VictorJuiz/thesis huggingface dataset:
Comprehension of Labrador Inuttitut Functional Morphology by Receptive Bilinguals

This study examines knowledge of grammar by receptive bilinguals (RBs) - heritage speakers who describe themselves as capable of fluent comprehension in Labrador Inuttitut (an endangered dialect of Inuktitut), but of little or no speech production in it. Despite the growing research on incomplete acquisition, RBs have yet to be studied as a specific population. Participants (8 fluent bilinguals, 17 RBs, 3 low-proficiency RBs) performed a morpheme comprehension task and a grammaticality judgment task. General measures of their comprehension and production abilities included a story retelling task as an overall assessment of comprehension, a vocabulary test, an elicited imitation task, and a production task. This data was complemented by language behaviour interviews. The results showed that RBs have good, though not perfect, comprehension and basic vocabulary, but speech production is very difficult for them. They have grammatical knowledge, but it is incomplete: Knowledge of some structures is robust, and their comprehension is fluent (past vs. future contrast, aspectual morphemes); others are missing (temporal remoteness degrees); and yet for others (case and agreement), RBs have the category and know its position in the word structure, but have difficulty connecting the features with the morphemes expressing them. These findings explain the significant asymmetry between comprehension and production in RBs: In comprehension, incomplete knowledge may result in loss of some aspects of meaning, but in many cases it can be compensated for by pragmatic knowledge and extralinguistic context, while in production, it can result in the selection of an incorrect morpheme or inability to select a morpheme. Low-proficiency RBs have partial comprehension, small vocabulary, and almost no production. They do not understand most functional morphemes; however, they show knowledge of the basic properties such as the position of the obligatory agreement marker on the verb. This study provides data on an understudied language and an understudied population at the extreme end of unbalanced bilingualism. The findings have implications both for the psycholinguistics of bilingualism and for language revitalization, especially in the context of a language shift in indigenous language communities, where RBs are often the last generation to have competence in the indigenous language.

Keywords: Inuktitut
receptive bilinguals
heritage language
bilingualism
incomplete language acquisition
Advisor: Johns, Alana
Perez-Leroux, Ana Teresa
Influence of Degradable Polar Hydrophobic Ionic Polyurethanes and Cyclic Mechanical Strain on Vascular Smooth Muscle Cell Function and Phenotype

Vascular tissue engineering (VTE) with the use of polymeric scaffolds offers the potential to generate small-diameter (<6 mm) arteries. In this thesis, a degradable polar hydrophobic ionic (D-PHI) polyurethane porous scaffold was synthesized with the objective of demonstrating its potential application for VTE. D-PHI scaffold synthesis was optimized, maximizing isocyanate and methacrylate monomer conversion. Through the incorporation of a lysine-based crosslinker, scaffold mechanical properties and swelling were manipulated. Furthermore, D-PHI scaffolds demonstrated the ability to support the growth and adhesion of A10 vascular smooth muscle cells (VSMCs) during two weeks of culture. This study also investigated the effect of a double porogen approach on D-PHI scaffold properties, demonstrating an increase in the total scaffold porosity and pore interconnectivity. Specifically, it was found that the use of 10 wt% polyethylene glycol and 65 wt% sodium bicarbonate porogens resulted in a porous (79±3%) D-PHI scaffold with the mechanical properties (elastic modulus=0.16±0.03 MPa, elongation-at-yield=31±5%, and tensile strength=0.04±0.01 MPa) required to withstand the physiologically-relevant cyclic mechanical strain (CMS) that is experienced by VSMCs in vivo. Furthermore, the effects of uniaxial CMS (10% strain, 1 Hz, 4 weeks) on human coronary artery smooth muscle cells (hCASMCs), which were cultured in a porous D-PHI scaffold, were studied using a customized bioreactor. Four weeks of CMS was shown to yield greater DNA mass, more cell area coverage, a better distribution of cells within the scaffold, the maintenance of contractile protein expression and the improvement of tensile mechanical properties. The in vitro and in vivo degradation as well as the in vivo biocompatibility of D-PHI scaffolds were also investigated. Following their subcutaneous implantation in rats (100 days), porous D-PHI scaffolds demonstrated more cell/tissue infiltration within their pores and degraded in a controlled manner and at a faster rate when compared to in vitro studies (120 days), retaining the mechanical integrity required during neo-tissue formation. This thesis provides significant insight into the role of the D-PHI scaffold in combination with physiologically-relevant CMS in modulating VSMC proliferation and phenotype. The findings of this work can be used to tailor vascular tissue regeneration by regulating VSMC function in a directed manner.

Keywords: Vascular tissue engineering
Polyurethane elastomer
Vascular smooth muscle cells
Scaffold
Soft tissue biomechanics
Cell proliferation
Scaffold porosity
Cell Phenotype
Cyclic mechanical strain
Biodegradation
Crosslinking monomers
Tensile mechanical properties
Advisor: Santerre, J. Paul
Simmons, Craig Alexander
Multiple Antenna Broadcast Channels with Random Channel Side Information

The performance of multiple input single output (MISO) broadcast channels is strongly dependent on the availability of channel side information (CSI) at the transmitter. In many practical systems, CSI may be available to the transmitter only in a corrupted and incomplete form. It is natural to assume that the flaws in the CSI are random and can be represented by a probability distribution over the channel. This work is concerned with two key issues concerning MISO broadcast systems with random CSI: performance analysis and system design. First, the impact of noisy channel information on system performance is investigated. A simple model is formulated where the channel is Rayleigh fading, the CSI is corrupted by additive white Gaussian noise and a zero forcing precoder is formed by the noisy CSI. Detailed analysis of the ergodic rate and outage probability of the system is given. Particular attention is given to system behavior at asymptotically high SNR. Next, a method to construct precoders in a manner that accounts for the uncertainty in the channel information is developed. A framework is introduced that allows one to quantify the tradeoff between the risk (due to the CSI randomness) that is associated with a precoder and the resulting transmission rate. Using ideas from modern portfolio theory, the risk-rate problem is modified to a tractable mean-variance optimization problem. Thus, we give a method that allows one to efficiently find a good precoder in the risk-rate sense. The technique is quite general and applies to a wide range of CSI probability distributions.

Keywords: Broadcast Channels
Precoding
Noisy Channel Side Information
Advisor: Lim, Teng Joon
Second Messenger-mediated Regulation of Autophagy

Autophagy is an evolutionarily conserved degradative eukaryotic cell pathway that plays a role in multiple cellular processes. One important function is as a key component of the cellular immune response to invading microbes. Autophagy has been found to directly target and degrade multiple intracellular bacterial species. In this thesis, I identify and characterize two distinct regulatory mechanisms for this pathway involving the second messengers: diacylglycerol and cyclic adenosine monophosphate (cAMP). Salmonella enteric serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterial species that has been shown to be intracellularly targeted for degradation by autophagy. While targeting of this species has been previously shown to involve ubiquitination, this pathway accounts for only half of targeted bacteria. Here I show that ubiquitin-independent autophagy of S. Typhimurium requires the lipid second messenger diacylglycerol. Diacylglycerol localization to the bacteria precedes autophagy and functions as a signal to recruit the delta isoform of protein kinase C (PKC) in order to promote the specific autophagy of tagged bacteria. Furthermore, I have found that the role of diacylglycerol and PKC delta is not limited to antibacterial autophagy but also functions in rapamycin-induced autophagy indicating a general role for these components in this process. Multiple bacterial species have been found to be targeted by autophagy and while some have developed strategies that allow them to avoid targeting, no bacterial factor has yet been identified that is able to inhibit the initiation of this process. Here I show that two bacterial species, Bacillus anthracis and Vibrio cholera inhibit autophagy through the elevation of intracellular cAMP and activation of protein kinase A. Using two different bacterial cAMP-elevating toxins, I show that multiple types of autophagy are inhibited in the presence of these toxins. This is indicative of a general inhibitory function for these toxins and identifies a novel bacterial defence strategy. This work characterizes both a novel regulatory signal for the induction of autophagy and identifies a novel bacterial tactic to inhibit this process. Together the data presented in this thesis provide novel insight into the regulation of autophagy and offer potential targets for modulation of this process.

Keywords: Autophagy
Second Messenger
Diacylglycerol
cyclic AMP
Advisor: Brumell, John
Business Models and Incentives in Rating Markets: Three Essays

This dissertation consists of three essays linking the business models of rating agencies to the rating decisions these agencies make as market intermediaries between buyers and sellers. The first study examines the link between a rating agency‟s primary revenue source and its rating decisions. Theoretically, rating payments could influence rating agency decisions or be counterbalanced by reputational rewards for rating accuracy. I explore this relationship in U.S. corporate credit ratings, where some agencies are primarily paid by bond issuers (sellers) and others by investors (buyers). Analysis of a balanced panel of 338 companies rated between 2005 and 2009 reveals that agencies produce differing ratings consistent with the preferences of their paying customers. Changes in buyer-paid ratings are more frequent and generally precede corresponding seller-paid rating changes. Seller-paid ratings are slower to incorporate negative information, particularly for rated firms in the financial services sector and firms with ratings above a critical grading cutoff. The second study complements the first by estimating the gap between the rating information disclosed by sellers and the information sought by buyers, again using evidence from U.S. corporate credit ratings. While seller willingness to pay for an additional rating is highly concentrated among a subset of relatively high-quality firms, buyers demonstrate more uniform interest in additional ratings for firms at all quality levels. This finding highlights an information gap among high-risk firms that is not a major focus of existing regulation. The third study focuses on rating decisions by government rating agencies, an alternative rating model to those examined in the first two studies. The empirical setting is Canadian film classification where the existence of multiple regional regulators has been justified by claims of variation in community standards. I find significant and increasing consistency in the regulatory decisions of these agencies, suggesting institutional isomorphism that brings into question the persistence of the parallel regional structure. Overall, these studies provide new empirical insight into the relevance of rating agency heterogeneity to firm strategy and policy. The findings may also be relevant to a variety of other settings involving information disclosure such as environmental impact and corporate social responsibility.

Keywords: Rating
Strategy
Information Disclosure
Credit
Business Model
Incentives
Rating Agency
Advisor: Silverman, Brian S.
Chemical Genomic Analyses of Plant-pathogen Interactions

The recently-emerged field of chemical genomics is centered on the use of small molecules to perturb biological systems as a means of investigating their function. In order to employ this approach for the study of plant-pathogen interactions, I established an assay in which Arabidopsis thaliana seedlings are grown in liquid media in 96-well plates. Inoculation of these seedlings with a virulent strain of the bacterial phytopathogen Pseudomonas syringae resulted in macroscopic bleaching of the cotyledons of these seedlings. This symptom was used as the basis for high-throughput chemical genomic screens aimed at identifying small molecules that protect Arabidopsis seedlings from infection. One of the first chemicals identified through this screen was the sulfanilamide compound sulfamethoxazole (Smex). This compound was later shown to also reduce the susceptibility of both Arabidopsis and wheat to infection by the fungal pathogen Fusarium graminearum, suggesting a broad spectrum of activity. More detailed investigations of Smex indicated that the protective activity of this compound did not derive from antimicrobial effects, and that this activity was not executed through common defence-related signalling pathways. The folate biosynthetic pathway enzyme dihydropteroate synthase is a known target of sulfanilamides, and it does appear to contribute to Smex-induced disease resistance, albeit in a folate-independent manner. In order to identify downstream mediators of Smex activity, I initiated two forward genetic screens intended to recover mutants with altered sensitivity to Smex in a seedling growth assay. Interestingly, while these screens yielded mutants with striking Smex sensitivity phenotypes, disease resistance phenotypes were not altered. Gene expression profiling of Arabidopsis tissues treated with Smex prior to bacterial inoculation suggested that this compound generally affects lipid signalling. Altogether, it is evident that Smex elicits a complex set of responses in Arabidopsis with apparently non-overlapping phenotypic outputs.

Keywords: plant-pathogen interactions
chemical genomics
high-throughput screening
molecular biology
Advisor: Desveaux, Darrell
Non-invasive Cardiac Output of Children in Health and Disease: Respiratory Gas Techniques

Cardiac output (Q) is an important determinant of the cardiovascular system‟s ability to meet the oxygen needs of the body. This dissertation addresses the non-invasive measurement of Q, in healthy children and those with heart and lung disease. 1) The correction factors for collision broadening, downstream difference and end tidal CO2 (PetCO2), used in the CO2 rebreathe (equilibrium) method, were evaluated. In lung disease, one is unable to assume a normal dead space to estimate arterial CO2 (PaCO2), and the use of any of these correction factors alone should be used with caution as they each exert a profound effect on the Q measurement. 2) A new equation to predict PaCO2 from PetCO2 in patients with CF was derived via multiple regression analysis, taking into account disease severity. 3) The validity and reliability of Q measures via the inert gas rebreathing technique (InnocorTM device) were evaluated. The highest intraclass correlation coefficients were attained during exercise (0.7-0.98), indicating excellent reliability of the device. Comparisons of Q measures from the InnocorTM (QInn) to the AMIS mass spectrometer system (QAmis) were made to assess validity. The bias (QInn-QAmis) and limits of agreement (±2SD) were 0.45 ± 1.9 L.min-1 and 0.27 ± 2.1 for children with congenital heart disease and healthy controls respectively, with no systematic differences between the two methods. 4) Assessment of cardiac output in Fontan patients demonstrated that an individualized, atrioventricular (AV) delay optimization was required. Moreover, there was a small but significant improvement in heart function with AV synchronized pacing (DDI) versus ventricular pacing (VVI), suggesting that further study with a larger sample of patients is warranted. The limitations and strengths of the measurement of non-invasive cardiac output in children, primarily via respiratory gas analysis, were delineated and recommendations were made for their use.

Keywords: cardiac output
children
exercise physiology
Advisor: Thomas, Scott
Supporting Public Health Policy Decision-making through Economic Evaluation: Applications and Methods

The extent to which economic evaluations of public health programs in Ontario are conducted and used by decision makers is currently very limited. This thesis supports public health decision-making through applied and methodological work. The applied work demonstrates different methods to evaluate the cost-effectiveness of public health interventions using the examples of seasonal and pandemic influenza immunization programs. The methodological component explores whether time horizon choice, one methodological consideration in economic evaluations, introduces bias. The economic evaluation of Ontario’s universal influenza immunization program (UIIP) uses primarily provincial health administrative databases to assess the impact of UIIP on health outcomes (quality-adjusted life years (QALYs), mortality), health care resource use (physician office visits, emergency department visits, and hospitalizations), and costs due to seasonal influenza. Ontario’s UIIP was found to be cost-effective compared to a targeted program. The economic evaluation of Ontario’s H1N1 (2009) mass immunization program uses a mathematical modeling approach to describe the pandemic as observed in Ontario. By removing immunization from the simulation, the impact of the program was evaluated. Outcome measures include health outcomes (attack rate, deaths, QALYs), resource use, and cost (physician office visits, emergency department visits, hospitalizations). The analysis found Ontario’s mass immunization program to be highly cost-effective despite high program cost. The methodological component investigates whether time horizon choice, a major methodological choice, introduces bias to economic evaluations. The existence, magnitude and direction of time horizon bias are demonstrated using a formal model. This work supports current guidelines in recommending a lifetime time horizon and provides a framework to discuss bias in economic evaluations. This thesis demonstrates different approaches to evaluate the cost-effectiveness of public health interventions, informs decision-making, and establishes the groundwork to guide future economic evaluations of public health interventions.

Keywords: health economics
public health
economic evaluation
decision-analysis
infectious diseases
mathematical modeling
Advisor: Krahn, Murray
Regulation of Core Splicing Factors by Alternative Splicing and Nonsense-mediated mRNA Decay

The majority of human genes are transcribed into a precursor messenger RNA (pre-mRNA) that is processed to produce multiple mRNA variants through alternative splicing. Although alternative splicing is known for its role in generating proteomic diversity, it can also regulate gene expression by introducing premature termination codons that target the spliced transcript for nonsense-mediated mRNA decay (AS-NMD). In order to understand the impact of AS-NMD on gene expression, I performed quantitative AS microarray profiling of NMD-inhibited human cells. Using this system, I address the prevalence, trans-acting factor requirements and the range of cellular functions regulated by AS-NMD. While this pathway had been implicated in homeostatic feedback regulation of genes encoding splicing-regulatory proteins, my results revealed highly conserved alternative exons regulated by AS-NMD in genes encoding basal or ‘core’ splicing factors. I further characterized one of these exons in the gene encoding SmB/B’, and demonstrated that SmB/B’ autoregulates its expression through AS-NMD. Furthermore, AS profiling revealed that knockdown of this core splicing factor affects the inclusion levels of additional alternative exons enriched in genes with functions in RNA processing and RNA binding. In summary, my results reveal a role for AS-NMD in regulating the expression of core splicing factors, as well as a role for the core spliceosomal machinery in coordinating a network of alternative exons in RNA processing factor genes.

Advisor: Blencowe, Benjamin
Flaxseed and Lower-dose Estrogen: Studies on Their Protective Actions and Mechanisms in Bone Using the Ovariectomized Rat Model

Flaxseed (FS) is a rich source of lignans and n-3 polyunsaturated fatty acids (PUFA), compounds that may help preserve normal bone cell function during aging. Understanding the effect of FS alone or combined with lower doses of estrogen therapy on bone and other estrogen-responsive tissues (e.g. uterus) is of particular interest to postmenopausal women who combine dietary bioactives (e.g. FS) with pharmacological agents (e.g. estrogen monotherapy) to attenuate postmenopausal bone loss. The overall objective of my research was to determine the effects and mechanisms of FS, alone or combined with lower doses of estrogen therapy, on bone and uterus health by measuring a comprehensive set of outcomes in the ovariectomized rat model of postmenopausal osteoporosis. The results demonstrated that FS enhances the protective effect of low-dose estrogen therapy (LD) on vertebral bone mineral density (BMD), three-dimensional microarchitecture and strength in ovariectomized rats. Moreover, FS exerts a stronger effect on bone outcomes when combined with LD than when combined with ultra-low-dose estrogen therapy (ULD). These studies also showed that FS feeding results in higher lignans and n-3 PUFAs in vertebrae, tibias and femurs. Histological analyses at the lumbar vertebra (LV) showed that there were no differences in TRAP-5β, CTX, or OPG/RANKL ratio between the FS+LD and LD groups. FS+LD did however result in lower protein expression of osteocalcin, a marker of bone formation and overall bone turnover, and higher expression of OPG compared to the negative control (NEG), while LD did not. While these findings suggest that FS+LD results in greater attenuation of deterioration of bone tissue compared to LD due to a reduction in bone turnover, significant differences between FS+LD and LD were not observed. Elucidating these specific mechanisms of action require further investigation. In the uterus, FS+LD did not induce greater cell proliferation or differences in qualitative indices of uterine morphology compared to LD. These findings suggest that there may be no increase in the risk of endometrial hyperplasia and carcinoma with FS+LD compared to LD. These findings may lead to the development of strategies that combine food bioactives and current pharmacological agents to more effectively normalize bone turnover during aging.

Keywords: Flaxseed
Lower-Dose Estrogen Therapy
Advisor: Ward, Wendy