VictorJuiz/thesis huggingface dataset:
Boron Subnaphthalocyanines: The First Unsubstituted Examples, New Boron Lewis Acids, Random Bay Position Halogenation, and Computational Material Screening

Boron subnaphthalocyanines (BsubNcs) are a class of materials that our lab has shown to be alloyed mixtures of derivatives that are randomly chlorinated in the bay positions, resulting from their formation from boron trichloride. These alloyed mixtures were shown to have a positive influence on the functionality of organic photovoltaics whereby an increase in the amount of bay position chlorination was found to increase power conversion efficiency. The bay position chlorinated BsubNcs were also found to be stable in the ambient environment within organic solar cells which also justified their further development. The alloying of these materials leads to a potentially unique opportunity to tailor the alloyed mixture for a desired application by blending pure or partially separated samples of BsubNcs. Herein we lay the groundwork for achieving this goal. We explore the separation of bay position halogenated (chlorinated and brominated) BsubNcs enabled by their functionalization with phenolic axial moieties. We develop an understanding of the dependence of their physical properties on the frequency of bay position halogenation and developed improved analytical techniques for this class of materials. We also present a new method for the synthesis of BsubNcs that circumvents the generation of bay position halogenated species, resulting in the first examples of pure unsubstituted BsubNcs. To achieve this, we proposed that a non-halide boron based Lewis acid is required, and that a balance of the Lewis acidity of the boron source and the Lewis basicity of the BsubNc precursor can guide the synthesis of BsubNcs. After achieving this desired outcome, we also explored the application of this method for the synthesis of the related boron subphthalocyanines (BsubPcs) and as the macrocycles were formed, we found potential for the broad application of this methodology. A computationally calibrated model to screen key material properties of BsubPcs for their accelerated development was also developed. We uniquely found a method that can achieve this with a standard laptop and software that is free to academia. We anticipate that incorporation of BsubNcs into the model will be possible as the key material properties have been determined for BsubNcs developed in this thesis.

Keywords: Borate
Boron
Boron Subnaphthalocyanine
Macrocycle
Materials Chemistry
Organic Electronics
Advisor: Bender, Timothy P
Quantifying Placental Function Using Cardiovascular Magnetic Resonance Imaging

This thesis presents the development of cardiovascular MRI methods for assessing placental oxygen exchange using a combination of human and sheep studies. An “inputs and outputs” approach was designed based on MRI measurements of blood flow and oxygen content to determine oxygen transport in the major placental vessels, which has previously only been possible using invasive techniques not suitable for human studies. The basis of the methodology relies on MRI blood oximetry, which uses magnetic properties of blood (T2) to derive oxygen saturation (SO2). MRI oximetry was validated in pregnant sheep, confirming the fidelity of the T2-SO2 relationship in-utero. The combination of MRI oximetry with vessel flow was applied to measure placental-fetal oxygen transport in normal pregnant sheep. The findings were in agreement with existing reference data obtained using invasive techniques, providing further validation of the approach, which was then applied in human pregnancies. Our results confirmed that streaming exists in the human fetal circulation, whereby the metabolically active heart and brain are supplied with blood with a higher oxygen content than the blood returning to the placenta via the right heart and main pulmonary artery (68±10% vs. 49±9%, P

Keywords: Human Pregnancy
Magnetic Resonance Imaging
Maternal Fetal Hemodynamics
Oxygen Transport and Consumption
Placental Function
Sheep Pregnancy
Advisor: Seed, Mike
Kingdom, John C.
Cell Division Compromises Epithelial Cell Polarity and Drives Tumor Progression

Epithelia are the predominant tissue type of the animal body and form major components of most organs. As with all tissues, the formation of epithelia during development and their stem cell-based renewal requires cell division. This presents a problem as dividing epithelial cells transiently lose apical-basal polarity, which could compromise epithelial integrity. How epithelial cells respond to challenges arising from cell division is not understood. To better understand the mechanisms of polarization and the impact of cell division on epithelial integrity, I have carried out a screen to identify novel epithelial polarity determinants. I evaluated the relationship between cell division and epithelial cell polarity using Drosophila embryos and imaginal discs as model systems. I conducted a screen to find novel genes required for the normal distribution of the apical determinant Crumbs (Crb), which revealed shrub, srpk, and the cell cycle regulator fizzy (Cdc20), as genes that are required for normal polarity. Embryonic mutants of fzy, which leads to an arrest at metaphase, confirms the transient loss in epithelial cell polarity during cell division. This led to an in-depth analysis of the impact of cell division on epithelial cell polarity. Reducing cell division suppressed the mutant phenotypes of polarity genes, arguing that cell division significantly challenges epithelial polarity suggesting a higher requirement for the function of polarity regulators. I then investigated epithelia where loss of polarity proteins such as Crb have no adverse consequences in a wildtype background. I found that accelerating cell division in such epithelia caused a loss of polarity and neoplastic tumor growth. Moreover, neoplastic growth is strongly enhanced when accelerated division is combined with a loss of Crb. Interestingly, neoplastic growth as well as the loss of epithelial cell polarity observed in polarity mutants can be rescued by blocking cell division. My findings indicate that the process of cell division not only increases tumor mass but also compromises epithelial polarity to drive tumor progression.

Keywords: cancer
cell division
cell polarity
EMT
mitosis
tumourigenesis
Advisor: Tepass, Ulrich
A “Shocking” Investigation into Life on Mars: Examination of the Structural and Chemical Effects of Shock in Hydrous Phases in Martian Meteorites

To determine when and if habitable environments existed on Mars, accurate measurements of the volatile and isotopic compositions of hydrous phases in martian meteorites are essential. However, past studies on these phases have routinely overlooked one of the most fundamental properties of martian meteorites — they are all inherently shocked, experiencing extreme pressure and temperature (P-T) conditions during impact and ejection from the martian surface. These intense P-T conditions are known to induce volatile loss and isotopic disturbances. Thus, if shock-induced chemical alteration is not properly accounted for, past interpretations about water and life on Mars based on measurements from hydrous phases may be misconstrued. As such, the objective of this thesis is to determine how shock deformation has affected the structure and chemistry of the three most common hydrous phases in martian meteorites (apatite, merrillite, and iddingsite) using detailed microstructural and petrographic analyses. Microstructural electron backscatter diffraction analyses of apatite and merrillite in martian meteorites reveals these minerals experienced localized shock-induced P-T conditions high enough to alter their primary martian water contents; with the first in-situ evidence of shock-dehydrogenation in phosphate minerals revealed by correlative electron energy loss spectroscopy. This evidence of shock-induced chemical alteration also indicates that unshocked phosphate minerals on Mars would dissolve faster in water-rock interactions, supplying more bio-available phosphorus for potential life than previously estimated. Additionally, the complex microstructures observed in the phosphate minerals, even in “low-shock” meteorites, suggests that their original H-isotope compositions may have also been altered by shock, necessitating re-evaluation of past models of Mars’ atmospheric evolution based on these H-isotope measurements. Finally, through detailed petrographic examination of shock features, it is inferred that iddingsite alteration in a terrestrially weathered martian meteorite was produced on Mars via water-rich deuteric alteration. The microstructural and petrographic analyses carried out in this thesis reveal significant shock-induced structural and chemical alteration of hydrous phases in martian meteorites, and new evidence of water-rich magmatism on Mars (deuteric iddingsite). These results indicate that past approximations of water and phosphorous abundances on Mars are likely underestimates, suggesting that habitable conditions for potential martian life were more prevalent than previously assumed.

Keywords: Mars
Meteorites
Advisor: Tait, Kimberly T
The 'Grey Area' of Consent: Understanding the Psychosocial Impacts of Trauma on Sexual Consent

In recent years, sexual consent education has proliferated and arguably become the most popular way of preventing gender-based violence (GBV), particularly on post-secondary campuses. However, mainstream consent programming applies a reductive conception of consent and lacks a trauma-informed lens. The concept of consent that much programming relies upon is binary (‘Yes’/‘No’) and obscures ongoing yet preventable harm in the ‘grey area’ of consent. This disproportionately impacts youth trauma survivors as they are more than twice as likely to be sexually (re)victimized compared to their peers without trauma histories; moreover, the psychosocial impacts of trauma, such as substance dependence, dissociation, or hypersexuality, refuse a binary model of consent. To explore these phenomena, I interviewed 8 diverse undergraduate students at the University of Toronto who self-identify as trauma survivors. Using intersectional feminist theory and critical trauma studies as a theoretical framework, the project provides an evidentiary and conceptual basis for rethinking consent education with a trauma-informed approach. I found that trauma survivors were able to shed light on more complex conceptualizations of consent because they could not subscribe to, or fit their experiences into, a neatly packaged version of ‘healthy,’ consensual sexual experience. Participants in the study said that they were previously taught that consent is the key to positive, healthy sexual experiences—as if bad or regrettable sex could be abolished through consent—and this message did not reflect their lived experiences. The awkwardness, ambiguity, or ambivalence that may arise out of subjective sexual experiences, and not just those of survivors of trauma, remains an understudied, critical gap in consent education. This study contributes to the evidence that we must attend to the grey areas of sex and harm in order to understand more nuanced dynamics for negotiating mutually pleasurable, ethical sex, as well as the more insidious and uncontested manifestations of GBV. By recognizing the limits of contemporary consent discourses, we can expand visions of sexual justice and prioritize talk of mutuality, interdependence, and compassion in order to foster a greater sexual ethic of care.

Keywords: Consent Education
Gender-based Violence
Sexual Consent
Sexual Violence
Sexuality Education
Trauma-Informed Practice
Advisor: Bialystok, Lauren
Neurostructural, Neurofunctional, and Neurocognitive Correlates of Cannabis Use in Adolescents with Bipolar Disorder

Adolescents with bipolar disorder (BD) have high rates of cannabis use, and cannabis use is associated with increased symptom severity and treatment resistance in BD. However, few studies have examined the association of cannabis use with neurostructure, neurofunction, and/or neurocognition in adolescent BD. As societal perceptions of cannabis benefits are increasing alongside decreasing perception of harm, addressing this gap is imperative. This thesis examines the neurostructural, neurofunctional, and neurocognitive correlates of cannabis use in adolescent BD. The over-arching hypothesis was that cannabis use in adolescents with BD would be associated with brain structure, brain function, and neurocognition. Structural and functional neuroimaging was completed using magnetic resonance imaging (MRI). Vertex-wise analysis revealed significant group effects on brain structure in frontal and parietal regions. Adolescents with BD and cannabis use (BDCB+) exhibited larger volume and surface area (SA) in parietal regions, and smaller thickness in frontal regions, relative to healthy controls (HC) and adolescents with BD and no cannabis use (BDCB−). BDCB− had smaller volume, SA, and thickness in parietal and frontal regions relative to HC. Resting state functional connectivity (rsFC) seed-to-voxel analyses revealed three significant clusters. First, rsFC between the left nucleus accumbens (NAc) seed and left superior parietal lobe was negative in the BDCB- group and positive in the HC group. Second, rsFC between the right orbitofrontal cortex (OFC) seed and right lateral occipital cortex was positive in the BDCB+ and negative in the BDCB- and HC groups. Finally, rsFC between the right OFC seed and right occipital pole was positive in the BDCB+ group and negative in the BDCB- group. Neurocognition was examined using a computerized automated test battery. There were between-group differences on tests of visuo-spatial working memory and sustained attention. Working memory scores were significantly impaired in BDCB+ relative to HC, and sustained attention was significantly impaired in BDCB- relative to HC. This thesis emphasizes the importance of integrating brain-based research to further elucidate clinical and behavioural attributes that manifest in adolescents with mood disorders. This study is the first step in understanding the brain-based origins of clinically relevant symptoms associated with cannabis use in adolescents with BD.

Keywords: Adolescents
Bipolar Disorder
Cannabis
Neurocognitive
Neurofunctional
Neurostructural
Advisor: Goldstein, Benjamin I
Elucidating the Role of FGF and RA Signaling during Pancreatic Differentiation using hPSC

Type 1 Diabetes is an auto-immune disease that results in the destruction of insulin-producing β-cells. Human pluripotent stem cells (hPSCs) can be differentiated to NKX6-1+PDX1+ pancreatic progenitors (PPs) and to NKX6-1+CPEP+ β-like cells in vitro, offering a potential source of cells for therapy. Although PPs are in clinical trials and β-like cells have been approved for clinical trials, recent publications demonstrated that both populations contain cells of non-pancreatic lineages. This suggests that pancreatic specification may require further optimization, and that the markers the field uses to guide differentiation may be inadequate. In this thesis, I set out to elucidate the role of FGF and RA signalling upon pancreatic specification, with the goal to improve β-cell differentiation. In Chapter 4, I used chemical and genetic tools to demonstrate that FGFR3 activation at stage 3 of differentiation inhibited PDX1+ Endoderm induction through the MEK/ERK signaling pathway. Impaired PDX1 specification was accompanied by a decrease in PPs and β-like cells and increase in the frequency of PDX1-SOX2+ cells. As a result, stage 4 cultures failed to generate pancreatic grafts in vivo and instead generated teratomas. Notably, FGFR and MEK inhibition during endocrine induction enhanced β-cell differentiation. In Chapter 5, I demonstrated that retinoid signaling during stage 3 influenced the efficiency and purity of PPs and β-like cells. Surprisingly, retinoid treatment at stage 3 was not required for PDX1 induction, however, it was necessary for efficient PP specification. Importantly, I demonstrated that treatment with the RA precursor retinol at stage 3 was superior to RA as it generated fewer CDX2+ cells and higher percentages of β-like cells. Consistent with these findings, I showed that the RA synthesizing enzyme, ALDH, was expressed by PDX1+ endoderm and PPs and sorting for ALDH+ using ALDEFLUOR, enriched for a population expressing higher NEUROG3 levels compared to unsorted cells. Based on these data, I proposed that ALDH could be used to mark endocrine competent PPs. Together, the knowledge from this thesis advances the field by providing strategies to improve current β cell differentiation protocols and by identifying markers that could be used to monitor PP purity and β-cell differentiation.

Keywords: Beta Cells
Diabetes
Fibroblast Growth Factor
Pancreas
Retinoic Acid
Stem Cells
Advisor: Nostro, Maria Cristina
New Tools for Diagnosis and Treatment of Bacterial Infections

The excessive and inappropriate use of antibiotics has contributed to the spread of antibiotic resistance, a serious challenge the global health industry is facing. To help preserve the effectiveness of current commercially available therapies, timely, accurate and user-friendly diagnostic tools are needed; advances in biosensing and microfluidics aim to address these limitations in conventional testing. With improvements in diagnostic testing comes the ability to administer personalized patient treatments, an area which has become increasingly explored. In wound care applications, for example, different wound types may display impairments in various phases of the healing process, requiring distinct therapeutics to improve patient outcomes. This thesis first explores the development of a diagnostic device for the rapid detection of methicillin-resistant Staphylococcus aureus, the most common cause of hospital- and community-acquired bacterial infections. The approach relies on nanoparticle-mediated microfluidic capture and electrochemical detection of clinically relevant concentrations of bacteria directly from patient nasal swab specimens. Next, an integrated and automated digital microfluidics platform was designed for simultaneous real-time antibiotic susceptibility testing and bacterial identification via fluorescence detection. This versatile all-in-one instrument with a small footprint allows automation of assay steps for simple sample handling, which can be easily customized for the desired application, without device redesign. Finally, multifunctional hydrogel wound dressings with programmable spatiotemporal release of biologically active agents, including small molecule antibiotics, growth factors and antibacterial silver, were investigated in vivo for personalized wound healing. The biocompatible wound dressings were fabricated via 3D printing, for simple fabrication that could be tailored to patient needs. Altogether, these studies present novel tools to better diagnose bacterial infections and treat wound patients through personalized medicine.

Advisor: Kelley, Shana O
Effects of Vitamin D Receptor (VDR), Age and Cholesterol-status on Aβ Peptide Accumulation in the Brain

Alzheimer’s disease (AD) is associated with accumulation of toxic amyloid-beta peptides, 40 and 42 amino acid lengths (Aβ40 and Aβ42) in brain. Calcitriol, natural ligand of the vitamin D receptor (VDR), activates P-glycoprotein (P-gp) to efflux these toxic peptides out of the brain and lower peripheral cholesterol, events that could be linked to brain cholesterol and Aβ formation via BACE1 from the amyloid precursor protein (APP). We applied an improved and facile enzyme-linked immunosorbent assay (ELISA) to measure the low endogenous Aβ40 and Aβ42 concentrations in mouse and guinea pig brains, with 1 instead of 5 M guanidine HCl (a chaotropic agent and protein denaturant) for homogenization, thereby increasing the sensitivity by 5×. We documented age-dependent (2, 4-8, or >10 months) elevation of mouse brain Aβ, showing that protein expressions of P-gp, neprilysin (Aβ degradation enzyme) and Cyp46a1, which metabolizes brain cholesterol, were reduced and calcitriol treatment partially mitigated the changes via P-gp induction with TNF-α and IL-1β reduction. We also examined age-dependent changes in the guinea pig (GP), a species with similar Aβ homology and cholesterol processing as humans, where Aβ40 and Aβ42 accumulation, P-gp and Lrp1 (for Aβ and cholesterol transport) reduction, and free cholesterol elevation commensurate with aging (9- to 40-weeks). In 8-week-old GPs, calcitriol treatment led to increased Aβ and cholesterol clearance processes due to higher P-gp and Lrp1 protein expression, with elevated neprilysin and Cyp46a1 mRNA levels in brain, and Cyp7a1 protein, Abca1, Abcg5, and Abcg8 mRNA levels in liver. Exploiting our collaborator’s surgical skill and stereotaxic instrument for injections into brain, we defined the biodisposition of hAβ40 after intravenous or intracerebroventricular injection in rats with calcitriol treatment. The exogenously administered hAβ40 was best described by a catenary-mammillary model with one cerebrospinal fluid compartment and a slow exchange within the brain compartments. The composite findings suggest that age, cholesterol status, and vitamin D deficiency are risk factors that can alter Aβ accumulation in brain. Age is a dominant risk factor for Aβ accumulation due to reduced clearance pathways and higher cholesterol levels in brain.

Keywords: Alzheimers disease
Cholesterol
Neuroscience
Pharmacokinetics
Vitamin D
β-amyloid
Advisor: Pang, K. Sandy
Modelling and Characterisation of the Thermomechanical Behaviour of Thermal Barrier Coatings

Thermal barrier coatings (TBCs) are adopted in aeroengines to enable higher operating temperatures. Whilst some progress has been made in their development, there remain major challenges to overcome. These challenges include processing defects, development and progression of undesirable thermal residual stresses and interphases. These challenges have motivated the undertaking of this study. Specifically, the main objective of this research is to develop reliable modelling techniques, which are supported experimentally, to assess the effect of defects, thermal residual stresses and interphases upon the structural integrity of TBCs. Four aspects were accordingly examined. In the first, we examined the effect of thermal cycling on the dynamic growth of thermally grown oxide (TGO) and mixed oxides (MOs) using an integrated finite volume (FV) – finite element (FE) model. We were able to accurately predict the growth of TGO and MOs at varied temperatures and show that the presence of undulated interface led to uneven growth of TGO. The second was concerned with the effect of thermal cycling, growth strain and stress relaxation of TGO stresses on the build-up of residual stresses in TBC. This was achieved using a coupled non-linear transient thermomechanical analysis that incorporated a modified FV-FE model. Model results revealed that the combined effect of growth strains and thermal cycling could lead to elastic, shakedown or ratcheting phenomena. The third involved the use of micromechanics and adaptive FE model to investigate the role of inherent microdefects on crack propagation and failure of TBC. This led to determining the effect of shielding and amplification of the stress field on the critical stress intensity factor of interacting microdefects. The fourth was concerned with examining the effect of YSZ/α-Al2O3 interphase upon the thermomechanical behaviour of TBCs using novel hybrid molecular dynamics-finite element simulations. Unlike existing work, our results show that assuming a line interphase between TC and TGO will lead to erroneous estimates of the effective stiffness of YSZ/α-Al2O3 system. In this thesis, we offer newly developed coupled mechanistic models to determine the varied thermomechanical stress states, failure modes and inelastic deformation that will undoubtedly improve our understanding and lead to better coatings.

Keywords: Coupled numerical modelling
Finite element analysis
Fracture mechanics
Molecular dynamics
Thermal barrier coatings
thermally grown oxide
Advisor: Meguid, Shaker A