VictorJuiz/thesis huggingface dataset:
HLA-B27-specific Immune Response to Influenza is Critically Dependent on ERAP-1 and on MHC-I Allelic Co-dominant Expression
Keywords: Ankylosing Spondylitis
ERAP
HLA-B27 and HLA-B7
HLA Transgenic Mice
Immunodominance
Influenza Infection

Genetic studies have demonstrated that both the HLA-B27 and endoplasmic reticulum aminopeptidase (ERAP) are contributing factors to the pathogenesis of ankylosing spondylitis (AS). In my studies I have used HLA transgenic (Tg) mice to examine the contribution of HLA-B7 and ERAP1 to the HLA-B27-mediated immune response to influenza (flu) infection, results of which could be used as proof of principle for AS. Influenza infection affects millions of individuals worldwide annually. Because of the well-established HLA allele-specific epitope recognition, I used flu infection in HLA Tg mice deficient of endogenous MHC-I expression; i.e., H2-D-/-, H2-K-/- or double knock out (DKO) in a proof-of-concept strategy to define the details of first, the interaction of HLA-B7 and HLA-B27 and secondly, the contribution of ERAP to allele-specific immunodominance. Immunodominance during a viral infection is influenced by many factors. To assess whether co-expression of HLA-B7 and HLA-B27 would influence the immune response in double HLA Tg mice, I created double Tg B7/B27 mice with intact ERAP expression on a DKO background. Following flu infection, the dominant anti-viral CTL responses was surprisingly directed predominantly at the B7-restricted NP418-426 epitope while the CTL response to the B27-restricted NP383-391 epitope was significantly reduced. Using chimeras and flu-specific tetramer staining I showed that the reduced B27/NP383-391 CTL response in B7/B27 Tg mice was due to negative selection of T cells specific to NP383-391 recognition. Secondly, recent genome-wide association studies (GWAS) with AS patients have shown that loss-of-function genetic variants of ERAP1 are protective, and that this relationship is seen exclusively in B27+ patients. To investigate these interactions in an in vivo model, I created single Tg B7 and B27 mice in the absence of ERAP. Following flu infection the B27/NP383-391 CTL response was reduced in B27/ERAP-/- Tg mice compared to B27/ERAP+/+ mice. No difference in the CTL response to the B7/NP418-426 epitope was observed between the B7/ERAP-/- and B7/ERAP+/+ mice. This is the first in vivo validation of the gene-gene interaction between B27 and ERAP1 which had been suggested by prior genetic studies.
Measuring the Inboard Side Scrape-off Layer of DIII-D Plasmas using Swing-probes
Keywords: DIII-D
Langmuir Probe
Nuclear Fusion
plasma
scrape-off-layer
tokamak

The scrape-off layer (SOL) plasma of a tokamak often has a complicated spatial dependence. The temperatures, densities and flow speeds can vary significantly on the same magnetic flux tube at different poloidal locations. To fully understand the plasma variation, we must make active measurements along the full length of the flux tubes by expanding our diagnostic capability to include the critically under-diagnosed inboard side. To accomplish this, a new pair of in-situ reciprocating Mach probes called Swing-Probes have been developed and deployed on the DIII D centerpost. This design is unique in that the probe swings vertically through the SOL plasma, taking measurements along a 180° arc with a 20 cm radius. Two electrodes maintain a Mach-pair orientation throughout the swing and provide measurements of saturation current, electron temperature, and parallel flow speeds. The probes can handle very high heat fluxes and have taken measurements up to the Last Closed Flux Surface (LCFS) in high-powered H-Mode at 10 MW. The Swing-Probe temperature and density measurements have been verified against the floor Langmuir probes, the core Thomson scattering and the divertor Thomson scattering systems in DIII-D for conditions where poloidal variation are expected to be small. Measurements have been taken across a wide range of plasma conditions and provide informative relationships between the plasma parameters at the entrance of the inner divertor and the crown of the plasma.The low-turbulence plasmas on the inboard scrape-off layer make it possible to clearly quantify the sheath-expansion around Langmuir probes. An I-V fitter has been developed which can account for sheath-expansion in a theoretically consistent way, improving the reliability of Langmuir probe data analysis. In an inner-wall limited experiment in DIII-D requested by ITER, the Swing-Probes made the first Langmuir probe measurements of an enhanced heat flux feature just outside the LCFS. These measurements match those made using infrared camera images of the centerpost in DIII-D and in other tokamaks and confirm that this feature should be accounted for in the designs of plasma facing surfaces in ITER.
Development of a Computer-aided-design-based Geometry and Mesh Movement Algorithm for Three-dimensional Aerodynamic Shape Optimization
Keywords: aerodynamic
CAD
mesh morphing
mesh movement
optimization
surface mesh morphing

This thesis focuses on the development of a Computer-Aided-Design (CAD)-based geometry parameterization method and a corresponding surface mesh movement algorithm suitable for three-dimensional aerodynamic shape optimization. The geometry parameterization method includes a geometry control tool to aid in the construction and manipulation of a CAD geometry through a vendor-neutral application interface, CAPRI. It automates the tedious part of the construction phase involving data entry and providesintuitive and effective design variables that allow for both the flexibility and the precision required to control the movement of the geometry. The surface mesh movement algorithm, on the other hand, transforms an initial structured surface mesh to fit the new geometry using a discrete representation of the new CAD surface provided by CAPRI. Using a unique mapping procedure, the algorithm not only preserves the characteristics of the original surface mesh, but also guarantees that the new mesh points are on the CAD geometry. The new surface mesh is then smoothed in the parametric space before it is transformed back into three-dimensional space. The procedure is efficient in that all the processing is done in the parametric space, incurring minimal computational cost. The geometry parameterization and mesh movement tools are integrated into a three-dimensional shape optimization framework, with a linear-elasticity volume-mesh movement algorithm, a Newton-Krylov flow solver for the Euler equations, and a gradient-based optimizer. The validity and accuracy of the CAD-based optimization algorithm are demonstrated through a number of verification and optimization cases.
Investigating the Mechanisms of Idiosyncratic Drug Reactions: Lessons from Nevirapine-induced Skin Rash in Female Brown Norway Rats.
Keywords: Animal Model
Idiosyncratic Drug Reactions
Immunotoxicology
Nevirapine
Skin Rash

Idiosyncratic drug reactions (IDRs) cause significant morbidity and mortality. At present it is impossible to predict who will have such reactions because the mechanisms involved are not understood. This work used nevirapine-induced skin rash in female Brown Norway rats as a model to investigate the mechanisms of IDRs. Specifically, we hypothesized that CD4+ T cells are mediating the rash, and the reactive sulfate metabolite of nevirapine induced the immune response by directly activating antigen presenting cells (APCs). Independent of which chemical species induced the rash (treatment with nevirapine or 12-OH-nevirapine), CD4+ T cells isolated from the lymph nodes of animals responded vigorously to the parent drug, but not to 12-OH-nevirapine even though oxidation of nevirapine to 12-OH-nevirapine pathway is required to induce the rash. This falsifies the basis for the PI hypothesis, which assumes that what the lymphocytes respond to is what induced the IDR. In the APC activation study it was found that nevirapine, 12-OH-nevirapine, and 12-OH-nevirapine sulfate all appeared to activate APCs to some degree. For instance, CD40 was upregulated in RAW264.7 cells and bone marrow-derived dendritic cells, while CD86 was upregulated in THP-1 cells. However, the effects were small and not limited to the reactive sulfate. Several interventions were also used to modulate the rash caused by nevirapine to learn more about possible risk factors; however, no results showed that any of them had a significant effect on the rash. This included depleting B cells and treatment with buthionine sulfoximine, retinoic acid, 1-methyl-tryptophan, lipopolysaccharide, imiquimod, or vitamin D. This animal model of an IDR allowed us to test mechanistic hypotheses that would be impossible to test by any other method. It provided insights into the mechanism of this IDR, and by extension, into the mechanisms of other IDRs.
Phonological Awareness Training for Struggling Readers in Grade 1 French Immersion
Keywords: at-risk readers
early identification
early immersion
early intervention
French immersion
struggling readers

This longitudinal study analysed the effectiveness of phonological awareness (PA) instruction on the reading development of struggling Grade 1 readers enrolled in an early French immersion (FI) program in Southern Ontario. To date, there have been no published studies of PA interventions for FI students who are considered to be at risk for later reading problems. The findings indicate that a phonologically-based intervention can effectively address PA deficits and facilitate reading acquisition for FI students from diverse linguistic backgrounds who are struggling to learn to read in French.Approximately 100 children with varied language backgrounds participated in the study during each school year. A new cohort was added each year for a period of three consecutive years. At-risk readers from each of the three cohorts were identified on the basis of their performance on English word reading and/or English PA measures that were administered. Pre-test measures were administered in November, and immediate post-test measures were administered in April. Delayed post-testing was conducted in February of the following two school years to assess the durability of treatment effects.Small groups of 3-4 struggling readers from intact classes were randomly assigned to experimental and control conditions in each of the three consecutive years. For 18 weeks, the treatment group was provided with English PA training in combination with letter-sound correspondence instruction, and the control group received English instruction designed to increase vocabulary development. At the conclusion of the intervention phase of the study, immediate post-testing indicated that the treatment group was closing the achievement gap in comparison to the typically developing readers on both English and French measures of PA and measures of French word reading. At this time point, there was still a significant difference between the control group's performance on these same measures and that of the typically developing readers. Delayed post-testing results indicated that the treatment group significantly outperformed the control group on French measures of elision, word reading, and word reading fluency.
Optimizing Neural Networks that Generate Iimages
Keywords: Neural networks

Image recognition, also known as computer vision, is one of the most prominent applications of neural networks. The image recognition methods presented in this thesis are based on the reverse process: generating images. Generating images is easier than recognizing them, for the computer systems that we have today. This work leverages the ability to generate images, for the purpose of recognizing other images.One part of this thesis introduces a thorough implementation of this "analysis by synthesis" idea in a sophisticated autoencoder. Half of the image generation system (namely the structure of the system) is hard-coded; the other half (the content inside that structure) is learned. At the same time as this image generation system is being learned, an accompanying image recognition system is learning to extract descriptions from images. Learning together, these two components develop an excellent understanding of the provided data.The second part of the thesis is an algorithm for training undirected generative models, by making use of a powerful interaction between training and a Markov Chain whose task is to produce samples from the model. This algorithm is shown to work well on image data, but is equally applicable to undirected generative models of other types of data.
Creation and Characterization of a Sensitized, Inhibitable Stress-Activated Protein Kinase
Keywords: Activated
Inhibitable
JNK
SAPK
Stress Activated Protein Kinase

Members of the Stress-Activated Protein Kinase (SAPK) family are involved in diverse cellular functions including extrinsic and intrinsic stress responses, cell proliferation, cell death and embryonic development. Prior studies that have inhibited, knocked out or overexpressed SAPK genes have implicated the family in a similarly diverse set of human pathologies including Alzheimer's disease, arthritis, cancer and diabetes. The presence of three genes in mammals termed α, β and γ, multiple (10) splice variants and the existence of a closely related kinase, p38 MAPK (also known as SAPK2) which is similarly regulated, has made determination of SAPK function particularly difficult. Here, I describe the creation and characterization of a novel series of SAPK mutant alleles that are sensitized and inhibitable. These mutants require no exogenous agonist for activity and can be inhibited rapidly through the addition of a small, cell permeable drug. In addition, inhibition is reversible through removal/dilution of the drug. I applied the sensitized alleles to evaluate the roles of SAPKs in cell lines. Further, expression of a sensitized, inhibitable SAPK allele was found to be active and chemically inhibitable in zebrafish where I show that SAPK signalling is involved in both convergent-extension cell movements as well as cell fate determination. The combination of sensitized activity and selective inhibition of the mutant SAPK alleles should accelerate understanding of the individual splice isoforms of this conserved family of protein kinase in normal cellular function and disease pathologies.
Examining the Role of Everyday and Autobiographical Memory in Social Cognition for Adolescents with Fetal Alcohol Spectrum Disorder
Keywords: Fetal Alcohol Spectrum Disorder
memory
participation
prenatal alcohol exposure
social cognition
theory of mind

One of the most persistent problems facing adolescents with Fetal Alcohol Spectrum Disorder (FASD) is social difficulty. Their social deficits are, in part, a consequence of the cognitive impairments they experience that can lead to social isolation. Everyday and autobiographical memory represent two forms of memory that have been linked to the development of complex, higher order social skills such as theory of mind and social problem solving. Yet, no studies to date had examined either everyday or autobiographical memory in adolescents with FASD, or the relationship between these forms of memory and social abilities. Thus, the research presented within this dissertation was conducted to address this knowledge gap. Three independent studies were conducted to examine the effect of FASD on everyday and autobiographical memory and the relationship between these forms of memory and higher order social skills known to be problematic for youth with FASD. The first study identified everyday memory deficits by comparing ratings of everyday memory performance between caregivers of children and youth with and without FASD. The second study demonstrated autobiographical memory recall weaknesses that were linked to theory of mind task performance in adolescents with FASD. The third study showed social problem solving difficulties in youth with FASD that were also significantly related to autobiographical memory recall. Finally, a proposed pilot intervention study is presented that could be implemented in the future using the data generated from the previous studies. Overall, the findings of this dissertation provide a preliminary evidence base suggestive of a role of neurocognitive impairment in the development of social deficits in adolescents with FASD. It is hoped that this information can be used as a foundation for future intervention studies that target everyday and autobiographical memory-related challenges as a means to facilitate social skill development for these youth.
Minority Language Acquisition and Retention: A study of Canadian-born Romanian Speaking Bilingual Children
Keywords: bilingualism
child language acquisition
first language acquisition
heritage languages
language maintenance
second language acquisition

Preserving a minority first language has been found to be very important for the overall personal and educational development of immigrant children. However, successful bilingual development involving a minority language is often challenging in situations where the majority language dominates communication not only provincially and nationally but also internationally. This dissertation investigates the conditions under which a first language (Romanian) can be acquired and maintained in an English-dominant setting as well as any impact that the L1 has on the L2 (English), to which the children are formally introduced upon entry to junior kindergarten. Three children participated in this longitudinal study from the commencement of junior kindergarten (~ 4;0) until the start of grade 1 (~ 6;0). For the purposes of charting development (or possible attrition), language proficiency was assessed in Romanian and in English through separate measures of lexical (PPVT and Romanian-adapted PPVT), phonological (CTOPP and Romanian-adapted CTOPP), and syntactic and narrative (picture-story based instruments) abilities. In addition, the children's communicative competence in the two languages was evaluated more holistically through audio recorded data of the children's interactions in various naturalistic situations. Information about the children's home language practices was also obtained through interviews conducted with their parents.The data collected allowed for a unique, psycholinguistically rich, and culturally well-rounded account of the bilingual development of Romanian-Canadian children. The results demonstrated that the children continued to develop their minority language alongside the majority language. However, the lack of formal schooling in Romanian seemed to have impeded the growth of the children's academic vocabulary and, possibly, narrative skills in Romanian. This could be rectified through formal minority language education. The findings also demonstrate that two years of schooling in English narrows and, in some respects, even erases the gap between the English-as-L2 children and their monolingual counterparts. This study provides unique data on bilingual Romanian-Canadian children. The specially adapted vocabulary and phonological tests in Romanian make it possible to examine the development of the minority and majority languages side by side. Also, the longitudinal design allows for capturing change over multiple points in time within each of the two languages.
Improvements to our Understanding of Toronto-area Atmospheric Composition
Keywords: GEOS-Chem
ozone
stratosphere
Toronto
tropospheric chemistry
University of Toronto Atmospheric Observatory

Using eleven years of trace gas column measurements at the University of Toronto Atmospheric Observatory (TAO), along with data from complementary sources, such as satellites, surface in situ measurements, and nearby rural column measurements, thisthesis aims to improve our understanding of the sources of air pollution and the causes of variability in atmospheric composition over the Toronto area.The relative influence of chemical production and direct emissions on Toronto-area O3 and CO were determined using GEOS-Chem model simulations. 28 pollution events (defined as enhanced O3 or CO lower-tropospheric (0-5 km) columns that coincided with surface O3 exceedances) were found in the TAO dataset between 2002 and 2010. O3 columns over Toronto during pollution events are influenced by urban and industrial anthropogenic NOx emissions, biogenic isoprene emissions from the eastern United States, and soil NOx emissions from the mid- and western United States. During pollution events, Toronto CO columns are greatly influenced by nearby fossil fuel emissions and isoprene oxidation. C2H6 columns are often enhanced during pollution events, as the sources of C2H6 are similar to those of O3 and CO. HCN columns are assumed to be enhanced in biomass burning plumes, and thus, aid in identifying transport of biomass burning emissions over Toronto. Sensitivity to meteorological conditions was examined as well, and five case studies were presented in detail.Passage of the polar vortex over the Toronto area was determined by increases in scaled potential vorticity (PV) that coincide with outliers in the HF stratospheric time series. Confirmed with polar PV maps and reductions in N2O stratospheric columns, 53 polar intrusion events were identified in the 2002 to 2013 TAO time series. The effect on HF, HCl, O3, and N2O was studied, and we found these events caused a significant increase in HF-column winter/spring variability, and a small increase (on average) in stratospheric O3 columns.The results of this thesis have contributed to improving our understanding of the causes and variability of ozone air quality and stratospheric ozone over a major metropolitan area.
Virtual Reference Interferometry: Theory Experiment
Keywords: Chromatic Dispersion
Dispersion
Dispersion test
Interferometry
Virtual Reference Interferometry

This thesis introduces the idea that a simulated interferogram can be used as a reference for an interferometer. This new concept represents a paradigm shift from the conventional thinking, where a reference is the phase of a wave-front that traverses a known path. The simulated interferogram used as a reference is called a virtual reference. This thesis develops the theory of virtual reference interferometry and uses it for the characterization of chromatic dispersion in short length (