction with Summarized Data

This dissertation reports on a series of five studies that were motivated by the need to incorporate information about similar patients into clinical decision making. The studies examined questions relating to the feasibility of a tool that could identify similar patients in health data repositories, and then use the resulting patient types for prediction of unknown values in the health record for a current patient. The main question addressed in this dissertation was: how well do predictions based on summarized clusters match predictions based on the original (unsummarized) data in terms of accuracy? The motivation for using summarized prediction in this dissertation is that summarization of sufficiently large numbers of cases removes the privacy concerns typically associated with using individual data. After an introductory chapter which establishes the motivation for the research and the overall research strategy, each of the five following chapters presents a case study in the use of cluster analysis in secondary analysis of patient data. Chapters 2, 3 and 4 utilized (MIMIC II) intensive care data. A set of patient types was developed in chapter 2 and the accuracy of predictions made with summarized data based on patient types was assessed in chapter 3. Chapter 4 focuses on the role of feature extraction in clinical prediction and compares the method used in chapter 3 with some other methods such as the K-nearest Neighbor method. Chapters 5 and 6 utilized the (ICES) cancer data from the province of Ontario. A set of patient types was developed from the cancer data (in chapter 5) and in chapter 6 the accuracy of predictions made with summarized data, based on the set of cancer patient types, was evaluated. The dissertation concludes in the final chapter with a review of the contributions (both empirical and methodological) made in the research as well as a listing of the limitations of the research and future research prospects. The main finding of this research was that relatively accurate predictions can be made based on summarized patient data in a way that does not raise privacy concerns. A secondary result is that when accuracy in prediction is used to select a particular partition of the patients, the resulted patient types can be quite interpretable. The present results point the way towards improved clinical decision support tools, and, possibly, the development of generalized health data search engines.

Keywords: Cancer
Clustering
Heath Informatics
Intensive Care Unit
Regression Analysis
Summarized Data
Advisor: Chignell, Mark H
Genetic and Epigenetic Crosstalk Define TP53-mediated Human Cancer Susceptibility

Deregulation of epigenetic programming is crucial to tumorigenesis, yet the extent to which epigenetics plays a role in cancer susceptibility remains unclear. This work details systematic molecular investigations of the familial cancer predisposition syndrome, Li-Fraumeni Syndrome (LFS), to garner a better understanding of the role of epigenetics in cancer susceptibility in humans. LFS is a prototypical cancer susceptibility syndrome characterized by a 73-100% lifetime incidence of developing at least one malignancy in affected individuals. The majority of LFS cases are associated with inherited or de novo mutations in the TP53 gene, encoding the tumor suppressor protein, p53. This work reports the first genome-wide survey of DNA methylation in peripheral blood leukocytes from carriers of germline TP53 mutations, and reveals that TP53 mutation carriers harbor a distinct DNA methylation profile relative to non-carriers overall, and in subgroup analyses stratified by cancer diagnosis. Many TP53 mutation-associated differential methylation marks occur at previously characterized p53 transcription factor binding sites. In particular, striking hypomethylation of the miR-34A promoter, a known tumor suppressor in the p53 regulatory network, is detected in leukocytes from LFS patients in two independent cohorts. By contrast, miR-34A promoter hypermethylation is a recurrent epigenetic event in primary LFS tumors of various histologies and correlates with poor clinical outcome in patients with choroid plexus carcinomas. These findings suggest a role for miR-34A as an important tumor suppressor in LFS, and demonstrate that loss of miR-34A by somatic epimutation may comprise a step in neoplastic progression in this clinical context. Detailed molecular investigations to better understand the functional role of miR-34A in the background of mutant TP53 reveal that miR-34A is essential for cell viability and regulates a network of noncoding RNAs, including components of the minor spliceosome, as well as various long non-coding RNAs. The function of miR-34A in cell cycle states may be mediated by these transcriptional changes. Collectively, this work provides the first insights into the mechanisms by which germline TP53 mutations may confer cancer predisposition and implicates a novel gene, miR-34A, in the pathogenesis of TP53-associated human cancer susceptibility.

Keywords: Cancer susceptibility
DNA methylation
epigenetics
Li-Fraumeni Syndrome
miR-34A
TP53
Advisor: Malkin, David
Hudson, Thomas J.
Characterizing the Effects of Extended Cannabis Abstinence on Cognitive Function in Patients with Schizophrenia and Non-psychiatric Controls with Cannabis Dependence

Background: While chronic cannabis use impairs cognition in controls, paradoxically, cannabis-using patients with schizophrenia demonstrate better cognitive function than non-using patients. It has been proposed that this relationship is driven by a higher functioning patient subgroup (trait effect) that is cognitively less impaired than their non-using counterparts. A caveat, however, is that most studies employed cross-sectional designs making it difficult to draw firm conclusions regarding causality. AIM: Therefore, we used a 28-day cannabis abstinence period to investigate the state-dependent effects of cannabis on key cognitive outcomes (e.g., HVLT, SDR, Digit Span) in cannabis dependent schizophrenia patients versus non-psychiatric controls. Hypothesis: We predicted that abstaining participants would experience improvements in working memory, and verbal memory and learning performance over time, and expected patients to have greater magnitude of change compared to controls. Method: Nineteen patients and 20 non-psychiatric male cannabis dependent participants underwent 28 days of cannabis abstinence. Cognition was assessed biweekly on Day 0, 14 and 28 using a comprehensive battery. Clinical symptoms were assessed weekly. Abstinence was encouraged using weekly therapy sessions and low cost contingency management confirmed by twice weekly urine assays. Results: Fort-two percent of patients and 55% of controls achieved end-point abstinence. This was biochemically verified by full cannabis elimination (Day28 urinary THC-COOH

Keywords: Cannabis
Cognition
Schizophrenia
Advisor: George, Tony P
Middle Aortic Syndrome and Renal Artery Stenosis: Disease Beyond the Arch

Background Middle aortic syndrome (MAS) is a rare childhood disease, often associated with renal artery stenosis (RAS). The etiology is unknown in most cases, but genetic and inflammatory causes have been described. Management of the associated hypertension can be medical, endovascular, or surgical, with variable success. Aims Our aims were to 1) evaluate management, and outcomes of MAS and/or RAS by etiology; 2) assess the peripheral vascular involvement and aortic disease; and 3) evaluate cardiac structure, function, and myocardial mechanics. Methods Aim 1: we conducted a systematic review of 630 MAS cases, and a retrospective cohort study of 93 children with MAS and/or RAS managed at the Hospital for Sick Children (HSC). Aim 2: a cross-sectional prospective study of 35 children with MAS and/or RAS was initiated at HSC (2014-2016). Carotid intima-media thickness (CIMT) and pulse wave velocity (PWV) were assessed using B-mode ultrasound and applanation tonometry. Aim 3: two-dimensional echocardiography and speckle-tracking echocardiography were used to assess left ventricular mass (LVM), diastolic function (E/a ratio) and myocardial strain. All cardiovascular measurements were compared to age, sex, and body surface area- matched healthy children. Results Of 630 cases in the literature, 70% had RAS, and the aortic disease was confined to the peri-renal aorta. Of 93 children managed at HSC, 70% received endovascular or surgical intervention, with a higher risk of intervention in children with unknown disease compared to those with genetic and inflammatory causes (HR=3, 95% CI [2,6]). Hypertension persisted in 65% of all patients for 2 [0.4-5] years after management. CIMT was increased in children with MAS and/or RAS compared to controls (0.54Âą0.10 vs. 0.44Âą0.05 mm, p

Keywords: Abdominal aorta
Aortic stenosis
Middle aortic syndrome
Renal artery stenosis
Renovascular hypertension
Vascular imaging
Advisor: Parekh, Rulan S
The Role of Short Chain Fatty Acids in Obesity

Short-chain fatty acids (SCFA) are produced by colonic microbiota, mostly from dietary fiber. Mice studies have shown that excess production of SCFA by the ‘obese microbiota’ (increased Firmicutes and decreased Bacteroidetes), may promote obesity via increased colonic energy availability. However, other studies have shown that colonic fermentation of dietary-fiber to SCFA may play a role in preventing obesity and diabetes. Thus, the primary goals of this work were to investigate whether overweight and obese (OWO) humans produce SCFA more efficiently than lean (LN) humans, and whether SCFA from colonic fermentation of two different fibers affect appetite hormone and glycemic responses. To achieve these goals, 2 studies in LN and OWO human subjects were performed. The first study confirmed higher fecal SCFA concentrations in OWO than LN humans. This could have been due to more efficient SCFA production by the ‘obese microbiota’, since colonic SCFA absorption, dietary intakes and markers for gut transit time were similar in LN and OWO subjects and, therefore, could not explain the difference in fecal SCFA between the groups. However, the second study did not confirm the higher SCFA concentrations in feces or in blood (either at fasting or postprandially following fiber consumption) in OWO compared to LN humans. Unexpectedly the increase in SCFA from inulin or resistant-starch’s fermentation did not affect glycemia or appetite hormone responses (excluding a possible effect of inulin on ghrelin). On the other hand, both fibers induced early effects that were not likely related to colonic fermentation: resistant-starch significantly reduced free-fatty acid rebound and second-meal glucose and insulin responses, while inulin significantly elevated the satiety hormone PYY. The results do not support the hypothesis that overweight/obesity is associated with increased colonic SCFA production. The acute effects of consuming resistant starch to reduce glycemic responses and of inulin to improve appetite hormones profiles are not likely a result of their fermentation to SCFA. However, a longer adaptation to high fermentable fiber intakes may yield different results. Therefore, longer term and larger scales human studies are warranted.

Advisor: Wolever, Thomas MS
Preclinical Evaluation of Synergistic Drug Combinations in Acute Myeloid Leukemia

The FDA-approved Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has significantly improved patient outcomes in B-cell malignancies, where BTK signaling is implicated in disease progression. Documented expression of constitutively active BTK in AML cells has generated interest in evaluating the potential therapeutic role of ibrutinib in the treatment of AML. We investigated the role of ibrutinib in AML by screening this drug against libraries of approved drugs in AML cell lines, identifying the poly(ADP-ribose) glycohydrolase inhibitor ethacridine lactate as a profoundly synergistic hit. This drug combination was preferentially cytotoxic to patient-derived AML cells over normal controls, and synergistic cell death was preceded by reactive oxygen species (ROS) production. Ibrutinib similarly synergized with current first-line AML chemotherapy agent daunorubicin. Interestingly, neither ethacridine, nor daunorubicin’s synergy with ibrutinib appeared to be BTK-dependent. Further study with the epidermal growth factor receptor (EGFR) inhibitor erlotinib—which also has preclinical anti-AML activity—revealed equally profound EGFR-independent synergy with ethacridine, with an increase in ROS that paralleled that induced by the ibrutinib-ethacridine combination. We determined that erlotinib-mediated potentiation of ethacridine accumulation was responsible for this combination’s synergistic cytotoxicity, and hypothesize that ibrutinib and ethacridine likely synergize via the same mechanism. In summary, we have identified a novel BTK-independent role for ibrutinib in AML, and for the first time, report a potential role for PARG inhibition as a combination candidate for AML therapy.

Keywords: Acute myeloid leukemia
Drug screening
Advisor: Schimmer, Aaron D
Infectious Agent Evolution in Bornean Orangutans

In this thesis I provide among the first detailed studies of orangutan host/parasite co-evolution by bridging the disciplines of molecular virology/parasitology and biological anthropology. I used the tools of both disciplines to study the evolution of three infectious agents: simian foamy virus (SFV), simian T-lymphotropic virus 1 (STLV-1), and the protozoan parasite, Plasmodium, in orangutans Genus Pongo. Key to my thesis is the importance placed on the use of accurate calibration dates informed by archaeological and fossil data. Using this approach, I examine the evolutionary history of these infectious agents, including an estimation of the ages of divergence. The results suggest that SFV is the oldest of these infectious agents in orangutans, dating to >4 million years ago. My results challenge a previous hypothesis surrounding the appearance of a unique cladistic pattern for orangutan SFV based on the Mount Toba supervolcanic eruption at ~73 kya. The results of the present research suggest that the events leading to the development of this clade pattern is ~1.6 million years old, which rules out the Toba supereruption. My results also showed that there is a statistically significant level of host-virus coevolution in orangutans. My thesis research indicates the Plasmodium parasites in orangutans are much younger than previously thought. Finally, I estimate the origins of PTLV-1 in orangutans to between 7-343.7 kya. Overall, my thesis shows that the Pleistocene was an important period for the evolution of these infectious agents in orangutans and that it is at least possible that some of this evolution occurred on the Indochinese mainland before orangutans reached the islands of Sumatra and Borneo.

Keywords: Co-Evolution
Evolution
Orangutans
Plasmodium
Simian Foamy Virus
Simian T-Cell Lymphotropic Virus 1
Advisor: Schillaci, Michael A