VictorJuiz/thesis huggingface dataset:
Involvement of Th17 Pathway in Adverse Drug Reactions: Mechanistic Investigation of Drug-induced Autoimmunity and Drug-induced Liver Injury

Clinical characteristics of idiosyncratic drug reactions (IDRs) suggest that they are immune mediated. Penicillamine-induced autoimmunity in Brown Norway rats was used as a tool for mechanistic studies of this type of IDR. It has been shown that T helper 17 (Th17) cells play a central role in many types of autoimmune diseases. This study was designed to test whether Th17 cells are involved in the pathogenesis of penicillamine-induced autoimmunity. In sick animals, interleukin (IL) 6 and transforming growth factor-β1, known to be driving forces of Th17 differentiation, were consistently increased following penicillamine treatment. IL-17 and IL-22, characteristic cytokines produced by Th17 cells, were increased in sick animals. Furthermore, the percentage of IL-17-producing CD4 T cells was significantly increased, but only in sick animals. Retinoic acid, which has been reported to inhibit Th17 cell development, made the autoimmunity worse, increased IL-6 production, and did not decrease the number of Th17 cells. An infiltration of CD8 cytotoxic T cells in the liver suggests that they may be the key player in causing liver toxicity induced by D-penicillamine. Drug-induced liver injury (DILI) is one of the major causes of morbidity, mortality, and drug candidate failure. Recently, it has been suggested that Th17 cells may play an active role in inflammatory human liver diseases. In a study of patients being treated with isoniazid, some patients developed mild liver injury. The percentage of Th17 cells in the blood of these patients significantly increased when the ALT increased, and this suggests that they play a role in the mechanism of this liver injury. Furthermore, IL-10-producing T cells also increased and this may have prevented the development of severe liver injury. In another study, two hours after treatment of mice with acetaminophen there was a significant increase in Th17 cells in the liver. This rapid response suggests that Th17 cells can be part of the innate immune response to liver injury. Our data provided evidence that Th17 cells are involved in both “toxic” and idiosyncratic liver toxicity. This pathway could be a new target for the therapeutic interventions to treat DILI.

Keywords: adverse drug reactions
T helper 17 cells
Advisor: Uetrecht, Jack
Doing Technological Time in a Pediatric Hemodialysis Unit: A Ethnography of Children

Since the 1960s, hemodialysis has been a common intervention for children with end-stage renal disease. For weeks, months or years, children’s activities are disrupted because they must return to the hospital to be dialyzed about three times a week, for three or four hours. Their childhoods are characterized by on-going temporal disruptions, socio-spatial dislocations and intermittent technological dependence. Little is known about how children experience hospital-based hemodialysis. The study’s purpose was to describe and interpret the children’s embodied situatedness in the temporal, spatial and technological regimes and relations of a hemodialysis unit. Time, space and technology were viewed as significant interrelated aspects of the unit and the unit was conceived as nested in the broader life contexts of the children. The theoretical framework merged concepts of sociology of children, human geographical and temporal perspectives and philosophy of technology. A focused ethnography with 11 children who received maintenance hemodialysis was undertaken at a Canadian pediatric urban hospital. The dominant theme emerging from the study findings was the notion of the children doing technological time. The children’s temporal and socio-spatial positions were an effect of their technologically mediated embodiment and shaped their perspectives, evaluations and expectations. Their accounts revealed that the rituals and routines of the unit were experienced as long and boring. Their situatedness also was comprised of socio-spatial segregation and isolation due to being tethered to hemodialysis machines in the unit’s corners. Adaptations included resignation, resistance and waiting in the short and long term to be released from hemodialysis. Having negative and positive perceptions and responses, the children held multiple and conflicting meanings about the unit’s timespace. The findings suggest that crucial changes in practices and policies are essential to envision ways to create with children an overall positive place that merges and balances technological care with child focused care.

Keywords: Children
Hemodialysis
Human Geography
Technology
Ethnography
Sociology of Children
Advisor: Peter, Elizabeth Helen
Bifunctional Systems in the Chemistry of Frustrated Lewis Pairs

Three classes of bifunctional compounds related to frustrated Lewis pair chemistry were studied. The first class, alkynyl-linked phosphonium borates, was strategically synthesized and the corresponding neutral alkynyl-linked phosphine boranes generated in solution. They were reacted with THF, alkenes and alkynes to undergo either ring-opening or multiple bond addition reactions, giving rise to zwitterionic macrocycles. In two select alkynyl-linked phosphonium borates, thermolysis resulted in unique rearrangements transforming the phosphino- and boryl-substituted alkynyl moieties into C4 chains. The alkynyl-linked phosphine boranes were further demonstrated to coordinate as η3-BCC ligands in Ni(0) complexes. The rigid nature of the coordination was confirmed by dimerization without cleavage of the Ni–B interaction upon the addition of acetonitrile or carbon monoxide. Moreover, reactions with Al-, Zn- and B-based Lewis acids prompted hydride transfer within the alkynyl-linked phosphonium borate and interesting functional group transfer reactions. The second class of the bifunctional systems, a series of gem-substituted bis-boranes, was subjected to reactions with tBu3P and CO2. The O-linked bis-borane was shown to coordinate the phosphino-carboxylate moiety with one B, while the methylene-linked bis-boranes were demonstrated to chelate the carboxyl group. The third bifunctional system class, vinyl-group tethered boranes, was examined to elucidate the mechanism of the frustrated Lewis pair addition reaction to olefins. Using a bis(pentafluorophenyl)alkylborane, the close proximity of the olefinic protons and the ortho-fluorine nuclei were evident by both NOE measurements and DFT calculations. Moreover, its reactions with phosphine bases suggested that an initial interaction between the highly electrophilic borane and the olefinic fragment precedes such frustrated Lewis pair addition reaction. Furthermore, a bis(pentafluorophenyl)alkoxyborane was synthesized and reacted with P-, N-, C- and H-based nucleophiles, demonstrating the wide range of Lewis bases that can be applied in olefin addition reactions with complementary regioselectivity.

Keywords: inorganic chemistry
main group elements
phosphine
borane
frustrated Lewis pairs
small molecule activation
Advisor: Stephan, Douglas
Internationally Educated Teachers in Canada: Transition, Integration, Stress, and Coping Strategies

This research investigates internationally educated teachers' (IETs) motivations to become teachers in Canada, learning in the initial teacher education programs, employment seeking experiences, as well as stress and coping strategies during their transition from the teacher education programs to the workplace. Twenty IETs from 12 different countries and areas participated in the study. Research data includes semi-structured interviews, field notes, short questionnaires, email, online chat records, and participants' writings. Narrative approaches (Clandinin & Connelly, 2000; Polkinghorne, 1995) were used to analyze interview and other qualitative data. In addition, I conducted descriptive analysis upon the questionnaires to triangulate the research findings. Research findings show that a number of intrinsic and extrinsic factors motivated IETs to take up or return to the teaching profession in Canada. All of the IETs in the study considered their studies in the teacher education programs useful, but a number of them expressed the wish that the programs should include more practical aspects. Some IETs experienced difficulties during their practicum due to their language and accents, heavy workload, classroom management issues, as well as balance between work and life. A few IETs also experienced conflicts and tension with their mentor teachers. Due to the challenging teaching job market in Ontario, and the disadvantaged situation for IETs, finding a teaching position was not easy for IETs. The main challenge was to obtain eligibility for teaching positions with school boards. IETs were frustrated with their employment, underemployment and unemployment. Research data from the IET Stress Scale showed that the top five stress factors for IETs in transition included finding a teaching position, teacher identity construction, balance between work and family, being observed and assessed, and heavy workload. Similar themes emerged from the interview data. IETs utilized various strategies to cope with their difficulties and stress. Most of the IETs expressed their desire to stay in the teaching profession in Canada. However, two IETs were reluctant to look for teaching positions due to their frustrating experiences with their mentor teachers. Two other IETs stayed in nonteaching or looked for jobs in other professions due to their difficult job seeking experiences.

Keywords: internationally educated teachers
teacher stress
coping strategies
teacher education
employment
professional integration
community of practice
identity
Advisor: Gagne, Antoinette
Effects of Phosphate-based Corrosion Inhibitors on Disinfectant Stability and HAA/NDMA Formation when in Contact with Copper, Iron, and Lead

This research examined the impacts of water quality, phosphate-based corrosion inhibitors and pipe wall exposure on free chlorine (HOCl)/chloramine (NH2Cl) degradation and haloacetic acid (HAA)/N-nitrosodimethylamine (NDMA) formation in simulated distribution system water mains and household plumbing at bench-scale and pilot scale. In bench-scale bottle tests, the reactivity of fresh/pre-corroded pipe materials with HOCl/NH2Cl in decreasing order was: ductile iron, copper, lead. The addition of phosphate-based corrosion inhibitors generally increased HOCl/NH2Cl degradation for fresh iron coupons, but decreased HOCl/NH2Cl decay only for fresh copper coupons. Generally, these corrosion inhibitors did not impact HAA formation. Copper corrosion products, including Cu(II), Cu2O, CuO and Cu2(OH)2CO3, catalyzed HAA and NDMA formation. For HAAs, copper catalysis increased with increasing pH from 6.6 to 8.6 and/or increasing concentrations of these copper corrosion products. Interactions of copper with natural organic matter (NOM), likely by complexation, and the subsequent increase in the reactivity of NOM were proposed to be the primary reason for the increased HAA formation.NDMA formation increased with increasing Cu(II) concentrations, DMA concentrations, alkalinity and hardness but was inhibited by the presence of NOM. The transformation of NH2Cl to dichloramine (NHCl2) and complexation of copper with DMA were proposed to be involved in elevating the formation of NDMA at pH 7.0. Finally, in pilot-scale modified pipe loop tests, copper catalysis of NDMA formation was confirmed, especially under laminar flow conditions, and iron was shown to possibly catalyze NDMA formation under turbulent conditions. Orthophosphate increased the catalytic effects of iron but decreased copper catalysis on NDMA formation by either modifying the properties of the iron-associated suspended particles or reducing the dissolved metal concentrations. Orthophosphate increased chloramine decay when in contact with iron, likely by promoting nitrite formation, but orthophosphate decreased chloramine decay for copper and lead by reducing the availability of metal corrosion products.

Keywords: Distribution system
Secondary disinfectant
Haloacetic acid
N-nitrosodimethylamine
Corrosion inhibitor
Iron
Lead
Copper
Advisor: Susan, Andrews
Tropical Severi Varieties and Applications

The main topic of this thesis is the tropicalizations of Severi varieties, which we call tropical Severi varieties. Severi varieties are classical objects in algebraic geometry. They are parameter spaces of plane nodal curves. On the other hand, tropicalization is an operation defined in tropical geometry, which turns subvarieties of an algebraic torus into certain polyhedral objects in real vector spaces. By studying the tropicalizations, it may be possible to transform algebro-geometric problems into purely combinatorial ones. Thus, it is a natural question, “what are tropical Severi varieties?” In this thesis, we give a partial answer to this question: we obtain a description of tropical Severi varieties in terms of regular subdivisions of polygons. Given a regular subdivision of a convex lattice polygon, we construct an explicit parameter space of plane curves. This parameter space is a much simpler object than the corresponding Severi variety and it is closely related to a flat degeneration of the Severi variety, which in turn describes the tropical Severi variety. We present two applications. First, we understand G.Mikhalkin’s correspondence theorem for the degrees of Severi varieties in terms of tropical intersection theory. In particular, this provides a proof of the independence of point-configurations in the enumeration of tropical nodal curves. The second application is about Secondary fans. Secondary fans are purely combinatorial objects which parameterize all the regular subdivisions of polygons. We provide a relation between tropical Severi varieties and Secondary fans.

Keywords: Tropicalization
Severi Varieties
Subdivisions of Polygons
Advisor: Khovanskii, Askold
Characterization of the Roles of TopoIIIα-RMI1 in Maintaining Genome Integrity

Bloom syndrome is a rare autosomal recessive disorder that is caused by mutations in the BLM gene. BLM associates with TopoIIIα and RMI1 to form a complex that is essential to maintain genome integrity. This complex catalyzes a dissolution reaction that resolves recombination intermediates containing two Holliday junctions without crossing over of genetic material. Dissolution activity is remarkable because it accounts for the in vivo role of BLM-TopoIIIα-RMI1 in suppressing sister chromatid exchanges. To further understand the biochemical roles that each member of the BLM complex plays in dissolution, I generated single-stranded catenanes that resemble the proposed intermediates at the latest steps of dissolution. Using this substrate, I demonstrated that TopoIIIα is a single-stranded DNA decatenase that is specifically stimulated by BLM and RMI1. Interaction between TopoIIIα and RMI1 is essential for the optimal decatenase activity. Furthermore, binding of RPA to single-stranded DNA substrate inhibits TopoIIIα decatenase activity. However, complex formation between BLM, TopoIIIα and RMI enables TopoIIIα to displace RPA and catalyze decatenation. Since the decatenase activity is presumed to be involved in many aspects of DNA metabolism, I investigated the roles of RMI1 and TopoIIIα in DNA replication in vivo. Using the molecular combing technique, I showed that RMI1 functions downstream of BLM to promote normal replication fork progression. In addition, BLM, TopoIIIα and RMI1 colocalize with one another in response to replication stress. Finally, interaction between TopoIIIα and RMI1 is essential for nuclear localization of the complex and for the complex to promote recovery from replication stress. This work defines molecular functions for RMI1 and TopoIIIα in DNA replication and repair, providing insight into their roles as suppressors of genome instability.

Keywords: BLM
topoisomerase IIIalpha
RMI1
genome integrity
Advisor: Brown, Grant
A 1-1-1-1 MASH Delta-Sigma ADC using Dynamic Comparator-based OTAs

Low intrinsic transistor gain in nanometer CMOS technologies imposes implementation difficulties of switched-capacitor (SC) circuits based on a conventional OTA used in delta-sigma ADCs. Zero-crossing-based circuits (ZCBCs) have been proposed as replacements for conventional OTAs in SC circuits, but the efficiency of existing ZCBC-based delta-sigma ADCs trails that of state-of-art conventional delta-sigma ADCs. The dynamic comparator-based OTA (DCBOTA) is a novel circuit block that performs an equivalent operation of a conventional OTA in a SC circuit by repeatedly detecting the input (Vg) sign and applying output current pulses to move Vg toward zero. The current pulse amplitude, set to the maximum at the beginning of a charge transfer phase, is decremented each time Vg crosses zero. Once Vg crosses zero at the minimum current pulse amplitude, the operation above ceases. The discrete-time nature of Vg comparison and current pulse injection in the DCBOTA allows use of a dynamic regenerative comparator, which is fast and scaling friendly, instead of the slow scaling-unfriendly open-loop zero-crossing detector used in ZCBCs. A small final Vg step size is required for high settling accuracy, but it can result in a long settling time. Analysis reveals that the DCBOTA settling time is minimized with a current pulse scaling factor of 3.59 for any final Vg step size. The comparator and switch noise affects the settling DCBOTA settling accuracy. The relationship between the minimum Vg step size, comparator noise, and switch noise for a given input-referred noise is shown. The DCBOTA consists of a dynamic regenerative comparator, control logic, and current pulse driver. The comparator evaluates the Vg sign when enabled by the control logic. The control logic enables and resets the comparator, and controls the current pulse amplitude. The current pulse driver applies either a positive or negative output current pulse when triggered by the comparator output. A 1-1-1-1 MASH delta-sigma ADC using DCBOTAs fabricated in a 65-nm CMOS technology achieved 70.4 dB of peak SNDR over a 2.5-MHz bandwidth dissipating 3.89 mW of power from a 1.2-V supply. Measurements show linear ADC power scaling over sampling frequencies provided by the dynamic operation of the DCBOTAs.

Keywords: DCBOTA
Delta-Sigma ADC
Advisor: Anthony, Chan Carusone
Aspects of Composite Likelihood Estimation And Prediction

A composite likelihood is usually constructed by multiplying a collection of lower dimensional marginal or conditional densities. In recent years, composite likelihood methods have received increasing interest for modeling complex data arising from various application areas, where the full likelihood function is analytically unknown or computationally prohibitive due to the structure of dependence, the dimension of data or the presence of nuisance parameters. In this thesis we investigate some theoretical properties of the maximum composite likelihood estimator (MCLE). In particular, we obtain the limit of the MCLE in a general setting, and set out a framework for understanding the notion of robustness in the context of composite likelihood inference. We also study the improvement of the efficiency of a composite likelihood by incorporating additional component likelihoods, or by using component likelihoods with higher dimension. We show through some illustrative examples that such strategies do not always work and may impair the efficiency. We also show that the MCLE of the parameter of interest can be less efficient when the nuisance parameters are known than when they are unknown. In addition to the theoretical study on composite likelihood estimation, we also explore the possibility of using composite likelihood to make predictive inference in computer experiments. The Gaussian process model is widely used to build statistical emulators for computer experiments. However, when the number of trials is large, both estimation and prediction based on a Gaussian process can be computationally intractable due to the dimension of the covariance matrix. To address this problem, we propose prediction methods based on different composite likelihood functions, which do not require the evaluation of the large covariance matrix and hence alleviate the computational burden. Simulation studies show that the blockwise composite likelihood-based predictors perform well and are competitive with the optimal predictor based on the full likelihood.

Keywords: Statistics
Composite likelihood
Advisor: Reid, Nancy
Bayesian Methods for Genetic Association Studies

We develop statistical methods for tackling two important problems in genetic association studies. First, we propose a Bayesian approach to overcome the winner's curse in genetic studies. Second, we consider a Bayesian latent variable model for analyzing longitudinal family data with pleiotropic phenotypes. Winner's curse in genetic association studies refers to the estimation bias of the reported odds ratios (OR) for an associated genetic variant from the initial discovery samples. It is a consequence of the sequential procedure in which the estimated effect of an associated genetic marker must first pass a stringent significance threshold. We propose a hierarchical Bayes method in which a spike-and-slab prior is used to account for the possibility that the significant test result may be due to chance. We examine the robustness of the method using different priors corresponding to different degrees of confidence in the testing results and propose a Bayesian model averaging procedure to combine estimates produced by different models. The Bayesian estimators yield smaller variance compared to the conditional likelihood estimator and outperform the latter in the low power studies. We investigate the performance of the method with simulations and applications to four real data examples. Pleiotropy occurs when a single genetic factor influences multiple quantitative or qualitative phenotypes, and it is present in many genetic studies of complex human traits. The longitudinal family studies combine the features of longitudinal studies in individuals and cross-sectional studies in families. Therefore, they provide more information about the genetic and environmental factors associated with the trait of interest. We propose a Bayesian latent variable modeling approach to model multiple phenotypes simultaneously in order to detect the pleiotropic effect and allow for longitudinal and/or family data. An efficient MCMC algorithm is developed to obtain the posterior samples by using hierarchical centering and parameter expansion techniques. We apply spike and slab prior methods to test whether the phenotypes are significantly associated with the latent disease status. We compute Bayes factors using path sampling and discuss their application in testing the significance of factor loadings and the indirect fixed effects. We examine the performance of our methods via extensive simulations and apply them to the blood pressure data from a genetic study of type 1 diabetes (T1D) complications.

Keywords: winner's curse
spike and slab prior
Hierarchical Bayes Model
Bayesian Model Averaging
Latent variable model
pleiotropy
genetic association studies
Markov chain Monte Carlo
path sampling
Bayesian inference
Advisor: Craiu, Radu V.
Sun, Lei