VictorJuiz/thesis huggingface dataset:
Voice as a Memory Cue

The study of human memory often focuses on the benefit of context congruency. In the auditory domain, perhaps the most important context cue is speaker's voice. The present set of auditory experiments was designed to further our understanding of voice as a memory cue. Words were spoken in voices that were congruent on either accent or pitch, both or neither. Voice reinstatement signified maximum congruency and occurred when the same voice spoke the word initially and in a subsequent memory test; voice congruency referred to either accent or pitch being comparable between presentations of a word. These stimuli were chosen to validate and extend earlier models of voice congruency based primarily on variations of pitch between speakers; we investigated multiple salient voice parameters. Experiment 1 found that voice reinstatement aids word and speaker recognition, and that voice congruency partially benefits word recognition. Experiment 2 used a different paradigm and found that voice reinstatement is required to boost word recognition when participants are not given instructions to attend to voice. Experiment 3 provided preliminary evidence that voice reinstatement benefits implicit memory. Experiment 4 examined whether voice effects vary with linguistic background; the benefit of accent congruency to word recognition appears to be augmented in bilinguals of the same language as the accented speaker voice. The first two experiments also utilized event-related potentials (ERPs) to discern the neural correlates underlying the use of voice in memory. Taken together, results indicate that the extent of voice congruency effects, as well as the characterization of ERP modulations reflective of memory components, depends on the task/paradigm used. For example, attention (or some extended processing) is required to observe partial voice congruency effects, while a voice reinstatement benefit appears to be more robust. Finally, this work serves as a starting point for future studies to understand voice congruency in implicit memory and in people with specific language abilities.

Keywords: auditory
evoked potentials
memory
Advisor: Alain, Claude
Learning how to "Skill" the Self: Citizenship and Immigrant Integration in Toronto, Canada

The underemployment of foreign-trained professional immigrants became an intense focus of Canadian immigration policy and integration programs in the 2000s, particularly in Toronto, which receives more immigrants than any other Canadian city. This thesis examines how government conceived of this `skilled immigrant underemployment problem' and in turn promoted particular solutions to address it. Rather than viewing the role of government as needing to intervene in the labour market, it largely focused on reforming individual immigrants. In particular, integration programs tended to focus on "soft skills" training, which construed individual immigrants as skills deficient and as requiring training in "Canadian workplace culture". This dissertation thereby examines the ways in which immigrants were urged to sell the self, and how they were asked to become particular kinds of Canadian workers and citizens. I argue that these integration programs largely did not ameliorate un(der)employment, for they did not address the systemic discrimination new immigrants faced. Rather, I show how they increased the regulation of the un(der)employed and attempted to shape subjectivities in line with values dubbed "Canadian", which were integral to post-Fordist forms of labour and (neo)liberal rationalities of government. More specifically, I demonstrate how immaterial labour is deeply assimilatory. Rather than merely produce material products, workers must embody a brand/product, affectively and effectively, in ways that are deeply classed, racialized and gendered. These behavioural dispositions, however, were rendered technical and thus governable through a skills discourse. Additionally, I argue that these interventions reproduced a transition industry that facilitated and contributed to the cycling of new immigrants through endless job fairs and other training programs, a process through which they became flexible and entrepreneurial citizens who accepted responsibility for their own "employability". These programs thus constituted a means of rationalizing and managing (un)employment insecurity and of reproducing and regulating flexible labor.

Advisor: McElhinny, Bonnie
Nanotechnology-based Strategies To Enhance Chemo-and Radiation Therapy In Breast Cancer

A major cause of cancer treatment failure is multidrug resistance (MDR) and radioresistance to standard therapies. Overexpression of ATP-binding cassette (ABC) transport proteins by cancer cells, which actively transport anti-cancer agents (e.g. doxorubicin, Dox) out of the cells against concentration gradients, is a major barrier to effective chemotherapy. Low levels of oxygen in tumors are responsible for radioresistance contributing to the failure of radiation therapy (RT) of solid tumors. This thesis concerns the development and evaluation of three nanoparticle delivery systems for overcoming tumor resistance to chemo- and radiotherapy. System 1: polymer lipid hybrid nanoparticles (PLN), co-loaded with a synergistic combination of anticancer agents Dox and mitomycin C (MMC) (DMsPLN), were found to overcome multiple membrane efflux pumps mediated MDR in vitro. Systemic administration of DMsPLN significantly enhanced therapeutic efficacy in orthotopic tumor models of Dox-sensitive and resistant human breast cancer cells, with low systemic toxicity compared to a clinically used liposomal formulation of Dox. System 2: cyclic Arg-Gly-Asp (RGD), a ligand that binds with αvβ3 intergin receptors preferentially expressed in angiogenic tumor blood vessels and certain cancer cells, was conjugated to DMsPLN. The Integrin-targeted RGD-DMsPLN resulted in a significant reduction in lung metastases of human breast cancer cells without producing drug-associated systemic toxicity as observed in mice treated with free Dox-MMC solutions. System 3: Manganese dioxide nanoparticles (MnO2 NPs) were developed and the reactivity of MnO2 towards peroxides was utilized to regulate the tumor microenvironment in a murine breast tumor. Intratumoral administration of MnO2 NPs simultaneously increased tumor oxygenation by 45%, and tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to RT alone. The design and application of these three novel nanotechnology platforms, in pharmaceutically acceptable NP formulations, provide promising therapeutic strategies for enhanced chemo- and radiation therapy of breast cancer.

Keywords: Breast cancer
Chemotherapy
Radiation therapy
Advisor: Wu, Xiao Yu
The Design and Use of a High throughput Microscopy Screen to Monitor Transcription Factor Localization in Saccharomyces cerevisiae

Cellular signalling networks control gene expression by modulating the activities of transcription factors through regulatory mechanisms that affect their transactivation or transrepression potential, DNA-binding affinity, localization, or abundance. This regulation often requires the site-specific phosphorylation of the transcription factor by a kinase. I have developed a high throughput microscopy screen and used it to monitor the nucleo-cytoplasmic distribution and abundance of 122 different GFP-tagged transcription factors in 84 different Saccharomyces cerevisae kinase mutant backgrounds and in wild type cells after exposure to eight different environmental stress conditions that modulate kinase signalling pathways. Thirty one GFP-tagged transcription factors exhibited changes in localization or abundance, mostly in response to an acute exposure to environmental stress rather than to the chronic loss of a non-essential kinase. These screens revealed that the Yero88c transcriptional repressor, which was not previously known to undergo changes in localization, translocates from the cytoplasm to the nucleus in response to multiple environmental stresses; its paralog, Yblo54w, displayed similar behavior. Yero88c and Yblo54w are known to repress the transcription of ribosome biogenesis (Ribi) genes in response to environmental stress and the downregulation of the TORC1 or PKA signalling pathways (Lippman Broach, 2009). I show that the nuclear accumulation of Yero88c and Yblo54w is inhibited by TORC1 and PKA signalling. Further analysis implicates the kinase Sch9 and the Tap42-associated phosphatase complexes in the regulation of Yero88c localization by TORC1. Serine-to-alanine substitutions at six putative PKA/Sch9 consensus phosphoacceptor sites in its sequence causes Yero88c to localize to the nucleus constitutively. These data suggest that under optimal growth conditions PKA and Sch9 phosphorylate Yero88c causing it to localize to the cytosol, whereas the activation of TORC1-regulated phosphatases in response to stress induces the dephosphorylation and nuclear accumulation of Yero88c resulting in the repression of Ribi genes and the attenuation of cell growth.

Keywords: cerevisiae
kinase
transcription factor
Advisor: Andrews, Brenda J
Transcranial Adaptive Beamforming via Ultrasonic Phased Arrays and its Application to 3D Imaging of Certain Types of Head Injuries

A new adaptive beamforming method for ultrasonic imaging via small-aperture phased arrays through composite layered structures, such as human skull, is developed. If there is a scattering layer between the phased array and the imaged volume, acoustic phase aberration and wave refraction at undulating interfaces between the barrier and the rest of the propagation media can cause significant distortion of an ultrasonic image pattern produced by conventional beamforming techniques. This distortion takes the form of defocusing the ultrasonic field transmitted through the skull and causes loss of resolution, overall degradation of image quality and generation of non-informative final sonograms. To compensate for the phase aberration and refractional effects, an adaptive beamforming algorithm is developed and examined. After accurately assessing the skull's local geometry and sound speed, the method calculates a new timing scheme to refocus the distorted beam at its original location. The procedure is in fact a construction of a matched filter that automatically adapts the transmission and reception patterns of the phased array to the local geometry and acoustical properties of the skull and cancels its distorting effects. Results of numerical simulations, developed to accommodate and verify the proposed theory, are provided and discussed. The simulation results are verified experimentally by applying the method on realistic human skull phantoms in water immersion setups. The developed adaptive beamforming algorithms were implemented on an open-platform phased array controller and a lab prototype of the imaging system was delivered. Results of 2D and 3D adaptive imaging through skull phantoms via 2MHz linear and matrix phased arrays are presented.

Keywords: Adaptive beamforming
Phase aberration
Phased array
Transcranial
Ultrasonic imaging
Advisor: Sinclair, Anthony N.
Maev, Roman Gr.
The Effects of Insulin and Insulin Sensitizers on Neointimal Formation after Arterial Injuries in Rodent Models

Restenosis, a common complication following angioplasty, is exacerbated in insulin resistant patients with or without diabetes. Our laboratory has previously shown that insulin decreases arterial injury induced neointimal hyperplasia in a rat model of restenosis, an effect abolished with a non-specific nitric oxide synthase (NOS) inhibitor. The vasculoprotective effect of insulin is also greatly diminished in high-fat fed rats, a model of insulin resistance. The first aim of this study is to further investigate the specific NOS isoform involved in insulin's action. The main finding was that insulin decreased iNOS expression but increased eNOS phosphorylation in injured vessels and this effect of insulin was associated with the improvement of endothelial-dependent vessel function. Furthermore, insulin also decreased neointimal hyperplasia induced by wire injury in mouse, an effect abolished in eNOS-null mice. Therefore, compounds, in particular metformin and resveratrol (RSV) that increase eNOS activation and improve insulin sensitivity, may potentially be beneficial. Metformin, the most commonly prescribed anti-diabetic drug, was found to improve insulin sensitivity but did not affect neointimal hyperplasia in rats fed normal or high-fat diet in the current study. Furthermore, AMPK activation, previously shown to protect against neointimal hyperplasia, was impaired in injured but not in uninjured vessels of metformin treated rats, which at least in part explains the ineffectiveness of metformin in our model. RSV, a polyphenol found in red wine, improved insulin sensitivity and decreased neointimal hyperplasia in high-fat fed rats. Further investigation of its mechanism of action found that the effect of RSV to decrease neointimal area was not mediated via SIRT1. Thus, a better understanding of the effects of insulin and insulin sensitizers in the vessel would be beneficial in bypassing vessel insulin resistance and further studies are still required to improve the outcomes especially for insulin resistant patients with or without diabetes.

Advisor: Giacca, Adria
Investigating the Effect of Vesicular Acetylcholine Transporter Expression on Central and Peripheral Function

Cholinergic neurons use the neurotransmitter acetylcholine extensively throughout the central and peripheral nervous systems. During normal and pathological aging (i.e. Alzheimer's disease) cholinergic neurotransmission decreases, particularly in the basal forebrain which supplies the cortex and hippocampus with cholinergic input. This thesis investigates the effect of vesicular acetylcholine transporter (VAChT) overexpression on cholinergic function. The biochemical characteristics of cholinergic neurons following VAChT overexpression were measured and the behaviour phenotype of these animals was evaluated. Furthermore, the effect of lifelong VAChT overexpression on the age-related impairment of hippocampal structure and function was determined. No overt differences in the expression levels of presynaptic cholinergic transcripts and proteins were observed following VAChT overexpression in mice. With this absence of presynaptic compensation, acetylcholine release in the hippocampus was found to be significantly elevated. While this increased level of acetylcholine release was not sufficient to significantly modify peripheral function, we observed behavioural phenotypes conducive to central cholinergic action. VAChT overexpressing mice exhibited decreased locomotion and enhanced response to novelty in the open field. In addition, these mice displayed a release of exploratory inhibition. These data support the ability of VAChT to modulate cholinergic tone and central cholinergic function. Using a model of normal aging, VAChT overexpression was found to enhance dendritic ramification in newborn neurons of the hippocampus. An improvement of the precision of spatial memory acquisition was also observed in aged mice overexpressing VAChT. These data provide direct immunohistological evidence that VAChT overexpression augments dendritic expansion in the hippocampus and that VAChT contributes to improved precision of hippocampal-dependant spatial memory. In conclusion, this thesis demonstrates that VAChT overexpression augments central cholinergic function related to locomotion, response to novelty and hippocampal structure and that these features may in part contribute to superior spatial memory during aging.

Keywords: acetylcholine
ChAT
choline acetyltransferase
cholinergic
neurotransmitter
VAChT
Advisor: Aubert, Isabelle
Characterizing the Role of Dietary Antioxidants as Immune-enhancing Molecules in Larval Anurans

The effects of stress (disruption of homeostasis) and stressors (factors that cause changes in homeostasis) and their impacts on animal health, physiology, behaviour and fitness have received enormous attention within the scientific community. From an evolutionary stand point, understanding the way in which animals cope with stress or how stress tolerance has evolved is important, as chronic stress can lead to loss of fitness. From an ecological stand point, identifying stressors within the environment and understanding how additive stressor effects can impact the way in which animals cope is crucial for understanding population declines and or possible extinctions. One coping mechanism used by some animal taxa is diet. When consumed, dietary antioxidants (secondary metabolites produced by plants) can provide protection from oxidative damage that can result from exposure to stressors. My dissertation focuses on the effects of these compounds on tadpole immune function. I choose to focus on tadpoles, as populations of numerous amphibian species are declining worldwide and some have gone extinct. In addition, tadpoles, which are strictly aquatic, are exposed to a wide variety of both abiotic and biotic stressors. I focus on three areas of study: 1) the effect of dietary antioxidants and natural stressors on immune function; 2) whether or not tadpoles detect these compounds in their food and whether or not they have the ability to self-medicate; 3) a potential trade-off between immune function and antipredator defense mediated by dietary antioxidants and the environmental availability of these compounds in natural tadpole habitats. My work will contribute to the field of ecology and amphibian biology by investigating the effects of these potentially beneficial compounds and the effects on amphibian immune function, in an attempt to determine if there are any natural immune enhancers to help amphibian's combat mortality via immunosuppression.

Keywords: Antioxdants
Diet
Larval anurans
Self-medication
Advisor: Baker, Robert
Localization of Heat Shock Proteins HSPA6 (HSP70B') and HSPA1A (HSP70-1) in Cultured Differentiated Human Neuronal Cells Following Thermal Stress

Heat shock proteins (Hsps) are a set of highly conserved proteins that are involved in cellular repair and protective mechanisms. In order to identify stress-sensitive sites in differentiated human neuronal cells, cytoplasmic and nuclear localization of two inducible members of the HSPA (HSP70) family was investigated, namely HSPA6 (HSP70B') and HSPA1A (HSP70-1). Stably transfected SH-SY5Y neuronal cell lines were generated that express YFP-HSPA6 and YFP-HSPA1A proteins. Following differentiation, transfected SH-SY5Y cells were exposed to mild heat shock at 43째C for 20 min. Immediately following heat shock, YFP-tagged HSPA6 and HSPA1A proteins localized to centrioles in the cytoplasm and nuclear speckles that are enriched in RNA splicing factors. Subsequently, both stress proteins associated with the granular component of the nucleolus which is the site of ribosomal subunit assembly and ribosomal RNA processing. Later in the recovery period, YFP-HSPA6 protein, but not YFP-HSPA1A, localized to the periphery of nuclear speckles that are sites of RNA transcription and RNA splicing. The present results identify centrioles, nuclear speckles, and the GC component of the nucleolus as potential stress-sensitive sites in differentiated human neuronal cells. The inducible HSPA6 and HSPA1A proteins exhibit similar localization to these sites. The unique association of the HSPA6 protein with the periphery of nuclear speckles identifies this nuclear site as being stress sensitive, and suggests that the little studied HSPA6 protein may be involved in the recovery of RNA transcription and/or splicing. HSPA6 is a strictly inducible protein, whose gene is present in the human genome but not in rat and mouse. Hence current animal models of neurodegenerative diseases are lacking a potentially protective member of the HSPA family. Sequence and structural analysis revealed that HSPA6 has three additional cysteine amino acids compared to HSPA1A. One of these cysteine amino acids, located in the linker domain, is not found in any other member of the human HSPA family. Identification of stress-sensitive sites in differentiated human neuronal cells could aid the design of therapeutic approaches to protect neurons from the progression of neurodegenerative diseases.

Advisor: Brown, Ian
α-Melanocyte Stimulating Hormone Prevents GABAergic Loss and Improves Cognitive Function in Alzheimer's Disease

In Alzheimer's disease (AD), the appropriate excitatory/inhibitory balance required for memory formation is impaired. In order to elucidate deficits in the inhibitory gamma-aminobutyric acid (GABA)-ergic system in AD and to establish a link between GABAergic dysfunction and cognition, the TgCRND8 mouse model of AD was utilized. TgCRND8 mice with established amyloid beta peptide (Abeta) pathology exhibit spatial memory deficits and altered anxiety. Concomitant with behavioural changes, GABAergic deficits are observed in the hippocampus. The GABAergic marker glutamic acid decarboxylase 67 (GAD67) mRNA and protein levels in the hippocampus as well as the number of GAD67+ GABAergic cells in the CA1 region of the hippocampus are significantly decreased. However, at this stage of Abeta pathology, the number of ChAT+ cholinergic cells in the septum remains unchanged, suggesting that cholinergic cells may not underlie behavioural deficits. The GABAergic loss may represent an early target in AD disease progression. By increasing inhibition, the physiological excitatory/inhibitory balance in the brain may be restored resulting in normal function. I found that the neuropeptide, alpha-melanocyte stimulating hormone (alpha-MSH), prevents the loss of GAD67 mRNA, protein levels and GAD67+ cells in the CA1 region of the hippocampus. In particular, alpha-MSH protects the loss of the somatostatin (SST) expressing subtype of GAD67+ inhibitory interneurons. SST is reduced in the CSF and brain of AD patients and SST levels are correlated with cognitive function. By preserving hippocampal GAD67+ cells, especially the SST+ subtype, alpha-MSH improved spatial memory in TgCRND8 mice and prevented changes in anxiety independent of altering Abeta; peptide load in the brain. alpha-MSH modulated the excitatory/inhibitory balance in the brain by restoring GABAergic inhibition and as a result, improved cognition in TgCRND8 mice.

Keywords: alpha-melanocyte stimulating hormone
Alzheimer's disease
cognitive function
GABAergic system
somatostatin
Advisor: McLaurin, JoAnne