VictorJuiz/thesis huggingface dataset:
Development of Nontargeted Screening Algorithms for Indoor Contaminants

Humans spend most of their lives indoors, but there are thousands of chemical contaminants in indoor environments and the majority of these remain undetected. The focus of this thesis was to develop methods for nontargeted screening and prioritization of previously unreported indoor chemical contaminants using high-resolution mass spectrometry. To achieve this, a one – stop suspect screening algorithm was developed incorporating retention time prediction, isotopic peak calculation and in silico MS2 prediction. The algorithm was benchmarked for halogenated compounds and was further applied to screen for previously unrecognized indoor contaminants. Among 39 chlorinated compounds detected, 18 previously unrecognized azo dyes were detected as the biggest class of indoor chlorinated compounds (Chapter 2). To further characterize the indoor sources of these chlorinated compounds, various consumer products were collected from Toronto homes and screened for toxic halogenated contaminants with an emphasis on chlorinated paraffins. Chlorinated paraffin compounds were detected in 84 of 96 products analyzed, including electronic devices and plastic children’s toys, despite these compounds being prohibited for manufacture or import in Canada as of 2013 (Chapter 3). In addition to direct emission sources, the indirect sources of indoor contaminants formed through indoor reactions were investigated. To achieve this, an R package (‘indoortransformer’) was developed to predict indoor transformation products of organophosphorus compounds (OPCs). By further expanding the R package to incorporate in silico MS2 fragmentation prediction, 40 OPCs were detected in 23 house dust samples among which 24 OPCs were predicted to be formed through indoor reactions (Chapter 4). To systematically investigate the emission of contaminants from indoors, wastewater samples were collected over a 1.5 year period during the COVID-19 pandemic and screened against the ToxCast and Tox21 databases. Among 1037 ToxCast compounds, 43 were detected with high frequency plus 8 additional dyes and OPCs. Several plasticizers and disinfectants also showed an increase in concentration during periods of public lockdown (Chapter 5). This thesis provides a systematic exploration of the occurrence, source, reactions and temporal trends of many indoor contaminants. Future studies are warranted to expand the nontargeted screening methods developed in the current study to additional indoor compound classes.

Keywords: Indoor Chemistry
Mass Spectrometry
Wastewater
Advisor: Peng, Hui
When the Mighty Fall: Moral Outrage Toward Powerful Perpetrators

Past work demonstrates that powerful individuals are more inclined to act unethically (e.g., Gruenfeld et al., 2008). As a result, people are routinely confronted with powerful transgressors. Power is a potent force in perception (e.g., Keltner et al., 2008) and, therefore, I investigate how a perpetrator’s power will impact people’s moral outrage towards bad behavior. Powerful transgressors, due to their control over valued resources and social influence, can cause greater harm to victims and are more likely to encourage unethical group norms, compared to less powerful transgressors. Therefore, across six studies, I hypothesized that powerful perpetrators would elicit greater moral outrage than less powerful perpetrators. Participants reported greater moral outrage toward powerful transgressors who acted unethically in hypothetical scenarios (pre-registered Study 1 and Study 2), real stakes economic games (Study 3), live interactions in a laboratory (Study 4), and recalled events (Study 5). This robust effect held in contexts when the perpetrator’s power was not directly relevant, regardless of the victim’s power, and generalized across a variety of unethical acts. It was mediated by perceptions that powerful transgressors inflicted greater harm to victims and encouraged unethical group norms (Studies 2 and 3). However, this effect was moderated by important individual differences and contextual variables. Specifically, this effect was eliminated or reversed for participants who heavily endorse system-justifying ideologies (Study 5) and towards admired leaders within one’s own group (Study 6). My findings highlight the importance of social features like power in influencing moral judgment, suggesting that moral perception does not occur in a social vacuum.

Keywords: morality
perception
Advisor: Stellar, Jennifer
Investigating the Impact of FGFR5 Expression on β-cell Metabolism, Maturity and Intracellular Signaling

Pancreatic β-cells exist in an incredibly dynamic microenvironment that impacts cell metabolism, maturity, and function. Our research group previously showed that pancreatic β-cells plated on laminin matrix express reduced levels of FGFR1, a kinase receptor linked to β-cell metabolism. Due to recent evidence that adult β-cells also express FGFR5, a co-receptor for FGFR1, we hypothesize that laminin would impact FGFR5 expression with consequent effects on β-cell metabolism. Using a genetically encoded sensor for NADPH/NADP+ redox state (Apollo-NADP+), we show overexpression of FGFR5 enhances glucose-stimulated NADPH metabolism in β-cell lines as well as mouse and human β-cells. This enhanced response was accompanied by increased expression of transcripts for glycolytic enzymes (Glucokinase/Gck, Pyruvate kinase M2/Pkm2) and the functional maturity marker Urocortin 3 (Ucn3). Culturing β-cells on laminin matrix also stimulated upregulation of endogenous FGFR5 expression, and similarly enhanced β-cell glucose-stimulated NADPH-metabolism as well as Gck and Pkm2 transcript expression. Collectively these data reveal that β-cells respond to laminin by increasing FGFR5 expression to enhance β-cell glucose metabolism. We next examined changes to intracellular signaling pathways activated by FGFR5 expression. Using live cell imaging and qPCR we showed that the FGFR5-induced changes to metabolism are due to activation of the MEK/ERK signaling pathway. We then examined if the metabolic changes induced by MEK/ERK activation, specifically increased glucose consumption, had subsequent effects on nutrient sensing pathways. Using Western immunoblot and a variety of live cell imaging techniques, we showed FGFR5-induced metabolism increased activation of the nutrient sensing mTOR pathway. Lastly, we used data mining to uncover gene correlations to FGFR5 based on a human online β-cell database. Findings from the data mining analysis were validated using qPCR and identified the gene Rcc2 (Regulator of chromosome condensation 2) as being upregulated by FGFR5 in β-cell lines. We then expanded our data mining approach to better understand changes associated with late-stage β-cell maturation by centering our analysis on UCN3, a β-cell maturity marker. Our UCN3 focused analysis allowed us to construct a “late-stage maturation map” for β-cells which identified correlation to notable integrin subunits and solute carrier genes.

Keywords: Beta cell
Diabetes
FGFR
FGFR5
Islet
Metabolism
Advisor: Rocheleau, Jonathan V.
Kilkenny, Dawn M.
Characterization of Duplex-Tetraplex Equilibria in DNA

The four-stranded non-canonical structures G-quadruplexes and i-motif are formed by G-rich and C-rich DNA strands, respectively. These tetrahelical structures form in biologically important loci of the genome and are the essential regulator of genomic events. For this reason, tetrahelical structures have become an important target for developing anti-cancer strategies. To design drugs that control the formation of tetrahelical structures at specific genomic loci, it is important to understand the forces controlling the conformational preferences of potentially tetraplex-forming DNA strands. This doctoral thesis aims to characterize the distribution of conformational states adopted by G- and C-rich DNA strands and molecular forces that modulate their conformational equilibria. The first part of this dissertation describes the use of volumetric methods to characterize the hydration properties and the ionic atmosphere of an i-motif from the promoter region of the c-MYC oncogene. Our study reveals that changes in volume, ΔV, and adiabatic compressibility, ΔKS, accompanying i-motif formation are nearly zero. The DNA releases its counterions to the bulk upon i-motif formation thereby ceasing to be a polyelectrolyte. In the second part of the dissertation, we employ a CD-based analytical approach to determine the conformational preferences of equimolar mixtures of complementary G-rich and C-rich DNA strands from the promoter regions of c-MYC, VEGF, and Bcl-2 oncogenes. The conformational distribution is sequence-specific and is modulated by environmental factors such as temperature, salt, and pH. Under physiological conditions, the G-quadruplex and duplex coexist in all three DNAs although in different proportions. In the final part of the dissertation, we report changes in volume and compressibility accompanying interconversions between the G-quadruplex, duplex, and coil conformations adopted by the G-rich DNA strand from the c-MYC promoter. We rationalized our data in terms of the hydration and intrinsic properties of DNA. In addition, we further use our data to construct the first pressure-temperature phase diagram of G-quadruplex stability. Taken as a whole, our studies provide insights into the formation of tetrahelical structures within the genome.

Keywords: G-quadruplex
i-motif
Nucleic Acid
Volumetric Study
Advisor: Chalikian, Tigran V
Measurement of the Cross Section of the Higgs boson Production in Association with a $Z$ boson and Decaying into $WW^*$

This thesis presents measurement of the production of the Higgs boson in association with a $Z$ boson in the $WW^*$ Higgs decay channel. In order to optimize sensitivity, this analysis focused on the leptonic final state which contains four charged leptons in addition to two neutrinos. The measurement was performed using 139$\,\mathrm{fb}^{-1}$ of data recorded by the ATLAS detector and obtained from proton-proton collisions of $\sqrt{s}={13}\,$TeV during Run-2 of the Large Hadron Collider. The signal process was measured with an excess of 4.5$\sigma$. The ratio of the observed cross section times branching ratio to the value predicted by the SM, assuming the existence of the Higgs boson with a mass of 125 GeV, was measured as $1.6\pm0.5$, which indicates consistency between the observed data and the SM prediction. The cross section times branching ratio of the $ZH\rightarrow Z(WW^*)$ process was measured as $0.31^{+0.10}_{-0.09}\,$pb. The uncertainties on this measurement are three times smaller than the uncertainties associated with the previous measurement of same process by the ATLAS experiment.

Advisor: Krieger, Peter W
The Challenges of Deploying an Algorithmic Pricing Tool: Evidence from Airbnb

This thesis studies the deployment of an algorithmic pricing tool, Smart Pricing (SP), on Airbnb's platform. SP is a machine learning algorithm that uses past data to predict demand and employs proxies that are correlated with the hosts' marginal costs to set prices for listings. Chapter 3 discusses why SP can provide benefits to hosts in the context of Airbnb, and how Airbnb hosts use SP on the platform. The reduced-form analyses of this chapter suggest that a lot of Airbnb hosts do not vary their prices with changes in the demand for short-term rentals, and adopting SP is associated with higher benefits for hosts who rarely change their prices compared to those who flexibly adjust their prices before adoption. However, hosts who rarely change their prices are surprisingly less likely to adopt SP. Chapter 4 builds upon the results of chapter 3 and develops a dynamic structural model to estimate the primitives of the host's pricing and adoption decisions. The ultimate goal is to run counterfactual analyses and quantify the impacts of SP on hosts and the platform, and to understand how the platform can improve the outcomes of the SP deployment. The estimation results identify a gap between the actual performance of the SP algorithm and the host's prior belief about it. Specifically, hosts with a pessimistic prior belief about SP think they will need to manually correct algorithmic prices if they adopt SP, and this belief is disproportionately stronger for hosts with higher adjustment costs, making SP adoption less attractive to them. The counterfactual simulations indicate that the introduction of SP has had a small positive impact on the average host profit and the total platform revenue. But this boost can be significantly raised if Airbnb educates hosts to correct their beliefs about the SP algorithm. The counterfactual analyses also demonstrate that, since the platform does not fully capture the host's private marginal cost in training the algorithm, using the estimated marginal costs from the structural estimation to re-train the algorithm can significantly increase the profitability of SP for both the average host and the platform.

Advisor: Mehta, Nitin
Soberman, David
Doctors' Efforts to Reform Medical Practice in England for Climate Change Mitigation: Insights for Implementing Medical Education and Training Reforms

In this study, I explore how the ideas and experiences of doctors who have attempted to reform medical practice in England for climate change mitigation can enhance the implementation of similar reforms in medical education and training. I draw upon theories of climate justice, the social responsibility of medicine, critical reflective practice, and learning as a socio-cultural process to frame and investigate the research problem. I draw upon the critical-interpretive paradigm and the methodological recommendations of the phronetic social science framework to design the study. Applying these ideas, I conducted an interview study with 18 English doctors representing diverse clinical specialties, official designations, career stages, and social backgrounds. I documented how these doctors conceptualized reform problems and solutions, and attempted to enact change between 2006 and 2020. I also inquired into what enabling conditions and barriers they encountered in the process, and how they regard the consequences of their efforts, and envision future action. I then analyzed how their reflections and insights can improve the implementation of ongoing efforts to reform medical education and training in England to address climate change mitigation. My analysis shows that doctors’ efforts to reform professional practice can be adapted and applied to reform medical education and training in a variety of ways. Significant among these are: exercising/leveraging formal authority and leadership to drive top-down change, seeking new job roles to work on climate change mitigation, securing sustained sources of funds for reforms, building alliances in and outside the health system, creating networks for collaboration, generating new socio-environmentally informed ways of conceptualizing and practicing illness prevention and healthcare, and pursuing professional learning to develop additional capabilities to enact change. The scaling-up and wider application of reform initiatives such as these can have significant impacts in mitigating the threats and harms of climate change in England. They can inspire similar action in health systems in other global contexts as well.

Keywords: Climate Change
Education Reform
Medical Education
Professional Education
Reflective Practice
Socio-Cultural Theories of Learning
Advisor: Niyozov, Sarfaroz
Pharmacological and Structural Characterization of Zinc Finger Ubiquitin-Binding Domain Proteins

Drug discovery is expensive, not only in terms of total cost but also in time. Approval of novel compounds for therapeutic use is rare, often due to poor translation of pre-clinical findings to clinical efficacy. Focus on pre-clinical target selection and validation with high-quality chemical tools can enable better functional understanding of the biology of drug targets and result in higher quality drug-like molecules, saving time and money. Humans have many proteins involved in cell regulation through the ubiquitin proteasome and autophagy lysosomal pathway, where dysregulation is often associated with disease. A subset of these proteins have non-catalytic zinc finger ubiquitin-binding domain (ZnF-UBD), a unique fold that primarily binds ubiquitin or ubiquitinated substrates for various roles in maintaining cellular homeostasis. Drug discovery efforts have focused on developing catalytic inhibitors, with limited success. There is a lack of chemical tools to understand the biology and role of the non-catalytic ZnF-UBDs, and the potential to exploit these domains as a therapeutic strategy has been underexplored. I hypothesize it is possible to develop potent, selective, and cell-active chemical tool compounds for the ZnF-UBD of HDAC6 and USP5, two proteins implicated in several pathologies; this thesis focuses on developing chemical tools against the ZnF-UBD of HDAC6 and USP5, and to explore the structural dynamics of the USP5 ZnF-UBD to expand the field of ZnF-UBD biology. To address this objective, I used a combination of computational, biophysical, and structure-based approaches. I characterized a chemical series to identify the first chemical probe, SGC-UBD253, that specifically targets the HDAC6 ZnF-UBD. Next, I discovered, characterized, and optimized a chemical series of compounds that potently and specifically target the USP5 ZnF-UBD, and inhibit USP5 activity. I show that targeting the USP5 ZnF-UBD is a novel and promising strategy for USP5 inhibition. Finally, I examined the structural dynamics of USP5 and the ZnF-UBD to demonstrate there are different conformations of the protein, and ZnF-UBD dynamics may play a role in ubiquitin binding to influence cleavage of ubiquitin substrates. Taken together, these findings provide the tools for further research into the roles of ZnF-UBD proteins in health and disease.

Advisor: Schapira, Matthieu
Traumatic Brain Injury: Sex and Gender Considerations Relevant to Rehabilitation

Traumatic brain injury (TBI) is a global cause of disability. Effects of TBI include cognitive, physical, and psychosocial disabilities. Although sex and gender considerations in research are considered important for good science, there is limited information on the extent to which sex and gender effects in TBI are recognized in rehabilitation. Further, the extent to which an educational tool targeted at persons with TBI and caregivers, can serve to improve knowledge, attitude, and skill on the topic for future integration within clinical practice has not been explored. Information is further lacking on differences in sex- and gender-based needs for men and women in the community specifically while transitioning to work and during the COVID-19 pandemic. As such, this thesis aimed to address these knowledge gaps by (1) understanding clinicians’ perspectives on the clinical impact of sex and gender in TBI rehabilitation, (2) exploring the effectiveness of education on sex and gender impacts in TBI for persons with TBI and caregivers, and (3) investigating differences in support service and workplace accommodation needs of men and women with TBI for transitioning into the community. The added impact of COVID-19 on employment status and mental health was also explored. The thesis was based on three studies. The first study, a qualitative descriptive design with semi-structured interviews with diverse rehabilitation clinicians highlighted limited attention on sex and gender topics in TBI rehabilitation and a need for resources that consider psychosocial factors. Results from the second study, a pilot pre-test/post-test randomized control-group trial revealed the potential for education to improve knowledge, attitudes, and skills on sex and gender effects in TBI, furthering the need for tools to help persons with TBI and caregivers address daily barriers post-injury. Finally results from the third study, an observational cross-sectional survey, demonstrated differences between men and women with TBI in transitioning to work and because of the pandemic, based on respective gender roles and behaviours. Findings from each study furthered the knowledge base on sex and gender considerations in TBI rehabilitation, with future attentions needed on developing sex- and gender-sensitive tools for clinical and non-clinical benefits.

Keywords: biological sex
education
gender role
rehabilitation
traumatic brain injury
work
Advisor: Colantonio, Angela
Lindsay, Sally
Tracking the Continuity of the Leviticus Laws of Genital Fluids in the Dead Sea Scrolls and Rabbinic Literature

This comparative study explores Leviticus’ rules on the impurity caused by genital fluxes as attested in the Dead Sea Scrolls and rabbinic literature to shed light on the state of halakhah in the pre-rabbinic stage. Using the five impurity categories of genital fluxes outlined in Lev 15 and 12, this study demonstrates the Dead Sea Scrolls' relevance as a textual product of the Second Temple period for tracking the antiquity of some rabbinic halakhic rulings. As a starting point, an analysis of the biblical exposition of each impurity category is undertaken, noting hermeneutical, textual, and text-critical difficulties in the text but selectively limiting the detailed examination to problems that have implications in the attestation of these rules in the Dead Sea Scrolls or other Second Temple period texts in comparison with their attestation in the rabbinic literature. The study pays particular attention to variant readings found in ancient translations (the LXX and the Targumim) and the Samaritan Pentateuch, and to cases of word choices in the DSS and other Second Temple period texts. It contends that these variants and word-choices are hermeneutically pertinent to our understanding of the state of halakhah in the Second Temple period when verified by their conformity with a particular position on a halakhic issue for which rabbinic opinions diverge. The investigation leads to the conclusion that difficulties in the biblical text are responsible for many divergences or innovations in later attestations of the biblical rules, and that many rabbinic rulings can be linked to the innovations or polemical texts in the Dead Sea Scrolls or to variant readings in ancient translations or versions of the Hebrew Bible. This study stands out from other comparative approaches to the DSS and rabbinic texts which tend to have broader perspectives by narrowing down the scope of the investigation to one type of impurity to demonstrate from that standpoint how a textual, text-critical, and hermeneutical analysis of the Dead Sea Scrolls texts can yield valuable pieces of evidence on the state of halakha in the Second Temple period, and thus shed light on the trajectory of halakhic development.

Keywords: Dead Sea Scrolls
Hebrew Bible
Jewish Law
Rabbinic Texts
Second Temple Period
Advisor: Meacham, Tirzah
Metso, Sarianna