VictorJuiz/thesis huggingface dataset:
Enantioselective Transition-metal-catalyzed Cyclizations via Difunctionalization of Alkenes

Asymmetric synthesis plays a critical role in the synthesis of modern pharmaceutical compounds which often contain complex stereochemical information and require a highly controlled synthesis. The Lautens group has developed numerous strategies to assemble heterocycles which often mirror key frameworks found in pharmaceutically important compounds as well as natural products. Chapters 1-4 describe a copper-catalyzed borylative cyclization strategy to access enantioenriched oxindoles, polycyclic indolines, and cyclobutanols. The in-situ generated chiral copper-boron species is proposed to undergo an enantioselective migratory insertion prior to intramolecular cyclization. The newly installed neopentyl boronate was readily converted to new carbon−carbon and carbon−heteroatom bonds. The methods were developed as a complementary strategy to established palladium-catalyzed domino cyclizations. Chapters 5-6 describe an asymmetric cobalt-catalyzed domino cyclization/C−H functionalization cascade. These reactions forge multiple new bonds in a regio-, diastereo- and enantioselective fashion. Early efforts detail the cleavage of aryl C−H bonds and their addition across 1,6-enynes in a hydroarylation cascade. The second part of the chapter discusses the development of a hydroacylation analog, using aldehydes as C−H bond donors. Chapter 7 describes a norbornene-mediated C−H functionalization Catellani-type reaction wherein two new carbon−nitrogen bonds are formed. The challenge in this process was optimizing an intermolecular process to outcompete an intramolecular cyclization. The second part of the chapter details preliminary efforts to undergo enantioselective palladium-catalyzed cyclizations where the cyclized palladium intermediate catalyzes a second cyclization prior to reductive elimination. The resulting tethered bisheterocyclic scaffolds demonstrated the utility of palladium catalysis in forging numerous new bonds.

Advisor: Lautens, Mark
Investigating Oxygen and Liquid Water Transport in Porous Transport Layers of Polymer Electrolyte Membrane Electrolyzers

The design of a porous transport layer (PTL) that exhibits effective two-phase transport characteristics and rigid contact at the catalyst layer (CL)-PTL interface is a prerequisite for improving the efficiency of polymer electrolyte membrane (PEM) water electrolyzers at high current densities (i > 4 A/cm2). In this thesis, key design considerations were presented based on extensive investigations performed via comprehensive numerical models and in operando imaging. A numerical investigation was performed to determine the impact of PTL structures on reactant liquid water delivery to reaction sites. A comprehensive model for designing PTLs was presented, where a stochastic model was used to numerically generate PTLs with realistic morphologies and tunable PTL structures, and a pore network model was used to perform two-phase flow calculations and determine their transport properties. A trade-off relationship was observed between achieving an effective CL-PTL interfacial contact and favourable reactant transport behaviour. Finer powder diameters and lower porosities improved the CL-PTL interfacial contact but led to the reduced permeability of liquid water. Conversely, increasing either powder diameter or porosity improved permeability but deteriorated the CL-PTL interfacial contact. Therefore, it is crucial to consider the operating conditions of an electrolyzer when designing PTLs. Mass transport behaviour in an electrolyzer operating at high current densities was studied using in operando imaging techniques. A sufficient reactant flow rate was essential for mitigating electrolyzer cell failures at high current densities. Specifically, the critical current density was observed when inadequate reactant water was supplied at high current densities. Both gas content in the PTL and mass transport overpotential significantly increased at the critical current density, and the electrolyzer failed to operate beyond the critical current density. Moreover, mass transport in the PTL surprisingly improved when patterned through-pores (PTPs) were implemented with a commercial PTL. The usage of a novel PTP PTL led to the reduced accumulation of product gas at the CL-PTL interface by 43.5%. Furthermore, PTPs led to more frequent gas removal, which subsequently improved water intake to the reaction sites. The findings in this thesis provide valuable insights for designing novel PTLs in PEM electrolyzers operating at high current densities.

Keywords: Neutron Imaging
Polymer Electrolyte Membrane Water Electrolyzer
Pore Network Model
Porous Transport Layer
Two-phase transport
Advisor: Bazylak, Aimy
The Influence of Curvature on Mantle Convection featuring a Temperature-dependent Viscosity

Convection in the silicate mantles or ice layers of terrestrial planets and moons is characterized by a strongly temperature-dependent viscosity. Mantle convection regime is first examined in 2D and 3D spherical geometry with varying mantle curvature (core-to-surface radii-ratio, f) and constant heating conditions and viscosity contrast across the mantle depth (ΔηT). The onset of the stagnant-lid regime occurs for different conditions for bodies with relatively small cores and relatively thin shells. Differences in mean temperature and flow fields observed between 2D and 3D geometry are amplified as relative core-size is decreased. This finding has implications for modelling the thermal evolution and evaluating heat extraction from the cores of small moons or dwarf planets. Next, I consider evolving conditions for a body the size of the Earth's Moon with f = 0.5. Typically, modelling methods employ a ΔηT that does not encompass the entire effective range of values for ductile flow. This may result in spurious changes in convective regime and overestimate heat extraction from the core. Improving upon conventional methods for viscosity modelling, I employ a novel constant-viscosity contrast modelling method that emulates a large effective viscosity contrast ΔηT = 10^10. With this adjustment, regime change is suppressed in the calculations tested. Moreover, the modelling approach I propose may be less computationally intensive and save resources. The generation of a magnetic field is associated with plate-tectonics because efficient heat extraction is required at the core-mantle boundary. However, the planet Mercury, which does not have plate-tectonics, features a magnetic field. The work presented concludes by investigating the evolution of the Mercurian mantle. I propose that an increased mantle thermal diffusivity due to an iron-poor composition results in a conducting mantle at present that is compatible with the heat extraction required by Mercury's magnetic field strength. The possibility of higher core heat extraction as follows a mantle transitioning from stagnant-lid convection to conduction may explain the origin of the Mercurian magnetic field.

Keywords: curvature
mantle convection
Mercury
secular cooling
stagnant-lid convection
viscosity
Advisor: Lowman, Julian P
Stressed, Sick, and Sad: A Transdiagnostic Investigation of the Translation of Stress into Depression through Neuroendoimmune Disruptions

Depression is a prevalent and disabling form of psychopathology that is frequently precipitated by experiences of stress. Disruptions in stress-sensitive biological systems, notably the immune system and hypothalamic-pituitary-adrenal axis, are strongly implicated in depression, and disturbances in these systems could reflect potential pathways through which experiences of stress are translated into depression. These systems, broadly subsumed within the neuroendoimmune system, may be highly responsive to stress and cognitive abilities related to stress management. To characterize the links between stress and depression and the potential influence of immune activity, the present study investigated the following: (1) the associations among perceived stress (across different time periods of life), proinflammatory immune markers, and depressive symptoms; (2) whether neuroendoimmune activity mediates the relationship between perceived stress and depressive symptoms; and (3) whether perceived stress and immune activity mediate the relationship between cognitive control and depressive symptoms. Fifty-nine medically healthy adult females with varying levels of depression participated in the study. Participants provided dimensional ratings of their depression symptoms and perceived life stress, and they completed a neuropsychological test of cognitive control. Plasma biomarkers of stress, including pro-inflammatory cytokines, C-reactive protein, and free cortisol, were assayed following a fasted morning blood draw. Consistent with hypotheses, both greater perceived stress and higher concentrations of the proinflammatory immune marker, interleukin-6 (IL-6), were associated with greater depressive symptoms. Although levels of IL-6 alone did not significantly mediate the relationship between perceived stress and depressive symptoms, when considered together, elevated concentrations of IL-6 and lower free cortisol mediated the relationship between severity of childhood stress and current depressive symptoms. Contrary to expectations, cognitive control was not significantly associated with stress, immune markers, or depression. The findings are interpreted in the context of a potentially long-term reduction in glucocorticoid tone triggered by early life stress that curbs cortisol output, produces chronic low-grade immune activation, and leads to depression vulnerability later in life. Overall, the study provides new insights into potential pathways among stress, the neuroendoimmune system, and depression, shedding light on how early life stress may be translated into depression in adulthood.

Keywords: depression
HPA axis
neuroendoimmune
proinflammatory immune
Advisor: Ruocco, Anthony
Interpersonal Perceptions of Mental Fatigue Vary with Willpower Theories

Some people, to varying degrees, believe that self-control becomes depleted with use. People with limited theories of willpower report that engaging in a strenuous mental activity causes them to be fatigued and unable to continue, while those with more nonlimited theorists report that they can do mental work without becoming depleted. Willpower theories may not only affect people’s own experiences of depletion, but may also affect their interpersonal perceptions and reactions. Chapter 2 first describes how people’s willpower theory affects their judgements of a target person based on knowledge of the target’s prior activity. A target who just engaged in an effortful activity (e.g., exam writing, working) is generally seen as less able (and fatigued) according to more a limited theorist, but the same target is seen as more able (and hardworking) according to a more non-limited theorist. These differing perceptions can affect partner selection (Chapter 2) and effort exertion during teamwork tasks (Chapter 3). In Chapters 4-6, I examine whether people are more compassionate or forgiving of a target’s self-control failure, if they perceive that target as potentially depleted due to prior mental exertion. Limited willpower theorists were no more likely to attribute a stranger’s poor exam grade to depletion (Chapter 4), but they did respond more compassionately to their romantic partners’ irritating behaviours when their partner was seen as potentially fatigued (Chapter 5). Seeing that limited willpower theorists were more in-tune to their partner’s potential depletion, Chapter 6 examines whether willpower theory affects people’s intentions to support their romantic partners in everyday life. This daily diary study found that limited theorists were more likely to see their partners as fatigued, but were also more likely to experience fatigue themselves – ultimately, limited willpower theorists were less likely to intend to provide support. Overall, this dissertation finds that self-theories of willpower can affect how people understand to and respond to the behaviour of others. However, while those with more limited willpower theories are more likely to perceive fatigue in other people, they are not necessarily more likely to respond with compensatory effort or additional support.

Keywords: attributions
excuses
lay theories
person perception
self-control
social support
Advisor: Inzlicht, Michael
Fundamentals of Porphyrin-lipid J-aggregation in Nanomedicine

Nanomedicine takes advantage of new, medically useful properties that arise from nanoscale control of material composition and structure. This thesis investigates a nanoscale photophysical phenomenon called J-aggregation within the context of porphyrin-lipid nanomedicine. Porphyrins are endogenous chromophores medically used as photosensitizers and optical imaging agents. Conjugating porphyrins to lipids enables their self-assembly into lipid nanoparticles. Interactions between porphyrins in the nanoparticle lipid membrane changes their photophysical properties. J-aggregation occurs when porphyrins are aligned head-to-tail and results in a dramatic red-shift in the absorption spectrum. Because J-aggregation relies on nanoscale dye–dye ordering it is sensitive to external stimuli that impact membrane structure, including temperature and interactions with biological species. In Chapter 1, porphyrin-lipid nanomedicine is first contextualized within the nanomedicine field. In Chapter 2, a background is provided on the mechanisms that alter the photophysical properties of dyes in nanomedicines and porphyrin J-aggregation is specifically reviewed. Chapter 3 examines the nanostructure-dependent photophysical properties of porphyrin-lipid aggregates in lipid membranes. Chapter 4 investigates the optical stability of J-aggregating porphyrin-lipid nanoparticles during exposure to serum proteins. Chapter 5 explores the potential utility of these J-nanoparticles for phototherapy and optical imaging applications. Lastly, Chapter 6 presents a discussion of new knowledge gained and potential future directions. From these fundamental studies, an assessment is provided of whether the unique nanostructure-dependent photophysical properties of J-nanoparticles are also potentially medically useful.

Keywords: bacteriochlorophyll
fluorescence
lipoprotein
liposome
photoacoustics
photothermal
Advisor: Zheng, Gang
Aging and Heart Failure Alter the Bone Marrow Derived Inflammatory Response and Impair Cardiac Remodeling Following Myocardial Infarction

Title: Aging and Heart Failure Alter the Bone Marrow Derived Inflammatory Response and Impair Cardiac Remodeling Following Myocardial Infarction Name: Tina Binesh Marvasti Degree: Doctor of Philosophy Year of convocation: November 2020 Institute of Medical Sciences, University of Toronto In adult humans, sudden loss of cardiomyocytes as a result of any strain or injury to the myocardium can potentially overwhelm the innate regenerative capability of this tissue. This results in formation of a collagen based scar, which could either stabilize or expand and result in ventricular dilation and heart failure. Considering the limited therapeutic options available to treat heart failure, autologous bone marrow stem cell based regenerative therapies have gained attention due to their promising results in myocardial function recovery post infarction in pre-clinical investigations. However the results from clinical investigations have been variable and relatively inconsistent. Inconsistencies in patient outcome and inconclusive data from some clinical trials has led us to hypothesis that patient intrinsic factors could play a crucial role in the quality and function of bone marrow derived stem cells which can influence the efficacy of their function in myocardial recovery. Factors investigated in this thesis were patients’ age and early cardiac dysfunction. I profiled the post ischemia immune modulating response originating from the bone marrow derived stem and hematopoietic progenitor cells. I developed and optimised a specific humanized mouse model for investigating human immune cells’ response to ischemia by transplanting patient CD34 stem cells in the bone marrow of NOD-SCID NSG mice and assessed patient specific characteristics that modify and dampen the proper immune response. Using these techniques, I demonstrate how lack of regulatory T cell (Treg) expansion in old patients’ bone marrow derived immune modulatory cells could lead to infarct expansion and left ventricular remodelling. I also show how the quality of bone marrow stem cells isolated from patients showing early stage heart failure symptoms indicate signs of bone marrow exhaustion. Here, we demonstrate the importance of how patient specific characteristics such as aging and early stage heart failure can modify the quality of bone marrow stem cells’ response to myocardial recovery. Future clinical investigations should consider adjunct complementary immune therapy and providing appropriate personalized therapy where characterization of patients’ immune profile would take the centre stage.

Advisor: Li, Ren-Ke
Activation and Stabilization of the Caspase-8 Survivalsome is Indispensable for Functional Toll-like Receptor 4 Dependent Signaling in Septic Neutrophils

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a complex, heterogenous, and redundant syndrome that is the leading cause of mortality in intensive care units worldwide. We investigated signalling mechanisms that mediate activation and termination of the response to infection by neutrophils – circulating white blood cells that are the primary agents of the early host response. While a failure of activation impairs antibacterial defenses, failure in terminating that response through a process called apoptosis contributes to systemic inflammation and tissue injury in septic patients. By investigating the intracellular biology that controls neutrophil activation and termination, we sought to identify potential targets to treat clinical sepsis. Using healthy human and septic patient neutrophils, we first showed the function of caspase-8, the apical caspase in the extrinsic cell death pathway, is modified by its phosphorylation. Caspase-8 tyrosine phosphorylation at tyrosine-380 established an anti-apoptotic signaling module we termed the survivalsome that promoted neutrophil III survival. Conversely, caspase-8 dephosphorylation at tyrosine-380 prevented survivalsome assembly and induced caspase-3 dependent neutrophil death. By inducing sepsis in a caspase-8 deficient mouse model, we demonstrated that in vivo caspase-8 deletion significantly reduces mortality, accelerates bacterial clearance, and limits lung injury. Serendipitously, we found an association between the variability of neutrophil response to lipopolysaccharide with caspase-8 variant expression. Neutrophils coexpressing both caspase-8 A and B isoforms demonstrated lower rates of apoptosis from baseline following lipopolysaccharide stimulation versus neutrophils expressing only A or B. Expression of caspase-8 isoforms further correlated with multiple organ dysfunction score and white blood cell count in septic patients. Since caspase-8 is phosphorylated in response to lipopolysaccharide, we investigated whether caspase-8 tyrosine phosphorylation at tyrosine-380 is required for functional Toll Like Receptor 4 (TLR-4) signal transduction. Using healthy human and septic neutrophils, we showed th ipopolysaccharide-induced TLR-4 activation increases caspase-8 tyrosine phosphorylation and MyD88 receptor-mediated signaling to trigger NF-B translocation and pro-inflammatory gene transcription. Finally, this PhD thesis uncovered a mechanism that stabilizes Src-induced caspase-8 tyrosine phosphorylation for phosphoinositide 3-kinase activation: heat shock protein 90 prevents ubiquitin-mediated degradation of caspase-8 and c-Src to prolong inflammatory neutrophil survival.

Keywords: Apoptosis
Caspase-8
Inflammation
Neutrophil
Signalling
Toll-Like Receptor-4
Advisor: Marshall, John C
Understanding the Complexity of Falls and Fall Prevention for Wheelchair Users with Spinal Cord Injury across the Continuum of Care

Wheelchair users with spinal cord injury (SCI) are at a high risk for falls; however, our understanding of falls and fall prevention in this population remains limited. This thesis, which is comprised of four studies, aimed to advance knowledge in these areas by exploring: (1) the challenges faced by administrators when implementing fall prevention policies and practices in SCI rehabilitation centres, (2) the factors that influence falls/fall risk for wheelchair users with SCI, (3) the psychosocial impact of falls, and the risk of falling on the lives of wheelchair users with SCI, and (4) the perspectives of wheelchair users with SCI on fall circumstances and fall prevention strategies/interventions. Findings from the first qualitative study in this thesis revealed that administrators (n=10) faced challenges with the fall prevention policies/procedures (e.g. not SCI-specific), clinicians (e.g. variable staff adherence), and patients (e.g. balancing risk vs. rehabilitation progress). In study two, photo-elicitation interviews conducted with wheelchair users with SCI (n=12) revealed one overarching theme (i.e. individualized, dynamic, and complex fall risk factors) and four themes: (1) falls and fall risk caused by multiple interacting factors; (2) dynamic nature of fall risk; (3) single factors perceived to reduce falls and fall-related injuries; and, (4) fall prevention experiences and priorities). In study three, photo-elicitation interviews conducted with wheelchair users with SCI (n=12) revealed two themes: (1) varying concern about falling/impact of falls; and (2) fear, falling, and limitations impact daily activities, parenting, work, and leisure/recreation. In study four, thirty-two wheelchair users with SCI participated and more than half of these participants reported a fall over six months. Most fell indoors, in the afternoon, and while transferring or wheeling over uneven ground. Two main themes were identified in study four from a photovoice focus group discussion with wheelchair users with SCI (n=11): circumstances surrounding the falls and preferences for fall prevention strategies/interventions. Current fall prevention approaches fail to meet the complex, dynamic, and individualized fall prevention needs of wheelchair users with SCI, and the psychosocial consequences that could arise from a fall or risk of falling. This thesis advances knowledge to guide fall prevention initiatives for this population.

Keywords: fall prevention
falls
spinal cord injury
Advisor: Musselman, Kristin E
Jaglal, Susan B
Culture, Institutions and Development in Africa

In my dissertation I explore the economic development of Sub-Saharan Africa with a particular focus on the role played by institutions and culture. In the first chapter, The Fruits (and Vegetables) of Crime, I provide experimental evidence that weak institutions that are unable to provide full protection of farm output causes distortions to agricultural production and reduced output as well as imposing social costs through local disputes. In the second chapter, How Cultures Converge with Arthur Blouin, we show, using a novel empirical approach identifying loanwords among languages, that the rate and direction of cultural convergence is endogenous to economic incentives and is shaped by strategic decisions reflecting these incentives. Finally, in the third chapter, Pumps, Prosperity and Household Power with Jeremy Shapiro, we provide experimental evidence that distributing small-scale irrigation pumps to women in farming households is an effective intervention to increase incomes and empowerment of women, in a context where institutional capacity has long constrained the adoption of large-scale irrigation investments.

Keywords: agriculture
culture
development
institutions
security
Advisor: Blouin, Arthur
Bobonis, Gustavo