VictorJuiz/thesis huggingface dataset:
The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer

Photodynamic therapy is a clinically approved cancer therapeutic that uses a photosensitizer, light, and oxygen to produce reactive oxygen species. The accumulation of reactive oxygen species (e.g., singlet oxygen) can induce cancer cell death via oxidative damage, with the intracellular location of a photosensitizer a key determinant governing the outcome of photodynamic therapy. Although photodynamic therapy is inherently targeted due to light irradiation, currently used photosensitizers lack cancer cell selectively, making off-target accumulation and production of reactive oxygen species in the desired tissues problematic. Moreover, the low-energy visible light used to activate the photosensitizer has limited tissue penetration depth, such that the intracellular location of the photosensitizer becomes more crucial. In this thesis, I demonstrate approaches for overcoming these challenges with photodynamic therapy. I first discuss Br-DAPI, a DNA-binding photosensitizer that localizes to the nucleus and induces double-strand DNA breaks upon irradiation. I next describe a dual-targeted photosensitization strategy, where a conjugate containing two photosensitizers (Br-DAPI and WinterGreen) localize to different subcellular organelles, where synergistic photocytotoxicity was achieved. Next, I seek to address the limitations with cancer selectivity and limited light penetration depth. To achieve cancer selectivity, I chemically modified a known photosensitizer, phenalenone, with a quinone substrate of human NAD(P)H:quinone oxidoreductase 1. When attached to the quinone, phenalenone is initially quenched in its ability to produce singlet oxygen, however phenalenone is liberated in the presence of cancer cells containing high levels of the enzyme (i.e., lung cancer cells), resulting in the production of cytotoxic singlet oxygen upon irradiation. To produce reactive oxygen species without the requirement of an external light source, I functionalized a chemiluminescent scaffold (i.e., Schaap’s adamantylidene-dioxetane) with the photosensitizer, Erythosin B, where deprotonation of the reactive phenol (modifiable with an enzyme responsive trigger) resulted in spontaneous chemiluminescent resonance energy transfer to the photosensitizer and production of singlet oxygen in cancer cells. The four projects in this thesis propose proof-of-principle designs to address key limitations with photodynamic therapy. The key molecules discussed demonstrate evidence to improve the efficacy of photodynamic therapy and lay the groundwork for future optimization such that they can be applicable in vivo models.

Keywords: cancer
light
photodynamic therapy
photosensitizer
reactive oxygen species
Advisor: Beharry, Andrew A
Multimodal Investigation of Chrna5 Nicotinic Receptors: Cellular and Synaptic Mechanisms of Cholinergic Modulation in the Prefrontal Cortex

Acetylcholine neurotransmission in the prefrontal cortex is essential for attention and executive function. Its disruption is implicated in multiple neurological disorders with serious cognitive deficits. However, there remain critical knowledge gaps in cellular and synaptic mechanisms of endogenous cholinergic modulation of prefrontal cortex, especially compared to better-characterized sensory cortical regions. In particular, the role of the alpha5 nicotinic receptor subunit encoded by Chrna5, which is expressed in deep-layer neurons in the prefrontal cortex remains unknown. Since Chrna5 is vital for higher-order cognition, it is essential to investigate the synaptic function of alpha5 nicotinic receptors and characterize Chrna5-expressing neurons mediating optimal cholinergic excitation. Here, I examine these questions using a multimodal approach comprising compound transgenics, optogenetics, patch-clamp electrophysiology, two-photon calcium imaging, and transcriptomic analyses in the mouse brain. First, I characterize prefrontal cholinergic signaling in a mouse model with attention deficits caused by genetic ablation of the alpha5 nicotinic subunit. These results identify Chrna5 as necessary for the rapid onset of endogenous cholinergic responses relevant for the fast timescales of attention. Using a nicotinic positive allosteric modulator NS9238, I successfully treat the deficit arising from Chrna5 disruption, restoring rapid onset of cholinergic neurotransmission in alpha5 knockout mice. Next, I probe the identity of Chrna5-expressing (Chrna5+) neurons and molecular determinants of their cholinergic properties. Through multiple approaches in novel Chrna5-Cre transgenic mice, I uncover a distinct population of Chrna5+ neurons with stronger and faster cholinergic responses. With single-cell RNAseq analysis, I identify these cells to be developmentally critical subplate neurons with differential expression of several GPI-anchored Lynx prototoxins. Using optophysiological approaches, I discover complex endogenous modulation of nicotinic receptors by Lynx prototoxins. Overall, this dissertation creates new understanding of prefrontal cholinergic modulation at the synaptic and cellular level. I identify the role of the alpha5 nicotinic subunit in ensuring rapid synaptic cholinergic transmission and preventing desensitization of these nicotinic responses. I discover a specialized subpopulation of Chrna5-expressing neurons with enhanced nicotinic responses that are dynamically regulated by distinct modulatory proteins. Together, my work uncovers molecular and cellular roles of Chrna5 relevant to cognition and identifies novel treatment approaches to restore cholinergic signaling.

Keywords: acetylcholine
electrophysiology
nicotinic receptors
optogenetics
prefrontal cortex
transcriptomics
Advisor: Lambe, Evelyn K
Life Cycle Greenhouse Gas Emissions of Renewable Jet Fuels Produced in Canada

Modern technology has enabled the transformation of renewable biomass and waste into renewable energy for the sectors of our society that use fossil fuels the most. This thesis contributes to knowledge on renewable jet fuels (RJF) and their potential greenhouse gas (GHG) emissions reduction benefits for the aviation sector from a Canadian context. The first part of this thesis quantifies the life cycle GHG emissions of ethanol produced using corn stover, an agricultural residue. Wide ranging results of 7.9 to 45 gCO2e MJ-1 were initially determined from two fuel life cycle assessment (LCA) tools that modelled corn stover ethanol. Harmonization of model parameters and assumptions in the two LCA tools led to similar estimates of 41 – 42 gCO2e MJ-1 although these values obscured substantial differences in GHG emissions at the individual contributor level, which can impact the fuel’s performance under different regulatory regimes. Next, the thesis conducted an LCA on RJF derived from corn stover or ethanol from corn stover. The LCA modelled Ontario and Québec RJF production using these regions’ corn production data. The study determined life cycle GHG emissions of 3.5 – 5.3 gCO2e MJ-1 for the Fischer-Tropsch jet fuel pathway while the ethanol-to-jet fuel pathway resulted in 28 – 36 gCO2e MJ-1 due to greater inputs in the ethanol production process. Québec benefitted from its low carbon intensity electricity but corn stover yields in Ontario were identified as advantageous. The last two parts of the thesis assessed the life cycle GHG emissions of RJF from canola, camelina, and carinata oilseeds. Respectively, GHG emissions from each oilseed-to-RJF are 16 – 58 gCO2e MJ-1, 53 – 72 gCO2e MJ-1, and 43 – 52 gCO2e MJ-1. Canola RJF values varied due to soil carbon effects from land use and land management changes. The range of results for camelina and carinata RJF are due to using input data from many sources and differences in modelling assumptions. A scenario maximizing camelina or carinata RJF production using Canadian marginal lands is estimated to reduce GHG emissions in aviation by up to 2 million tonnes of CO2e emissions per year in 2050.

Keywords: Biofuel
Greenhouse Gas Emissions
LCA
Life Cycle Assessment
Renewable Jet Fuel
Sustainable Aviation Fuel
Advisor: Saville, Bradley A
MacLean, Heather L
Towards Understanding the Behaviour of the External FRP-Reinforced Concrete Structures under Changing Climate Trends

Over the last thirty years or so, extensive research has been carried out on FRP sheets and concrete structures retrofitted with external FRP sheets under various loading and environmental conditions. Despite the excellent performance of FRPs in improving strength and ductility of structures under different conditions, information on the behaviour of FRPs under changing climatic trends including the global rise in temperature and increased number of freeze-thaw cycles etc. is not clearly understood. This study was undertaken to address this gap. In this study, over 200 specimens of FRP materials and FRP strengthened structures were tested under different temperature protocols. The test plan included FRP sheet coupons, FRP-FRP bond specimens, FRP-concrete bond specimens, FRP wrapped concrete cylinders, and FRP-strengthened reinforced concrete (RC) beams. Two main variables in this study were; the type of FRP (carbon FRP (CFRP) and glass FRP (GFRP)) and the temperature protocol; 1) sustained temperature (ST), 2) sustained deformation with increasing temperature (SD), 3) sustained load with increasing temperature (SL), and 4) freeze-thaw (FT) cycles. The exposure to elevated temperatures showed a sharp decrease in the mechanical properties of the FRP around the glass transition temperature (Tg) of epoxy. In contrast, freeze-thaw cycling showed a negligible impact on the FRP sheet behaviour. The results of FRP-FRP and FRP-concrete bond specimens investigated at sustained elevated temperatures and under sustained load protocols also showed reductions in the bond strength beyond the glass transition temperature. FRP wrapped concrete cylinders tested under room conditions showed remarkable improvements in strength and ductility of concrete. These gains were reduced severely at sustained elevated temperatures beyond the Tg. Again, the freeze-thaw cycles showed minimal effect on strength and ductility enhancements provided by the wraps. Results from the thermal study on shear-critical RC beams suggest that anchored FRP wraps can significantly improve the shear capacity of the beams at room temperature but that will reduce at a temperature of 60oC. In the analytical part of this study, models were developed to estimate the temperature reduction factors for FRP materials and FRP strengthened concrete members subjected to various temperature conditions.

Keywords: Climate Change
FRP
FRP sheet coupons
FRP wrapped members
FRP-concrete bond specimens
FRP-FRP bond specimens
Advisor: Sheikh, Shamim Ahmed
Fixed Target Sample Delivery for Serial Crystallography and Ultrafast Study of Bismuth by Electron Diffraction

This thesis reports on developing a fixed target sample delivery system utilized in X-ray crystallography and the ultrafast study of lattice dynamics in bismuth crystals upon photoexcitation by ultrafast electron diffraction (UED). The advent of novel ultrabright X-ray sources, such as the X-ray free electron laser (XFEL), necessitated the development of a platform for rapid and reliable delivery of protein crystals employed in the scheme known as serial femtosecond crystallography (SFX). The development of a micropatterned silicon-based crystallography chip constructed by nano-fabrication methods combined with spectroscopic mapping is outlined in the scope of this thesis. The crystallography chip capable of trapping more than 25000 crystals with the help of spectroscopic mapping more effectively exploits the expensive XFEL beam time by providing a significant improvement of the X-ray hit rate. This fixed target method enables the study of proteins with more demanding conditions by minimizing the sample consumption and reducing the stress-induced damage due to crystal handling. The application of the crystallography chip for resolving the structure of carboxy myoglobin, along with the further implementation of the crystallography chip in synchrotron light sources, is discussed. Besides developing a platform for serial crystallography, the ultrafast dynamics of bismuth crystal upon laser excitation are investigated in the second part of this thesis. It has been shown that by laser excitation of the bismuth crystal's valence electrons above 2.5 percent, a significant atomic movement in the diagonal axis of the crystal's unit cell is initiated due to a Peierl distortion reversal. The increased electronic temperature alters the electronic energy surface, enabling large amplitude movement of the atoms up to 40 picometers. This significant atomic displacement leads to the rise of anisotropic disorder in (-110) crystallographic direction, plus entering the lattice into a more symmetric state. Furthermore, the role of strong phonon-phonon interaction in the emergence of this disorder and the distribution of the energy in the lattice is investigated. Finally, the use of the fast collapse of (-110) diffraction peaks for pump and probe arrival time determination is described. The implementation of a silicon nitride chip to facilitate rapid data collection in an irreversible regime for the application of time zero determination is extensively discussed.

Keywords: fixed target
protein crystallography
sample delivery system
Serial Crystallography
ultrafast electron diffraction
X-ray Diffraction
Advisor: Miller, R.J.Dwayne DM
Navigating Academic Leadership Hierarchy: Exploring Black Male Faculty Members’ Advancement to Senior-Level Leadership Positions in Ontario Universities

The purpose of this study was to explore how Black male faculty members navigated the academic leadership hierarchy to attain senior-level leadership in Ontario universities. The literature highlighted the underrepresentation of Black male faculty members in senior-level leadership, the product of racial inequities and discrimination despite institutional commitments to equity in Canadian universities. Critical race theory (CRT) underpinned this study and acted as a vehicle to understand the impact of racism, anti-Black racism and oppression on Black men who aspired to leadership positions in academia. Inevitably, this study documented ways to disrupt and dismantle systemic racism that impeded the advancement opportunities of Black male faculty members in senior-level leadership in academia. Interviews with 11 Black male faculty members in senior-level leadership revealed that Black men experience major barriers/challenges in academia but were able to successfully advance into senior-level leadership because of numerous navigating strategies they employed.

Keywords: Anti-Black Racism
Black male faculty
Black men
Critical Race Theory
Navigating Leadership
Racialized faculty
Advisor: Ryan, James
Robust, pH-responsive Hydrogels as Actuators for Small-scale Medical Devices

Miniaturization of medical devices as minimally invasive tools for disease diagnosis and treatment can lead to improved patient experience and outcomes. However, its size limits the available power to drive onboard systems and wireless power transfer via electromagnets is challenging due to scaling effects and range dependency. Chemical reactions have been used as onboard power. However, this method can generate undesired waste products in the human body. There is a need for actuators that use minimal power with minimal waste generation to impart functionality in miniature medical devices. The proposed project is to develop pH-responsive hydrogels and combine them with magnets for a novel hybrid hydrogel magnet actuator. The environmentally responsive hydrogels will add functionality without additional power and minimal volume uptake. The magnets will enable a fast mechanism response. In this work, a pH-responsive hydrogel that swelled in basic pH was developed, used in a hybrid hydrogel magnet actuator, and applied to an automatic fluid sampling capsule. An analytical model was also formulated to predict the hydrogel forces and swelling for actuator design.

Keywords: Hydrogel actuators
Magnetics
Mechanism design
Microrobotics
Physical intelligence
Wireless capsules
Advisor: Diller, Eric
Mitigating Greenwashing Concerns in the Green Bond Market

This dissertation examines whether the issuers of high-quality green bonds differentiate themselves by bonding with two reputable organizations that impose high green bond transparency standards -- the Climate Bonds Initiative (CBI) and the Luxembourg Green Exchange (LGX), and whether the bonding mechanism effectively mitigates investors' greenwashing concerns. I document evidence that is consistent with a separating equilibrium. Specifically, I find that the bonding issuers (i.e., issuers that obtain CBI certifications for their green bonds or list their green bonds on LGX) demonstrate higher post-issuance transparency and a larger reduction in carbon emissions while also receiving a larger green premium than the non-bonding issuers. Further analyses document differences between the CBI and LGX regimes. The CBI regime, which requires certification against a green taxonomy but allows for private communication, is more effective at screening issuers that achieve larger carbon reduction, whereas the LGX regime, which accepts broad categories of green projects but requires public disclosure on a centralized platform, is more effective at screening issuers that provide higher post-issuance transparency. Interestingly, only the LGX-listed green bonds receive a significant green premium. Moreover, green premium is more concentrated in the LGX-listed green bonds with high ex-ante transparency commitment. Furthermore, in the secondary market, green bonds from issuers that end up providing high post-issuance transparency tend to have higher liquidity. The CBI-certified or LGX-listed green bonds with high post-issuance transparency tend to have even larger liquidity benefits. Taken together, consistent with prior survey evidence in Chiang (2017) and Sangiorgi and Schopohl (2021), the findings in this dissertation corroborate that high post-issuance transparency may effectively mitigate investors’ greenwashing concerns, facilitate low-cost environmental financing, and bolster market liquidity.

Keywords: ESG transparency and accountability
green bond standard
green finance
Advisor: Callen, Jeffery
Lu, Hai
Three Essays on The Economics of Video Games Platforms

Digital platforms distributing software products, such as the App Store, Google Play, and Steam, comprise a vital role in the digital economy. They facilitate the exchange of digital goods and services between firms and consumers and are the central marketplaces in the software industry. Nevertheless, the dynamic effect of platform design on firms and consumers remains under-investigated. This work examines the role of digital platforms, specifically video game platforms, on firm decisions and consumer behaviors from a dynamic perspective. In the first chapter, I investigate how platform commission changes affect software developers’ innovation efforts and their consequences on platform revenue. Using a unique dataset of video games in the Early Access Program on Steam, I study how commission schemes can change both the product update decisions and the release decision to Steam's main Store of developers. In the counterfactual analysis, I further examine the impact of varying platform commission rates on product development decisions and find that lowering commissions can lead to more updates, but developers are over-investing in Early Access. This chapter is based on my job market paper with Avi Goldfarb and Nitin Mehta. The second chapter, a collaborative work with Daniel Goetz, examines the peer effect of the product adoption decisions of friends and strangers on consumers' purchase behavior. Using data on microtransactions in an online gaming app, I show that the marginal effect of friends' product adoptions is roughly twice as large as the marginal effect of strangers' product adoptions but that the two types of peer effects are substitutes. An estimated network diffusion model implies that peer effects from strangers alone can account for 69% of the total lift in product adoptions from social interactions. The third chapter studies the peak-end effect of consumer behavior on online software product usage. I examine this question empirically using data from two popular free-to-play online games and document three facts about user behavior: app usage (games played) clusters temporally in sessions, negative outcomes tend to prolong sessions, and positive outcomes at the end of a session decrease time to the next session. This chapter is also a joint work with Dan.

Advisor: Goldfarb, Avi
Treatment Response Biomarkers of Accelerated Low Frequency Repetitive Transcranial Magnetic Stimulation in Major Depressive Disorder

AbstractRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive form of brain stimulation for the treatment of major depressive disorder (MDD). One substantial knowledge gap with rTMS is that clinically applicable treatment response biomarkers of rTMS in MDD remain elusive. This thesis contains three studies that are based on the data from two open-labeled clinical trials, and these studies aim to address the need for biomarkers by providing preliminary evidence on the utilization of electrocardiography (ECG) and electroencephalography (EEG) parameters as treatment response biomarkers of accelerated low frequency (LF) right hemisphere (R) dorsolateral prefrontal cortex (DLPFC) rTMS in MDD. The first (n=19) study aims to investigate the effect of accelerated 1Hz R-DLPFC rTMS on heart rate (HR) and heart rate variability (HRV), as well as the association between HR and HRV with treatment outcome. In this first study, HR significantly decreased during the rTMS period. Resting HR, HR during the rTMS period, and the degree of rTMS-induced HR reduction were all significantly negatively associated with treatment outcome prior to Bonferroni correction; Resting HR remained significantly associated with treatment outcome post Bonferroni correction. Furthermore, the second study (n = 24) aims to validate the results of the first study using data from a separate clinical trial. For this second study, HR also significantly decreased during the rTMS period prior to Bonferroni correction. Resting HR, HR during rTMS, and the degree of HR reduction were not significantly associated with treatment outcome; however, the trend of association remained the same as that of the first study. Lastly, the third study aims to investigate the association between baseline TMS evoked potential (TEP) N100 amplitude and 1Hz R-DLPFC arTMS treatment outcome. For this third study, baseline N100 amplitude was significantly associated with treatment outcome. The change in N100 amplitude from baseline to follow-up was significantly associated with treatment outcome prior to Bonferroni correction. In conclusion, the collective result of these three studies is generally in agreement with previous studies and provide additional preliminary evidence for future studies of larger sample sizes to further investigate the biomarker potential of ECG and EEG parameters.

Advisor: Downar, Jonathan