VictorJuiz/thesis huggingface dataset:
The Sexualized and Gendered Tortures of Virgin Martyrs in Medieval English Literature

This work examines the literary English traditions of four Virgin Martyrs: Agatha of Catania, Agnes of Rome, Juliana of Nicomedia, and Katherine of Alexandria. The primary focus surrounds the narratological developments and alterations of these women’s sex-specific or -emphasized tortures. In addition to torments, other details, which may not initially appear sex-specific in nature, are also considered. As recent scholarship has shown, Virgin Martyrs’ lives tend to conform to a relatively standardized core narrative by the later Middle Ages. This study considers to what extent the lives of these four saints actually conform and to what extent they retain individualism despite this homogenizing trend. An analysis of each narrative’s progression from early Latin sources, when available, through fifteenth-century English texts, which supplements the current scholarly trend of examining Virgin Martyrs as a collective group, is also provided. The tracing of these legends’ sex-specific characteristics allows for clear identification of similarities and deviations within various sources. Five appendices, each including an analytical table, are included to aid in the visualization of this progression. The tables, which allow for quick and easy identification of variations through chronologically listed sources, demonstrate this process in a concise and user-friendly manner and should be utilized alongside examinations of these legends as presented in each of the central chapters. The first chapter, on Agatha, addresses her breast amputation and its symbolic implications for femininity and motherhood, as well as the argument that Virgin Martyrs ‘Become Male’ during their passiones. The second chapter, on Agnes, explores her traditionally eroticized relationship with Christ, the motif of concealment, and Virgin Martyrs’ conventional brothel experience. The third chapter, on Juliana, focuses upon the Warrior Virgin Martyr tradition, her physical and spiritual struggle with the devil, and the tradition of familial rejection. The final chapter, on Katherine, considers her position as supreme Bride, her limited physical trials, and her relationship with the Blessed Virgin. The final appendix contains a comparative chart of Virgin Martyr legends within the Legenda aurea, which indicates the frequency of motifs and plot devices in these lives.

Keywords: Virgin Martyrs
Sexualized Torture
Medieval English Literature
Hagiography
Saints
Advisor: Orchard, Andy
Cell- and Cell-based Gene Therapy for Experimental Acute Lung Injury and Sepsis

The acute respiratory distress syndrome (ARDS) and its less severe form, acute lung injury (ALI), are among the leading causes of morbidity and mortality in critically ill patients. Commonly induced by conditions associated with severe pulmonary inflammation, ALI results in disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Sepsis is another frequent and often fatal clinical condition for patients in the intensive care unit. It is characterized by a combination of infection and systemic inflammatory response syndrome (SIRS). Current effective treatment strategies for both ALI/ARDS and sepsis are lacking. We first examined the potential therapeutic role of mesenchymal stromal cells (MSCs) alone or together with the vasculoprotective factor, angiopoietin-1 (ANGPT1), for treatment of experimental ALI in mice. MSCs significantly reduced LPS (lipopolysaccharide)-induced pulmonary inflammation, as reflected by cell counts in bronchoalveolar lavage (BAL) fluid and pro-inflammatory cytokine levels in both BAL fluid and lung parenchymal homogenates. More importantly, administration of MSCs transfected with human ANGPT1 plasmid (MSCs-pANGPT1) completely reversed LPS-induced permeability in the lung (i.e., ALI). A follow-up study showed that MSCs remained effective in rescuing mice with LPS-induced ALI; however, the additional benefit from ANGPT1 was no longer observed. To further evaluate MSC-based therapy in a more clinically relevant model of acute injury, the cecal-ligation-and-puncture (CLP) model for sepsis was employed. Our results demonstrated that MSCs can reduce both systemic and pulmonary inflammation, as well as renal and liver dysfunction/injury, as reflected by plasma urea and bilirubin levels, in septic mice. Most notably, MSCs reduced sepsis-associated mortality from 45% to 24%. Our data demonstrate the feasibility and effectiveness of MSC- and MSC-based gene therapy for experimental ALI and sepsis, and provide the basis for the development of an innovative approach for the prevention and treatment of clinical ALI/ARDS and sepsis.

Keywords: cell therapy
cell-based gene therapy
acute lung injury
Acute Respiratory Distress Syndrome
mesenchymal stromal (stem) cells
angiopoietin
inflammation
sepsis
Advisor: Stewart, Duncan John
Juvenile GM2 Gangliosidosis: A Model for Investigation of Small-molecule Therapies for Lysosomal Storage Diseases

Juvenile GM2 gangliosidosis (jGM2) is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase A (Hex A) resulting in GM2 ganglioside accumulation in brain. Like many other lysosomal storage diseases (LSDs), no specific treatment currently exists. In order to establish clinical outcomes for the investigation of potential therapies for jGM2, I collected comprehensive information on the natural history of the condition by studying retrospective and prospectively a cohort of 21 patients with the disease, and reviewing previously published reports of 134 patients. Several symptoms at disease onset, symptom latencies, and the survival curve were described. Genotype-phenotype correlations and neuroradiological findings were also studied. Based on pre-clinical results in animal models, we studied substrate reduction therapy (SRT), with miglustat, in a phase I/II clinical trial to assess its pharmacokinetics (PK), safety, tolerability in infantile and jGM2. Miglustat showed a PK profile similar to the one found in adult patients. The drug was found to be safe and well-tolerated in patients with jGM2, with diarrhea and weight loss being the most common drug-related adverse events. The analysis of efficacy showed that SRT was unable to arrest the full neurological progression of the condition; however, relative stabilization of cognitive function was noted, which was consistent with brain MRI findings. Because of the limited efficacy obtained with SRT, enzyme-enhancement therapy was considered to be an attractive alternative therapy for the late onset forms of GM2 gangliosidosis. Screening of a FDA-approved library of approved therapeutic compounds resulted in the identification of pyrimethamine, as a potential pharmacological chaperone for mutant forms of Hex A. Relative enhancements of enzyme activity and protein levels were observed in patient cells treated with therapeutic concentrations of drug. Applying the same principles, ambroxol was identified as a potential PC for mutant glucocerebrosidase (GCC), the lysosomal enzyme that when deficient causes Gaucher disease (GD). Significant increases of residual mutant GCC were observed in cultured patients cells with type 1 GD. In conclusion, principles developed in the course of studies on jGM2 were shown to be useful for the investigation of novel small-molecule therapies for LSDs, associated with significant neurodegeneration.

Keywords: pediatrics
biochemical genetics
Advisor: Clarke, Joe T. R.
One-hit Stochastic Decline in a Mechanochemical Model of Cytoskeleton-induced Neuron Death

Much experimental evidence shows that the cytoskeleton is a downstream target and effector during cell death in numerous neurodegenerative diseases, including Parkinson's, Huntington's, and Alzheimer's diseases. However, recent evidence indicates that cytoskeletal dysfunction can also trigger neuronal death, by mechanisms as yet poorly understood. We studied a mathematical model of cytoskeleton-induced neuron death in which assembly control of the neuronal cytoskeleton interacts with both cellular stress levels and cytosolic free radical concentrations to trigger neurodegeneration. This trigger mechanism is further modulated by the presence of cell interactions in the form of a diffusible toxic factor released by dying neurons. We found that, consistent with empirical observations, the model produces one-hit exponential and sigmoid patterns of cell dropout. In all cases, cell dropout is exponential-tailed and described accurately by a gamma distribution. The transition between exponential and sigmoidal is gradual, and determined by a synergetic interaction between the magnitude of fluctuations in cytoskeleton assembly control and by the degree of cell coupling. We concluded that a single mechanism involving neuron interactions and fluctuations in cytoskeleton assembly control is compatible with the experimentally observed range of neuronal attrition kinetics. We also studied the transit of neurons through states intermediate between initial viability and cell death. We found that the stochastic flow of neuron fate, from viability to cell death, self-organizes into two distinct temporal phases. There is a rapid relaxation of the initial neuron population to a more disordered phase that is long-lived, or metastable, with respect to the time scales of change in single cells. Strikingly, cellular egress from this metastable phase follows the one-hit kinetic pattern of exponential decline now established as a principal hallmark of cell death in neurodegenerative disorders. Intermediate state metastability may therefore be an important element in the systems biology of one-hit neurodegeneration. Further, we studied the full spatiotemporal dynamics of death factor pulses released from dying neurons to emphasize the effects of the cell-to-cell coupling strength on neuron death rates. The rate of neuron cell loss monotonically increased with increased diffusion-dependent intercellular communication. Death factor diffusion effects may therefore be important moderators of one-hit neurodegeneration.

Keywords: neuron
neurodegeneration
programmed cell death
cell death
one-hit model
mutant steady state
cytoskeleton
cell mechanics
metastability
stochastic kinetics
contagious apoptosis
death factor diffusion
Advisor: Lumsden, Charles
Subcortical Ischemic Vasculopathy In Alzheimer's Disease: Brain-behaviour Relationships

The presence of white matter hyperintensities (WMH) and silent infarcts on magnetic resonance imaging is a common finding in elderly individuals. This subcortical ischemic vasculopathy is associated with age and cerebrovascular risk factors and can increase the risk of dementia, yet the contribution of subcortical vascular disease to the clinical profile and progression of Alzheimer’s disease patients is still relatively poorly understood. This study assessed the presence, severity and progression of WMH and lacunar infarcts and studied their relationship with measures of brain function and cognition in 64 patients with Alzheimer’s disease. Both a visual rating scale and volumetric tissue segmentation analysis were used to evaluate brain-behaviour relationships of WMH seen on T2-weighted and Proton Density MRI scans. In addition to describing the topographical distribution of WMH and lacunes, and examining sex differences, the volume and location of WMH were correlated with executive function, frontal lobe perfusion, and medial temporal lobe atrophy. The results confirm and extend previous findings suggesting that WMH are located primarily in the frontal and parietal regions and are associated with mild decline in tasks of executive function. WMH severity was not associated with a decrease in frontal lobe perfusion as measured by Single Photon Emission Computed Tomography. The investigation of different WMH subtypes revealed that lacunar infarcts were found most often within deep WMH. At one year follow-up, progression was seen in deep WMH, specifically in the frontal lobe and in lacunes found within the periventricular regions. Furthermore, progression in WMH was associated with a decline in cognition. Taken together, these studies indicate the utility of measuring WMH by subtype (periventricular and deep WMH and lacunes) in understanding progression patterns and brain-behavior relationships. Since, subcortical ischemic vasculopathy may be potentially preventable; this study underlines the need to study interventions that address risk factors for the development of small vessel cerebrovascular disease, which may be helpful in preventing disability in the elderly.

Keywords: Alzheimer's Disease
Magnetic Resonance Imaging
Advisor: Black, Sandra
An Intrinsic Mechanism of Asymmetric Cell Division and Extrinsic Mechanism of Stem Cell Maintenance Underlies Adult Stem Cell Behaviour

The interplay between extrinsic and intrinsic processes as they influence a cell’s behaviour is a perennial question in both cellular and developmental biology. In this thesis these two issues are examined in the context of adult stem cells, a somatic stem cell present in the adult murine brain and a germline stem cell present in the adult Drosophila melanogaster ovary. I find that both of these distinct cell types exhibit patterns of non-random chromatid segregation in which the stem cells retain chromosomes carrying the older DNA strands. This unusual behaviour seems to exclusively occur in the context of differentiation, when one cell remains a stem cell and the other goes on to differentiate. Following these studies, the effects of extrinsic processes are tested in adult murine stem cells. It is determined that such cells can only produce neural progeny regardless of their association with foreign environments. These results argue against the phenomenon of stem cell plasticity which is proposed in several other systems and seem to support a primarily intrinsic-centered view of stem cell behaviour. However, the role of adhesion mediating proteins is next studied in such cells to determine their requirement for specific environments. The results of these experiments suggest that adult murine neural stem cells require association with support cells expressing E-Cadherin. Because the loss of such association results in a loss of stem cell number, these data show that intrinsic processes are insufficient to account for all stem cell behaviour. Indeed, based on these data and the results of other studies, it is hypothesized that the extrinsic association of stem cells in these diverse systems determines their polarity and subsequent intrinsic processes that enable these to divide asymmetrically. The implications of this theory are discussed with a view to general biological issues, the proximate mechanisms underlying these phenomena and the ultimate reasons these occur.

Keywords: Stem Cell
Asymmetry
Advisor: Kooy, Derek van der
Synaptic Transmission in the Leaner Mutant Mouse Calyx of Held/MNTB Synapse

The effects of alpha1A subunit mutations on presynaptic Ca2+ channel activity and functional development of synaptic properties remain elusive. The calyx of Held/medial nucleus of the trapezoid body synapse is an ideal model for studying the developmental effects of presynaptic voltage-gated Ca2+ channel (VGCC) impairment on synaptic function since simultaneous voltage-clamp recordings can be made directly from the pre- and postsynapse. The alpha1A subunit leaner (tgla/la) mutation induced a profound reduction in synaptic transmission after hearing onset (> postnatal day 12; P12), with relatively preserved relationship between presynaptic Ca2+ current (Pre-ICa) and release and G-protein-mediated inhibition. Some synaptic properties were more reflective of an immature state, while other properties displayed a delay in maturation after P12. Direct presynaptic recordings from P15/16 tgla/la nerve terminals revealed a decrease in the density of Pre-ICa, elevated activation threshold and slowing in the kinetics of VGCCs, all of which contribute to the deficit in transmitter release. Fractional contribution of P/Q-type channels to total Pre-ICa and their role in vesicle release was markedly reduced. N-type Ca2+ channels and close association of VGCCs to release sites was not sufficient to fully compensate for impaired P/Q-type channel function. The extent to which compensatory mechanisms preserve synaptic transmission at tgla/la synapses was further constrained by the developmental narrowing of the action potential waveform. Activation of the cAMP pathway by forskolin or direct modulation of VGCCs by cdk inhibitors rescued deficits in transmitter release at P15/16 tgla/la synapses. The major effect of roscovitine was a slowing of presynaptic VGCC deactivation kinetics accompanied by a leftward shift in the activation curve. Activation of the cAMP pathway or direct modulation of presynaptic VGCCs may serve as two potential pathways to facilitate release and improve neuronal communication at synapses normally compromised by impaired P/Q-type channel function. While significant for the tgla/la mutant, these studies provide an important advancement in our understanding of the crucial developmental and functional roles of P/Q-type Ca2+ channels in driving the maturation of synaptic properties at central synapses. These findings may improve our understanding of the pathophysiology of presynaptic VGCCs and elucidate essential mechanisms underlying the tgla/la phenotype.

Keywords: Calcium Channels
Leaner Mutant Mouse
Calyx of Held
Synaptic Transmission
Development
Presynaptic
Roscovitine
Advisor: Snead, O. Carter
The Effect of Ddr1 Deletion on the Expression of Genes Involved in Atherosclerotic Vascular Remodeling and on the Development of Atherosclerotic Calcification

The effect of Ddr1 deletion on the expression of genes involved in atherosclerotic vascular remodeling and on the development of atherosclerotic calcification Pamela J. Ahmad, PhD Institute of Medical Science, 2008 During atherosclerosis, collagen molecules, which are abundant in the healthy vessel, are extensively degraded, re-synthesized or newly synthesized, and remodeled to induce profound changes in VSMCs as they colonize and expand atherosclerotic lesions. The central theme of this thesis was to investigate the effect of genetic deletion of a collagen receptor, DDR1, on VSMC processes during atherosclerosis. In the first study, we demonstrated a role for DDR1 as an important regulator of gene expression in synthetic VSMCs. We have profiled the expression of vascular collagen matrix molecules, MMPs and TIMPs in synthetic VSMCs and we have demonstrated that deletion of Ddr1 is sufficient to accelerate ECM remodeling in synthetic VSMCs, which may influence cell migration during atherosclerosis. Moreover, we have extended our knowledge of DDR1 function in synthetic VSMCs, by demonstrating that DDR1 limits VSMC proliferation in a complex matrix microenvironment representative of the ECM produced in the vessel wall during vascular disease. In the second study, we investigated the role of DDR1 in atherosclerotic calcification, a feature of advanced atherosclerotic disease. Here, we demonstrated that intimal calcification in Ldlr-/- mice fed a high-fat/ high-cholesterol diet may be mediated through the initiation of a chondrogenic transcriptional regulatory program and that deletion of Ddr1 significantly attenuated the frequency and extent of atherosclerotic mineralization in vivo, as well as the ability of vascular smooth muscle cells to calcify in vitro, suggesting an important role for DDR1 in VSMCs as a positive regulator of this pathological process. In our third study, we provided evidence of a biochemical association between MMP-2 and DDR1b in VSMCs, which involves a direct interaction between MMP-2 and the extracellular region of the DDR1 receptor. In addition, we reported an association between endogenous MMP-2 and Stat1 in VSMCs, providing a platform for future research to investigate the functional consequences of these novel interactions.

Keywords: collagen receptors
atherosclerosis
vascular smooth muscle cell
calcification
Advisor: Bendeck, Michelle
Development of a Novel Visualization and Measurement Apparatus for the PVT Behaviours of Polymer/Gas Solutions

The Pressure-Volume-Temperature (PVT) for polymer/gas solutions is an important fundamental property of which accurate data measurement has not been reported until recently. The diffusivity, solubility, and surface tension are critical physical properties of polymer/gas solutions in understanding and controlling polymer processing such as, foaming, blending, and extracting reaction. However, the determination of these properties relies on accurate PVT data as a prerequisite. Due to the difficulties involved in measuring the specific volume while maintaining a sufficiently high pressure and temperature to achieve a single-phase polymer/gas solution, accurate PVT data or volume swelling measurement of polymer/gas solutions is not yet available. In this research, a new methodology was proposed and developed for direct measuring the PVT properties of polymer melts saturated with high-pressure gas at elevated temperatures. The ultimate goal is to develop and construct an apparatus that would provide more accurate fundamental properties through PVT measurement to the foaming industry, which is heavily involved with polymer/gas mixtures.

Keywords: PVT, Volume Swelling
Polymer/Gas Solutions, Surface Tension
Advisor: Park, Chul B.
Droplet Deposition in Solid Ink Printing

Introduced in 1991, solid ink color printing technology is widely used in the office printing, prepress proofing, and wide format color printing markets. Ink droplets are first deposited on a rotating drum and then transferred to paper to reproduce images with high print quality. The objective of this thesis is to develop scientific knowledge of ink droplet deposition, which is needed for precise image buildup on the drum surface. The first problem studied in the thesis is droplet formation from the printhead with varied working voltages and jetting frequencies. Attention is paid to the formation of satellite droplets, the contraction of ligaments and the startup of high frequency jetting. The jetting conditions for obtaining consistent droplet generation with satellites are determined. A theoretical model is developed to predict the lifetime of ligaments. The second problem we studied is the deposition of single droplets on solid surfaces. The surface texture and final shape of deposited droplets are correlated with impact conditions, which include printhead temperature, substrate temperature, distance from printhead to substrate, and the type of substrate surface. An analytical model is developed to evaluate the interaction of oscillation and viscous damping in the droplet during impact. The third problem covered in the thesis is the deposition of multiple ink droplets on the drum surface. Interaction between droplets causes drawback effect, which degrades print quality. We define a parameter to quantify the drawback effect with varied deposition conditions. A simple model is provided to predict conditions for making continuous lines based on the results of two ink droplets deposition. To understand the hydrodynamics in causing drawback effect, a series of experiments using large liquid droplets are carried out. Focus is put on the evolution of spread length and dynamics of contact line. Correlations for maximum and minimum spread lengths are developed, which are used to reveal the cause of drawback effect in the deposition of ink droplets.

Keywords: droplet deposition
solid ink
inkjet printing
droplet generation
pulsed jet
droplet coalescence
Advisor: Ashgriz, Nasser
Chandra, Sanjeev