VictorJuiz/thesis huggingface dataset:
The Irish Diaspora in Comparative Perspective: St. John's, Newfoundland, Halifax, Nova Scotia, and Portland, Maine, 1880-1923

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.

Keywords: Irish
Diaspora
Ethnicity
Identity
Canada
United States
Newfoundland
Nova Scotia
Maine
New England
Advisor: McGowan, Mark
Sex Combs in Motion: Cell Dynamics of the Cellular Processes Involved in the Sex Comb Rotation in Drosophila melanogaster

A sex comb is a male-specific group of bristles located on the first leg in many species of the Drosophilidae family. (Atallah et al, 2009). This row of bristles is a secondary sexual trait, displaying high morphological divergence during evolution. In many Drosophila species, the sex comb undergoes an interesting morphogenetic process, in that this group of bristles rotates during development. This work focuses on studying the cellular dynamics involved in sex comb rotation in Drosophila melanogaster. To do this, I studied the rotation processes in wild type flies, artificially selected lines and mutants such as sex comb distal and bric à brac [PR72]. Change in sex comb length is a common evolutionary modification observed several times during sex comb evolution. To study the phenotypic effect of changing the number of sex comb teeth, I used lines artificially selected for high and low number of sex comb teeth and large effect mutants. Consistent with previous studies, I observed that selection modulates bristle number without disrupting other morphological features while the ectopic sex combs in large effect mutants display several changes. For example, artificial selection is able to uncouple the number of sex comb teeth and the degree of rotation, while the large effect mutant can affect both simultaneously. Then, I studied the cellular processes involved in the rotation of wild type Drosophila melanogaster sex combs during the pupal period. Although sex comb phenotypes in adult legs show little variance, the underlying cellular behaviours show temporal and spatial variation from leg to leg. In order to better understand how the sex comb rotates, I characterized the cellular dynamics of sex combs of different lengths: the mutant bric à brac [PR72] and the artificially selected lines. As a result, I propose three hypothetical models concerning the source of the force of rotation and suggest that a push from the region distal to the sex comb is the model that best explains current data.

Advisor: Larsen, Ellen
Investigating the Cytotoxic Mechanisms of Hepatotoxicity Induced by Xenobiotics and their Metabolites

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.

Keywords: Toxicology
Advisor: O'Brien, Peter
Discovering Genes Responsible for Kidney Diseases

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.

Keywords: gene
kidney disease
mouse model
ENU mutagenesis
Advisor: Quaggin, Susan
Charity and the Economy of Power: The Ospedale di Santa Maria della Scala and Siena's Network of Charity in the Sixteenth Century

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.

Keywords: Siena
Charity
Santa Maria della Scala
Renaissance State
Advisor: Terpstra, Nicholas
Glucose-6-phosphate dehydrogenase deficiency: A possible risk factor for neurodegeneration associated with aging and amphetamine use

Glucose-6-phosphate dehydrogenase (G6PD) regenerates the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), which is important for reactive oxygen species (ROS) detoxification. ROS have been implicated in the development of neurodegenerative diseases in aging as well as the neurotoxic effects of amphetamine analogs. Using a mutant G6PD-deficient mouse model, we investigated the potential neuroprotective role of G6PD in aging-related and amphetamine-initiated neurotoxicity. Aging G6PD-deficient mice exhibited increased DNA damage along with neurodegenerative changes including a marked loss of Purkinje cells. Locomotor deficits linked to cerebellar function were observed in aging G6PD-deficient mice, but no cognitive deficits were detected. Electrophysiological measurements in hippocampal slices showed substantial amplifications of synaptic function in aging G6PD-deficient animals. Conversely, lifespan was increased in aging homozygous G6PD-deficient mice compared to heterozygous G6PD-deficient mice and wild-type G6PD-normal mice. The potential protective role of G6PD against ROS-initiating neurotoxins was examined using 3,4-methylenedioxyamphetamine (MDA), the major active metabolite of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). Although MDA caused deficits in motor function linked to the substantia nigra, and in cognition measured by taste aversion learning, these deficits were not exacerbated in G6PD-deficient mice, and homozygous G6PD-deficient females were actually protected from one gender-specific MDA-initiated learning deficit observed in wild-type animals. My results show a complex role for G6PD. On one hand, G6PD protected against the neurodegenerative effects of oxidative stress in aging mice at the macromolecular, cellular and behavioural levels while the substantial electrophysiological alterations in G6PD-deficient mice suggest that cognitive deficits remain to be discovered. In contrast, the enhanced lifespan of G6PD-deficient mice suggests that a reduction of products from the pentose phosphate pathway including NADPH may have benefits, which mechanisms also remain to be examined. The absence of a modulatory role for G6PD in some learning deficits caused by MDA in adult mice suggests limitations in the protective ability of G6PD, while the reduction in another MDA-initiated behavioural deficit in G6PD-deficient females reveals the same paradoxical potential seen in aging mice. While G6PD appears to exert a predominantly neuroprotective role, particularly in aging, the beneficial outcomes from G6PD deficiency may be relevant to the high prevalence of it in humans.

Keywords: aging
toxicology
glucose-6-phosphate dehydrogenase
behavioural testing
amphetamines
metabolism
neurotoxicity
neuroscience
Advisor: Wells, Peter G
Analytical and Numerical Results for Some Classes of Nonlinear Schrödinger Equations

This thesis is devoted to the study of nonlinear dispersive partial differential equations of Schrödinger type. The main questions we investigate are long-time behavior or occurrence of a finite time singularity, as well as stability properties of solitary wave solutions. The derivative nonlinear Schrödinger (DNLS) equation is a nonlinear dispersive model that appears in the description of wave propagation in plasmas. The first part of this thesis concerns a DNLS equation with a generalized nonlinearity (gDNLS). We first investigate numerically the possible occurrence of singularities. We show that, in the L2-supercritical regime, singularities can occur. We obtain a precise description of the local structure of the solution in terms of the blowup rate and asymptotic profile, in a form similar to that of the nonlinear Schrödinger equation (NLS) with supercritical power law nonlinearity. We also show that the gDNLS equation possesses a two-parameter family of solitary wave solutions and study their stability. We fully classify their orbital stability or orbital instability properties according to the strength of the nonlinearity and, in some instances, their velocity. In linear quantum mechanical scattering theory, the phenomenon of resonant tunneling refers to the situation where incoming waves are fully transmitted through potential barriers at certain energies. In the second part of this thesis, we consider the one-dimensional cubic NLS equation with two classes of external potentials, namely the ‘box’ potential and a repulsive 2-delta potential. We demonstrate numerically that resonant tunneling may occur in a nonlinear setting: Taking initial condition as a slightly perturbed, fast moving NLS soliton, we show that, under a certain resonant condition, the incoming soliton is almost fully transmitted. As the velocity of the incoming soliton increases, the transmitted mass of the soliton converges to the total mass.

Keywords: Derivative nonlinear Schrödinger equation
Nonlinear Schrödinger equation
Numerical simulations
Blowing-up Solutions
Rate of Blow-up
Dynamic Rescaling
Solitary waves
Soliton dynamics
Orbital stability/instability
Resonant tunneling
Advisor: Sulem, Catherine
Functional Analysis of Neuralized in Notch Signaling and Germline Stem Cell Maintenance

The development of an organism requires precise determination of cell fate. The Notch pathway acts as a major coordinator during development, by regulating cell fate in a wide variety of tissues in multicellular organisms. A critical step in activation of Notch signaling is endocytosis of the Notch ligands, Delta and Serrate. Ligand endocytosis is regulated by one of two E3 ubiquitin ligases, Neuralized or Mind bomb. Neuralized (Neur) is composed of a C-terminal RING domain, which is required for Delta ubiquitination, and two Neur homology repeat (NHR) domains. Here, I characterized the two NHR domains. We have previously shown that the NHR1 domain is required for Delta trafficking and I further determined that NHR1 also affects binding and internalization of Serrate. Furthermore, I showed that the NHR2 domain is required for Neur function and that a point mutation in NHR2 (Gly430) abolishes Neur ubiquitination activity, thereby affecting ligand internalization. I also provided evidence that Neur can form oligomers in cultured cells and in fly tissues, which regulates Neur activity, by extension, ligand internalization. Finally, I investigated the role of Neuralized in germline stem cell (GSC) maintenance. Specifically, I found that Neuralized is required for GSC maintenance and the NHR and RING domains are indispensable for this function. Furthermore, I showed that Neuralized is a downstream target of the Jak/Stat pathway in GSC maintenance. Interestingly, I also provided evidence that Notch may not be required for GSC maintenance, suggesting that Neur can function independent of Notch signaling in GSCs. Altogether, my studies demonstrate that Neur plays critical roles in regulating cell fate in different developmental contexts.

Keywords: Neuralized
Notch Signaling
Germline Stem Cell
Advisor: Boulianne, Gabrielle
Computational Analysis of RNA-binding Protein Target-site Selection and Function

Gene expression is extensively regulated by the binding of RNA-binding proteins (RBPs) to cis-regulatory elements encoded in mRNA. A robust literature has emerged regarding the stability and intracellular distribution of transcripts genome-wide. However, clear binding preferences have only been reported for a few RBPs, and these binding data collectively explain only a small portion of these post-transcriptional events. I developed the RNA Regulatory Element Analysis and Discovery (RNA-READ) pipeline, which takes as input positive (e.g., regulated transcripts) and negative gene lists (e.g., the co-expressed transcripts not affected by the same post-transcriptional event), and outputs the RNA cis-regulatory element that distinguishes the positive from the negative transcripts. First, RNA-READ tests for enrichment of previously reported RNA motifs, then it performs novel RNA motif discovery to identify the consensus RNA motif that best discriminates between the positive and negative transcripts. An important innovation of the RNA-READ pipeline is that it considers both sequence and structural constraints on binding of RBPs. I consider two binding classes: (1) the RBP binds to mRNAs with primary sequence-specificities; (2) the RBP binds to elements in mRNAs defined completely by structure (i.e., shape recognition). I have shown that computationally estimated target-site accessibility improves prediction of sequence-specific binding for various RBPs, with >22% average relative decrease in error versus using only sequence information. The predictive power is further increased with the introduction of structural-context constraints to the single-stranded target sites. Furthermore, I showed that computationally estimated intrinsic mRNA secondary structure is also helpful for determining RBP binding via shape recognition. I identified specific structural elements enriched in dsRBP Staufen targets versus non-targets. I applied the RNA-READ pipeline to the datasets that measured translation, stability and localization of transcripts in the Drosophila early embryo and identified numerous significant associations between the presence of motif matches and specific regulatory outcomes.

Keywords: RNA-binding protein
RNA cis-regulatory element
RNA secondary structure
Post-transcriptional regulation
Advisor: Morris, Quaid
Lipshitz, Howard