VictorJuiz/thesis huggingface dataset:
Texaphyrin Architectures for Biomedical Applications

The class of texaphyrins are macrocycles with unique photophysical and chelation properties. These desirable properties have led to extensive clinical evaluations, however, FDA approval has never been obtained. We believe the fundamental properties of texaphyrins, most notably the robust metalation ability, warranted the development of novel texaphyrin architectures to potentially solve inherent limitations of previous texaphyrin entities. In the development of novel texaphyrin architectures, a texaphyrin-phospholipid conjugate was synthesized and demonstrated the capability to self-assemble into nanovesicles termed nanotexaphyrin. A library of 18 distinct metallonanotexaphyrins was synthesized, possessing strong structural and chelation capabilities. To enhance the clinical translability of these nanoparticles, a novel method was developed to enable the post-insertion of metal ions into preformed free-base nanotexaphyrin. Moreover, we demonstrate this methodology to create mix and matched metallonanotexaphyrins, offering the ability to selectively tune the multifunctionality of nanotexaphyrin for desired applications. A proof-of-concept 111In-Mn-nanotexaphyrin was developed and showed selective tumour uptake and retention for in vivo MRI-SPECT imaging in orthotopic PC3 prostate cancer mice. Additionally, we further evaluated Mn-nanotexaphyrin for MRI applications, creating a novel one-pot instantaneous chelation and self-assembly protocol for this contrast agent. Evaluations on a VX-2 head and neck tumour bearing rabbit for sentinel lymph node (SNL) mapping suggest Mn-nanotexaphyrin may serve as a contrast agent in lymphoscintigraphy procedures. Finally, the photophysical properties of texaphyrins were analyzed by creating a large library of metallotexaphyrin-antenna conjugates, using a coumarin, rhodamine B, or saturated hydrocarbon. Using classical structure-activity relationship analysis, the library emission data suggests metallotexaphyrin emission wavelengths can be tuned through the use of antenna in combination with metal ion. In doing so, the appearance or disappearance of emission bands can be precisely controlled. The work conducted in this thesis aimed to develop novel texaphyrin architectures that could serve a role in biomedical applications. The fundamental work performed here lays the foundation for others to perpetuate this field, where a multicollaborative effort can truly realize the potential of the texaphyrins.

Advisor: Zheng, Gang
Effects of Osteoblast-Specific GαS Overexpression on Skeletal Development and Response to Catabolic and Anabolic Stimuli Using a Transgenic Mouse Model

GαS is a heterotrimeric G protein that transduces signals from cell surface G protein-coupled receptors to stimulate intracellular signaling cascades. Clinically, tight regulation of GαS levels and activity are required for bone homeostasis and aberrant GαS activity is known to cause various bone disorders. Our lab has previously found a 6-fold variation in GαS protein levels in lymphocytes from children, suggesting significant variability in cellular GαS levels amongst individuals. To examine the effects of increased GαS expression on bone in vivo, our lab has generated a transgenic mouse model of osteoblastic GαS overexpression (HOM-Gs mice) driven by the 3.6 kb Col1a1 promoter. HOM-Gs mice demonstrated increased trabecular bone mass compared to wild type (WT) mice. Furthermore, HOM-Gs cortical bone was porous and mechanically weak. This skeletal phenotype showed a pronounced progression with age. Continual accrual of trabecular bone occurred in HOM-Gs mice, whereas a loss of bone was observed in WT mice. Histologically, these changes in skeletal morphology were shown to be mediated by increased bone turnover. At the cellular level, HOM-Gs mice exhibited overactive osteoblasts resulting in increased bone formation and increased resorption through enhanced osteoclastogenesis. In response to anabolic (intermittent) parathyroid hormone (PTH) treatment, HOM-Gs mice displayed enhanced increases in trabecular bone mass compared to WT mice. Moreover, HOM-Gs mice demonstrated robust anabolic effects in trabecular bone from treadmill exercise when WT mice did not respond. Interestingly, HOM-Gs mice responded catabolically, similar to WT mice, to low calcium diet, but were resistant to the catabolic effects of continuous PTH. Collectively, these results suggest that stimulation of GαS signaling in the presence of additional GαS protein drives bone anabolism when sufficient calcium levels are present. Despite the increases in bone mass however, no biomechanical improvements were observed, indicating that bone formation was favored at the cost of bone quality.

Keywords: Biomechanics
Bone
GNAS
G protein
Parathyroid Hormone
Trabecular
Advisor: Mitchell, Jane
Grynpas, Marc
Exploring and Harnessing the Role of Hypoxia Inducible Factors in Vascularizing Modular Tissue Constructs

In my doctoral work, I identified hypoxia-inducible factor (HIF) as a primary mechanism driving modular tissue-induced vascularization, and harnessed it to enhance blood vessel formation in this platform. HIF orchestrates a range of cellular responses, but its role in driving vascularization of engineered tissues has yet to be specified. In the first pillar of my work, HIF was inhibited using pharmacological and genetic methods to define its contribution to vessel formation in modular tissues. Both inhibitory methods, systemic digoxin delivery and shRNA-mediated inhibition of HIF-1 in graft endothelial cells (EC), reduced vascularization and oxygenation of tissue constructs. Moreover, these methods elucidated different mechanisms underlying HIF-mediated vascularization. Systemic digoxin treatment reduced early recruitment of endothelial progenitor cells and monocytes/macrophages to implants. Inhibition of HIF-1 in graft EC reduced their angiogenic function in normal and serum-reduced conditions in vitro, highlighting the importance of HIF in graft-derived vascularization. After defining the significance of its role, we harnessed HIF to enhance rapid and mature vessel formation in modular tissues. In the second pillar of my work, microparticles releasing HIF-stabilizing deferoxamine (DFO) were incorporated into EC-only modular constructs, on the premise that local HIF stabilization would drive vascularization even in the absence of mesenchymal stromal cells (MSC). Indeed, vessel densities were increased at day 7 and 21, corresponding with increased vessel maturation and perfusion at day 21. Furthermore, DFO-releasing microparticles increased the recruitment of neutrophils and alternatively activated macrophages to the implant. Although vessel formation was rescued to some degree, it was not comparable to that in MSC-containing modular constructs. Nonetheless, the mechanisms elucidated here could be harnessed to develop strategies that tune vascularization in modular tissues, and to improve engraftment of therapeutic cells.

Advisor: Sefton, Michael V
Non-Alcoholic Fatty Liver Disease: Investigating the Impact of Bariatric Care and the Role of Immune Function

Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH) and cirrhosis. It is one of the most common causes of chronic liver disease resulting from obesity. 74-98% of morbidly obese individuals have NAFLD at the time of bariatric surgery. Post-bariatric surgery, NAFLD significantly improves but some patients continue to have persistent disease, particularly fibrosis. The pathogenesis of NAFLD is complex. In addition to insulin resistance, recent research suggests a potential role for liver immune function and intestinal microbiota (IM). The objectives of this research were 1) to prospectively evaluate the impact of bariatric care on metabolic and liver histology parameters by studying two bariatric care interventions: the routinely prescribed pre-operative very-low calorie diet (VLCD) and the Roux-en-Y gastric bypass (RYGB); and 2) to explore in a cross-sectional study whether there are differences in liver immune cells between NAFLD and healthy subjects and whether there are associations with intestinal microbiota (IM). Specifically, the plan was to assess: 1) liver histology post-VLCD and factors associated with NAFLD; 2) the effects of RYGB on liver histology and the factors associated with persistent NAFLD at 12-months post-RYGB; 3) liver immune cell counts in NAFLD compared to controls and the association between these cell counts and IM. We found that at the time of surgery (post-VLCD), the prevalence of NAFLD was low, likely due to the effect of the VLCD. Those with NASH had higher insulin resistance and presence of diabetes prior to the diet. At 12-months post-RYGB there were further improvements in anthropometry, metabolic measurements and liver histology. However, those with persistent NAFLD had less improvement in waist circumference and glycemic control. The cross-sectional study showed that specific liver immune cells, namely CD163, CD20 and CD45 were significantly increased in NAFLD versus controls and that immune cell counts were significantly correlated with specific bacterial taxa. In conclusion, both VLCD and RYGB have beneficial effects on metabolic and histological parameters but those with persistent NAFLD are more metabolically impaired despite similar interventions. Other potential mechanisms, such as a potential interplay between IM and liver immune cells, require further investigation.

Keywords: Bariatric Surgery
Gut Bacteria
Immune Function
NAFLD
Obesity
Advisor: Allard, Johane P
The Identification and Management of Sepsis in the Prehospital Setting

Introduction: Sepsis is a syndrome characterized by organ dysfunction due to a dysregulated host response to infection and remains a leading cause of morbidity and mortality across the world. Early identification and prompt treatment are essential to improving outcomes of patients with sepsis, and in established healthcare systems Emergency Medical Services (EMS) paramedics are often the first healthcare contact for these patients. To promote earlier identification and timely delivery of effective treatment, a better understanding of the epidemiology of patients with sepsis who are encountered by EMS is required. Objective: This thesis 1) describes characteristics of patients with infections and sepsis encountered by EMS in a large Canadian province, 2) validates existing approaches for the identification of infections and sepsis by paramedics, and 3) evaluates the impact of a current EMS treatment on process and patient outcomes. Synthesis: The one-year incidence of sepsis among EMS-transported patients was 2.1%. For patients with sepsis, the in-hospital mortality rate was 28% - accounting for 12% of all deaths occurring in EMS-transported patients. Paramedics documented suspicion of sepsis in only 11% of patients with infections and 9% of patients with sepsis. To improve identification, operational characteristics (e.g. dispatch categories) and temperature measurement can identify patients with higher risk of infection. Then simple screening strategies can be applied to these patients to identify those at high-risk for sepsis diagnosis. Intravenous fluid treatment by paramedics for patients with sepsis was associated with reduced mortality in patients with low initial systolic blood pressure, but harm in patients with high initial systolic blood pressure. Conclusion: EMS systems should implement simple screening strategies to promote earlier identification of patients with infections and sepsis, who are at high-risk for mortality and require urgent intervention.

Keywords: Diagnosis
Paramedic
Sepsis
Advisor: Scales, Damon C
Characterization of NEK10 Tyrosine Kinase Activity in the Cellular Response to DNA Damage

Protein kinases are signal transduction molecules implicated in most biological processes that, through signal reception, amplification and transduction, direct cellular responses to various stimuli. Deregulation of protein kinases can lead to the formation of many diseases, such as cancer. Kinases are critical for the DNA damage response (DDR) and coordinate a series of processes such as cell cycle arrest, DNA repair, and apoptosis. Defects in the DDR leads to an accumulation of mutations that can promote tumorigenesis. In response to DNA damage, ATM/ATR, DNA-PKcs, and CHK1/2 kinases orchestrate a signalling program directed towards the tumour suppressor p53, which coordinates the DDR. Emerging studies implicate multiple other kinase cascades in the cellular response to DNA damage including members of the NimA related kinase (NEK) family (NEK1, NEK10 and NEK11). The work presented in this thesis focuses on NEK10, a largely uncharacterized member of the NEK family. Mutations and lowered expression of NEK10 have been associated with various human malignancies. Previous work implicated NEK10 in the regulation of the G2/M checkpoint in response to UV-C through ERK1/2 pathway hyperactivation. Work presented herein describes a function for NEK10 in the regulation of p53 transcriptional activity. NEK10 directly phosphorylates p53 on Y327 and mutation of this site (Y327F) results in hypomorphic p53 function and a decrease in the transcription of p53-target genes. Accordingly, NEK10-deficient cells display heightened sensitivity to DNA damaging therapeutics. Furthermore, NEK10 acts as a dual-specificity kinase with prominent tyrosine kinase activity. I have uncovered a key determinant of NEK10 specificity towards tyrosines within its activation loop, allowing for the generation of a tyrosine kinase-specific NEK10 mutant (I693P). In collaboration with Dr. Michael Yaffe, we identified the substrate recognition sequences for the tyrosine kinase activity of NEK10, revealing 77 NEK10 candidate substrates within the human proteome. Collectively, my studies establish NEK10 as a factor in the cellular response to DNA damage, furthering our understanding of its physiological function. This work also lays a foundation for future studies of NEK10 in the context of tumorigenesis, and establishes a rationale for the exploration of NEK10 inhibitors as sensitizers to genotoxic cancer treatments.

Advisor: Stambolic, Vuk
Co-construction of Pedagogical Documentation by Children and Educators in Early Learning Environments

This qualitative, design-based research study aimed to examine the factors that influence and are influenced by the co-construction of pedagogical documentation by educators and children in early learning settings. Throughout a six-month study period, seven early childhood educators located at three early learning settings in Nova Scotia were asked to co-construct documentation with the children, by the children, and for the children. Using qualitative research methods, including interviews, questionnaires, site visits, document sampling and a child focus group, data were collected and then analyzed using a thematic analysis approach within a social constructivist research paradigm. Findings, which were organized within the themes of value and validation; reflection and relationships; and processes and practicalities, indicate that the factors involved in this co-construction process are complex and varied. The factors that influenced the co-construction process ranged from the practical considerations of time, setting, materials, and technical support to educator values, attitudes and beliefs about the involvement of children in the documentation process. Factors that were influenced by the process included the educator-child relationship; educator’s perception of children’s abilities to reflect and recall their experiences (metacognition); the inclusion of children’s voices as an element of intentional program planning, and parents’ understanding of how and what their child learns in a play-based setting.

Keywords: children
co-construction
early childhood educators
early learning
pedagogical documentation
Advisor: Pascal, Charles
Two Essays on Empirical Asset Pricing

The main theme of my doctoral research is empirical asset pricing. The first chapter of this thesis focuses on the time series predictability of stock returns. I provide improved methods for estimating a predictive regression model system where the future aggregate stock return is regressed on the current value of a single predictor, and the innovations are correlated normal random variables. I propose improved estimators of the predictive slope which practically eliminate finite-sample biases and achieve small mean squared errors. I develop fast computing methods for evaluating the probability distribution of the OLS predictive slope, which enables an exact performance measurement of these estimators. This also facilitates a comparison of several prominent tests of return predictability with respect to their actual test sizes. The usefulness of these econometric methods is illustrated using U.S. equity data. The second chapter is a joint work with Ruslan Goyenko and Chayawat Ornthanalai. We study the determinants of option illiquidity measured by relative bid-ask spreads of intraday option transactions on S 500 firms over an extended period. We find that market makers' hedging costs significantly impact option illiquidity with the future rebalancing cost dominating the initial delta-hedging cost. Inventory risk and adverse selection also contribute to the cross-sectional variation in option illiquidity, with the latter effect intensifying around information events. We find that option-induced order flows predict their underlying stock returns only when option illiquidity simultaneously increases. This suggests that shocks to option illiquidity help to distinguish abnormal order flows that contain private information from those induced by liquidity trading. We show that a simple stock portfolio strategy contingent on option illiquidity shocks yields a risk-adjusted return of 16.35% per year.

Keywords: Empirical asset pricing
Advisor: Kan, Raymond
Terminal Economy: Politics of Distribution in Highland Papua, Indonesia

Anthropologists have long debated the relationship between local scales of politics and global capitalism. This dissertation examines regional politics in (West) Papua—a contested territory where Indonesia encompasses New Guinea—in relation to the forces that incorporate the region into the world economy. It focuses on the Balim region of the Central Highlands, home to Papua’s largest indigenous population. It examines struggles around the distribution of material goods, especially basic food staples sold by merchants or distributed as government aid and rations. State distribution programs in the region have expanded under Special Autonomy, a decentralization reform implemented to defuse the conflict between Jakarta and the West Papuan independence movement. Combining ethnographic interpretation with economic history, the dissertation proceeds in three steps. First, it traces the transformation of the Balim food regime under the extractive forces of global capital—which has targeted Papua as a resource frontier, and compelled Indonesian migrant livelihoods to depend on commerce in Papua. The history of extraction and commerce set the stage for Autonomy’s expansion of food distribution—an expansion that has accelerated the indigenous shift away from self-sufficient food production. Next, the dissertation examines key sites in the incorporation process: peri-urban markets and minivan terminals that are nodes in regional distribution. These sites, where indigenous women sell produce and newcomer merchants sell imported goods, have been theaters of indigenous uprisings, inter-ethnic conflict, and commercial regulation initiatives. Finally the dissertation traces trajectories of indigenous youth who work in and around infrastructures, to show that the labor of mobile youth shapes how state distribution functions. Together, these threads illustrate how indigenous participation in Balim regional politics has sought to enact some control over the process through which the regional economy is relegated to an end-point position. Overall, the dissertation advocates for a world-systems anthropology that shows how global and material forces recur across scales. These forces confront populations at contested peripheries of Global South countries with the double burden of responding to their incorporation, and experiencing state distribution partly as a form of displacement.

Keywords: capitalism
distribution
infrastructure
livelihoods
regional economy
Advisor: Li, Tania
Patient-Centered Interventional Outcomes for Children with Severe Neurologic Impairment

Decisions about surgical interventions for children with neurologic impairment are difficult for families, in part because of the limited evidence about outcomes. This thesis addresses three knowledge gaps about interventional outcomes in this population from varying perspectives. The included studies considered qualitative and quantitative outcomes after a specific intervention (feeding tube placement) in the broad population of children with neurologic impairment and evaluated outcomes after all surgical interventions in children with neurologic impairment caused by two specific genetic diagnoses (trisomy 13 and 18). First, in our qualitative systematic review of 13 studies describing family experiences after feeding tube placement for children with neurologic impairment, we found that feeding tube placement has diverse and variable effects on children and their families, with noted benefits and challenges. Second, in a study using health administrative data to evaluate healthcare utilization before and after feeding tube placement among children with neurologic impairment, we found that rates of unplanned hospitalization are stable during the two years after compared to the two years before the procedure (rate ratio 0.93 with 95% confidence interval: 0.62-1.41). This finding was consistent across a range of types of healthcare utilization (e.g., emergency room and outpatient visits) and across clinically relevant subgroups (e.g., children with and without anti-reflux procedures). Finally, we described survival and surgical interventions among children with neurologic impairment from trisomy 13 and 18. We found that a small subgroup of children (10-13%) survives a decade or more, and that children with trisomy 13 and 18 who undergo surgical interventions have high one-year survival (approximately 70%). These three studies inform important decision-making conversations between families of children with neurologic impairment and their clinicians.

Keywords: Feeding tubes
Neurologic Impairment
Pediatrics
Trisomy 13 and 18
Advisor: Guttmann, Astrid