VictorJuiz/thesis huggingface dataset:
The Mechanisms of Genome Entry in Bacteriophage HK97

The process of entry of the bacteriophage genome into host cells is poorly understood. In this thesis, I used bacteriophage HK97 as a model to investigate the mechanisms of entry. Phage genome entry begins with adsorption of HK97 to the outer membrane receptor, LamB. Next, the phage DNA passes from the phage capsid through the barrier of the cell envelope to reach the cytoplasm where it can be replicated. The mechanism behind the transfer of the DNA is unknown, though it involves interactions between host and phage components. Using host gene knockout mutants, I searched for proteins involved in entry of bacteriophage HK97 and identified required proteins found within the host cell envelope, FkpA and PtsG. These proteins are not required by all phages including some with a high degree of sequence identity compared to phage HK97. I also found a phage HK97 protein, gp15, whose expression was able to block entry of the same phages that required both PtsG and FkpA. Changes in the requirement of a phage for either FkpA and PtsG for entry and the sensitivity of a phage to gp15 correlated with sequence divergence in one particular phage protein, the tape measure protein (TMP). I illustrated that TMP sequence is responsible for dictating the requirements for FkpA and PtsG as well as the sensitivity to gp15 by exchanging TMPs between phages. The requirement for PtsG and the sensitivity to gp15 were mapped to residues between 452-600 within the HK97 TMP. PtsG mediates entry of the HK97 genome through a direct interaction with these residues within the TMP, and gp15 blocks entry by trapping the PtsG TMP complexes to prevent the formation of the structure that mediates entry.

Keywords: bacteriophage
FkpA
genome entry
PtsG
superinfection exclusion
tape measure protein
Advisor: Davidson, Alan R
Applications Of The Signed Distance Function To Surface Geometry

In studying the geometry of a submanifold, it is often convenient to represent the submanifold as the zero set of an appropriately chosen defining function. For a hypersurface, a natural function to consider is its signed distance function. In this thesis we study the differential geometry of surfaces embedded in Euclidean 3-space by expressing the curvatures and principal directions of a surface in terms of the derivatives of its signed distance function. This allows us to derive many established and new results using simple multivariable calculus. After first defining the signed distance function to a surface and demonstrating its basic properties, we prove several integral formulas involving the surface's principal curvatures, including a generalization of the divergence theorem. We then derive a complex linear differential equation in the principal radii and directions of the surface that is based on the Mainardi-Codazzi equations, and establish a connection between the function in this equation and the surface's support function. These are used to obtain a characterization of the principal directions around an umbilical point on a surface, and to reduce the Loewner index conjecture for real analytic surfaces to a problem about the location of the roots of a specific class of polynomials. Finally, we extend our generalized divergence theorem to submanifolds of arbitrary co-dimension equipped with a Riemannian metric.

Keywords: 30C15
53A05
53B20
Differential Geometry
Surfaces in Euclidean Space
Advisor: McCann, Robert
Elucidation of the Plasmacytoid Dendritic Cell Response to HIV-1

Plasmacytoid dendritic cells (pDCs) are a specialized type I interferon (TI-IFN) producing cell of the innate immune system; they are critical in the control of HIV-1 infection. pDCs isolated from the blood during HIV-1 infection demonstrate profound dysfunction in their ability to produce the prototypic TI-IFN, IFN-α. In this thesis, I explore the factors that lead to pDC dysfunction during HIV-1 infection. Tim-3 (CD366), typically associated with activated T cells and of current interest as a target for immunotherapy, was identified on pDCs and shown to be upregulated during HIV-1 infection. Tim-3 expression in HIV-1 infection correlated with pDC dysfunction. Similarly, in healthy donors, Tim-3 expression was PI3K-dependent and induced in response to both TLR activation and in response to IFN-directly. Strong toll-like receptor (TLR) agonists, such as CpG, imiquimod and Sendai virus were potent inducers of Tim-3, leading to subsequent dysfunction. The mechanism of action of Tim-3 was also explored. Anti-Tim-3 antibodies did not affect pDC function. However, surface Tim-3 associated with submembrane disruption of TLR after activation. Tim-3 staining intensity inversely correlated with decreased IRF7 staining and intracellular Tim-3 co-localized with p85 and IRF7 within LAMP1+ lysosomes. Most surprisingly, we found that HIV-1 itself was a poor inducer of Tim-3 expression. Thus, we investigated the agonistic capacity of HIV-1 on pDCs. When the amount of TLR7 triggering viral RNA was taken into consideration, influenza virus was a vastly superior pDC agonist. Efficient uptake of HIV-1 was observed, but failed to initiate a response, however, if a second agonist was added to the culture, HIV-1 augmented that response in a TLR7 dependent manner. Thus, we investigated the possibility of HIV-1 structural proteins in the evasion of the pDC response. We found that chemical agents that target the zinc-finger nuclease region of the nucleocapsid increased IFN-α production in response to HIV-1 stimulation. Thus, I propose a putative model of pDC dysfunction during HIV-1 infection where HIV-1 is endocytosed and remains dormant within the pDC endosome with the capacity to augment the response to secondary pathogens leading to disproportionate responses and Tim-3 upregulation.

Keywords: HIV
Interferon
Plasmacytoid Dendritic Cell
Tim-3
Advisor: Ostrowski, Mario A
Addressing Uncertainties in Health Utilities

Uncertainties in health utilities have received little attention in the literature. Health utility is a preference-based quality of life measure. It is commonly used to calculate quality-adjusted life years and to conduct cost-utility analysis. Under-estimation of the uncertainty of health utilities will lead to under-estimation of the uncertainty of the results of any economic evaluation that requires the use of health utilities. This thesis focuses on addressing uncertainty in health utilities in three areas: (1) the underestimation of uncertainties of health utilities derived from mapping algorithms and the derivation of methods to address it, (2) the challenge with prediction error in multi-attribute utility instrument valuation studies with small sample size and an emphasis of the use of shrinkage estimators as a potential solution, and (3) the underestimation of uncertainties of health utilities derived from multi-attribute utility instruments with an emphasis of the use of multiple imputation as a potential solution. For each issue, theoretical statistical explanations are provided and then followed by the proposed methods to address those issues. Simulation methods are also used to explore the usefulness of the proposed methods.

Keywords: Empirical Bayes
Health Utilities
Mapping Algorithms
Multiple Imputation
Shrikage Estimator
Uncertainties
Advisor: Pullenayegum, Eleanor M
Willan, Andrew R
Functional Analysis of Novel Prognostic Markers of Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Global expression profiling of patient tumours has identified hundreds of genes controlling NSCLC progression and patient survival. Our laboratory previously identified a robust 15-gene prognostic signature predictive of NSCLC patient outcome. We hypothesized that these genes may contribute to malignant progression of lung cancer. This thesis probes the functions of three signature genes as a means to classify their expression changes as causal or responsive to NSCLC. In the first study, the signature gene L1CAM was found to promote both NSCLC metastasis and cell migration and invasion. This was supported by in silico analyses, which showed that L1CAM expression is consistently an independent prognostic factor in multiple large cohorts of NSCLC patients. The second study identified the signature gene TRIM14 as a putative NSCLC tumour suppressor. Loss of TRIM14 function increased in vitro proliferation and in vivo tumorigenicity of NSCLC cell lines. To exert its function, TRIM14 interacts with apoptosis-inducing factor possibly regulating its stability. The third study explored the efficacy of molecularly targeting prognostic biomarkers such as the signature gene MDM2 in primary tumour xenograft models of NSCLC. MDM2 inhibitors were found to effectively inhibit NSCLC tumour growth by activating the p53 tumour suppressor pathway and cell cycle arrest, confirming a role for MDM2 in the oncogenesis of NSCLC. Overall, these results demonstrate that prognostic gene signatures constructed using genomics approaches are a powerful tool to uncover genes having critical roles in lung cancer progression.

Keywords: lung cancer
Non-small cell lung cancer
Advisor: Tsao, Ming S
Factors Affecting Safety Performance of Construction Workers: Safety Climate, Interpersonal Conflicts at Work, and Resilience

A safety plateau in safety performance has been observed in many countries or regions. In order to continuously improve safety performance, the key is to identifying factors affecting safety performance. This research examined four factors, namely, safety climate, individual resilience (IR), interpersonal conflicts at work (ICW), and organizational resilience (OR) that may contribute to explaining safety outcomes. A self-administered survey was used. From 2013 to 2016, 1281 surveys were collected from 180 construction sites of Ontario, Canada. This thesis composed three papers, which leads to the following conclusions: • Safety climate not only affects physical safety outcomes but also employees’ job stress level. • ICW is a risk factor for safety performance. • IR has the potential to mitigate post-trauma job stress and interpersonal conflicts of construction workers. • Management commitment is the key to promoting a good safety culture. • Safety awareness is the most important individual factor affecting construction workers’ safety performance. • Team support, especially the support from coworkers, has a significant positive impact on construction worker’s safety awareness. Several original contributions were made: • This study designed and tested questions of individual resilience. • This study is the first empirical study investigating the impact of individual resilience on safety outcomes. • This study is the first study testing the antecedents of interpersonal conflicts at work and the resulting safety outcomes in the construction industry. • This study designed and tested organizational resilience questions in the context of construction industry. • This is the first study testing the mechanism about how the resilience factors interact with each other and eventually affect safety outcomes. • This study is the first study using structural equation modeling (SEM) to quantify organizational resilience. Accordingly, the following recommendations were provided: • Construction organizations need to not only monitor employees’ safety performance but also their psychological well-being. • Safety professionals may consider adding coping skill training programs to improve the individual resilience of their workforce and reduce conflict-related safety outcomes. • Construction organizations can improve employees’ safety awareness by promoting a good team-level safety culture, and by building a good reporting and learning culture.

Keywords: conflicts at work
individual resilience
organizational resilience
safety climate
Advisor: McCabe, Brenda Y.
Essays on Macroeconomic Development

Agricultural productivity is important for understanding international income differences. The international labor productivity differences are much larger in agriculture than in non-agriculture. Moreover, poor countries have higher agricultural employment shares. Therefore, my thesis studies why cross-country labor productivity differences are much larger in agriculture. In the first chapter, I argue that the prevalence of untitled land in poor countries lowers their agricultural productivity. Since untitled land cannot be traded across farmers, it creates land misallocation and distorts individuals' occupational choice between farming and working outside agriculture. I build a model to quantify the impact of untitled land. I find that economies with higher percentages of untitled land would have lower agricultural productivity; land titling can increase agricultural productivity by up to 82.5%. The second chapter studies agricultural productivity through technology adoption. Cross-country differences in capital intensity are larger in agriculture than in non-agriculture, reflecting differences in agricultural technology adoption. I build a model featuring technology adoption in agriculture. As the economy develops, farmers gradually replace the traditional technology with a modern technology which has higher capital intensity and higher productivity, as is observed in the U.S. historical data. For countries at different stages of development, my model can explain 1.56-fold more of agricultural productivity differences compared to a model without technology adoption. I further show that land misallocation in agriculture impedes technology adoption and magnify productivity differences. The third chapter, co-authored with Diego Restuccia and Raul Santaeulalia-Llopis, uses detailed household-level micro data from Ethiopia to study factor misallocation and its impact on agricultural productivity. We find substantial factor misallocation across farmers in agriculture. An efficient reallocation of resources can increase aggregate agricultural output and productivity by 127 percent. Land rentals substantially improve resource allocation, with market-based rentals much more effective in reducing misallocation. Exploiting regional variation in land rentals resulting from the implementation of a land certification reform, we find that more land rentals are associated with lower misallocation and higher agricultural productivity: a one percentage point higher land rental is associated with a 0.8 percentage points higher agricultural productivity.

Advisor: Restuccia, Diego
Integrated Functional and Genomic Analysis of High-Grade Serous Ovarian Cancer

Epithelial ovarian cancer is the fifth-leading cause of cancer-related death for women in North America and is responsible for over 100 000 deaths/year worldwide (Ferlay et al., 2015). High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype and the vast majority of women are diagnosed with advanced stage disease (Bowtell, 2010). The current standard treatment is aggressive surgery combined with adjuvant and/or neo-adjuvant platinum/taxane-based chemotherapy. Despite initial efficacy of standard therapy, resistant cancer recurs and 70% of patients die within 5 years after initial diagnosis (Bast et al., 2009). Further understanding of the molecular and cellular features that promote HGSC progression may assist in identifying new opportunities for therapeutic intervention and ultimately improve the prognosis of women with HGSC. My research has generated an extensive functional and genomic characterization of serous ovarian cancer cell lines and provides a framework for identifying vulnerabilities associated with distinct molecular features. Using this dataset, I have focused on the identification of genes encoding for highly expressed cell surface molecules. I have identified a novel role of the tetraspanin CD151 in serous ovarian cancer. I have found that CD151 depletion impairs survival, proliferation and tumor growth in murine models of a subset of HGSC cell lines. In search of the mechanism underlying CD151-dependency, I have uncovered a novel association for CD151-dependency in cancer cells with mesenchymal features. In particular, high ZEB1 and ZEB2 expression is tightly coupled with CD151-dependency and thus, may be used as biomarkers for stratifying tumors requiring CD151 for growth. Moreover, CD151-binding antibodies block the migratory capacity of CD151-dependent cells, thereby implicating CD151 in metastasis and dissemination of HGSC tumors. These studies provide a resource of characterized HGSC cell lines and suggest that CD151 may be a biological target in HGSC tumors.

Keywords: cancer
CD151
genomics
high-grade
ovarian
rna interference
Advisor: Rottapel, Robert
Influence of Hydrodynamic Events on Circulation and Thermal Habitat in Coastal Embayments of the Great Lakes

Coastal embayments act as the main interface between urban and agricultural run-off and the waters of the Great Lakes. They make a large contribution to the water quality of the Great Lakes for their size. Given the relentless urbanization occurring in Ontario, it is now critical to understand how water circulation within these confined coastal bays determines the health of the aquatic ecosystem. This research tackles three interconnected aspects of embayment physics and littoral circulation. First, the mechanisms that contribute to the flushing of coastal embayments are assessed. Lake water level fluctuations provide an important role in flushing shallow coastal embayments in the Great Lakes, especially if the embayment has a resonant response. Specifically, long-period waves can excite resonance in coastal embayments, which greatly increases the flushing rates. Three shallow coastal embayments of Lake Ontario and Lake Huron are analyzed and the difference in their responses to similar long-period waves is found to be explained by resonance. Second, water stratification and its effect on the physical processes in coastal embayments is studied. Toronto Harbour, which is taken as a case study, is characterized by considerable thermal variability as a result of diurnal heat fluxes and large amplitude movements of the thermocline of Lake Ontario. During the ice-free period an array of benthic and surface temperature loggers were deployed to obtain the spatio-temporal distribution of water temperatures. Cold intrusions were found to quickly flow from the lake into the harbour and lead to rapid drops in temperature that may be associated with a variety of negative effects on many aquatic organisms. Finally, frequent water level oscillations are shown to drive significant exchange between Toronto Harbour and Lake Ontario. Analysis of water currents, water levels and temperatures is used to determine the hydrodynamic characteristics of the lake-harbour system and demonstrate that strong water level fluctuations with a period of one-hour dominate the exchange flows in the shallow embayments of the harbour, which is in contrast to the conventional wisdom that water circulation in coastal embayments of the Great Lakes is always dominated by baroclinic processes driven by differential heating or upwelling events.

Keywords: Internal waves
Modelling
Physical limnology
Resonance
Surface waves
Thermal habitat
Advisor: Wells, Mathew G
Impacts of Climate Variability and Change on Eastern North Pacific Tropical Cyclones

Damages inflicted by tropical cyclones (TCs) worldwide have increased in recent decades with climate change and variability playing key roles in altering TC characteristics. In this thesis, the impact of natural variability is explored, using ENSO conditions, and climate change on the nature of eastern North Pacific (ENP) TCs. The first research objective of the thesis focused on a spatial-temporal separation of ENP storms based on El Niño-Southern Oscillation (ENSO) phase (temporal variability, El Niño, La Niña, neutral) and regional storm stratification (spatial variability, east and west). The western development region (WDR) storms were found to be more sensitive to influences of ENSO. In particular, during El Niño years, there were more WDR storms. The second research objective explored the ENSO impact on the trajectory of ENP storm tracks by examining the locations for genesis and downgradation points and storm track movements. The storm tracks were strongly influenced by ENSO phases, with significant differences detected for many ENSO pairings. However, when storm data are regionally separated the latitudinal movement of WDR storms tend to be more extensive during El Niño conditions and as a result there are more landfalling TCs. The third research objective of the dissertation explored the importance of near-time sea surface temperatures (SSTs) on storm intensities. SST thresholds were found that were critical for the sustenance of stronger ENP storms that achieve hurricane and major hurricane status. Significantly, the minimum SST threshold varied between the MDR subdivisions. For major hurricanes, the SST requirements for EDR and WDR are substantially lower than that found in the North Atlantic basin at 28.25°C. Although SSTs appear to contribute little in determining the ultimate maximum storm intensity for ENP storms in general, when ENP storms are regionally divided, SSTs are found to be highly associated with the WDR major hurricanes. Evidently the recent warming shown in the distribution of storm-bounded SSTs has led to the rise of maximum potential intensity for ENP storms. Overall, the common theme that emerged from these three studies is that ENP storm characteristics associated with WDR are inherently more sensitive to climate variability and change.

Keywords: eastern North Pacific basin
El-Nino Southern Oscillation
sea surface temperature
tropical cyclone
western development region
Advisor: Gough, William A
The Effect of Operational Control Quality on Operational Efficiency and Cost of Capital: Evidence from U.S. Bank Holding Companies

Recent high profile and costly operational risk events have focused the attention of bank managers and regulators on operational risk management practices since the early 2000s. This led the Basel II Accord to recognize operational risk as a separate risk. In this study, I examine whether operational control quality is associated with operational efficiency and the costs of debt and equity capital for a large sample of U.S. bank holding companies. I measure banksâ operational control quality using two measures: (1) the incidence of actual operational risk events as an ex-post observable proxy for weaknesses in operational controls, and (2) an index-based measure of operational risk management quality (ORMQ) as an ex-ante proxy, created via textual analyses of Form 10-K filings. First, I find that operational efficiency, derived from a frontier analysis, is significantly higher among banks with higher operational control quality. Second, I find that banks with stronger operational controls are associated with lower costs of debt and equity capital. These results are incremental to controlling for the quality of the internal control over financial reporting. Furthermore, in the changes analyses, I find that remediating firms exhibit higher operational efficiency and lower cost of capital estimates, while non-remediating banks are associated with no significant change in their operational efficiency estimate but exhibit a significant higher cost of capital. I also examine the net effect of operational control quality on equity valuation and find a positive association between operational control quality and equity prices. In addition, I observe that banks with higher operational control quality exhibit higher earnings persistence. Overall, the findings of this thesis suggest that operational controls have significant effects on banksâ operations and cost of capital, and that the operational risk information in banksâ Form 10-K filings is credible.

Advisor: Mohanram, Partha S.
Richardson, Gordon D.