VictorJuiz/thesis huggingface dataset:
A Comparison of the Response of Intramuscularly Delivered Neonatal and Adult MSCs to Distant Source of Inflammation

Transplanted mesenchymal stromal cells (MSCs) have been shown to modulate host inflammatory responses in a wide range of immune disorders and tissue injuries. However, little is known of the relationship between MSC tissue source and their rate of response to an inflammatory trigger. We hypothesized that a neonatal source of MSCs, intramuscularly (IM)-delivered, will downregulate a distant source of inflammation more efficiently than an MSC population derived from an adult tissue source. The immunomodulatory response of MSCs was assessed systematically in-vitro, and comprehensively in-vivo from an anatomically distant location to the inflammatory trigger. The key anti-inflammatory tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6)–only expressed upon stimulation–has been used as a surrogate to scrutinize the response time of human umbilical cord perivascular cells (HUCPVCs), and human and mouse bone marrow MSCs (BMMSCs). In-vitro, HUCPVCs, human and mouse BMMSCs were stimulated with recombinant TNF-α over various exposure times and concentrations. HUCPVCs showed higher sensitivity to TNF-α stimulation compared with hBMMSCs, but expression level varied across donors. Both human derived MSC sources showed higher response to TNF-α stimulation than mBMMSCs. Following the in-vitro studies, a unilateral hind paw inflammation was created in-vivo with carrageenan in immunocompetent mice. The three sources of MSCs were IM-delivered in the contralateral quadriceps, at the first inflammatory peak. Post 24h, the TSG-6 level in the tissue at the site of cell injection was significantly higher in the HUCPVC compared to the hBMMSC group, and all measures of inflammation were downregulated more rapidly. Since HUCPVCs showed earlier response to inflammation compared with BMMSCs, we believe neonatal MSCs may be a stronger candidate to treat inflammatory diseases than adult BMMSCs.

Keywords: Adult
Bone Marrow Mesenchymal Stromal Cells
Inflammation
Mesenchymal Stromal Cells
Neonatal
Umbilical Cord Perivascular Cells
Advisor: Davies, John E.
Experimental Characterization of Membrane Fouling under Intermittent Operation and Its Application to the Optimization of Solar Photovoltaic Powered Reverse Osmosis Drinking Water Treatment Systems

This thesis presents a novel experimental characterization of reverse osmosis membrane fouling from the intermittent operation of solar powered water treatment systems. This thesis also depicts the development of an analytical membrane fouling model and a design framework to configure location-customized solar photovoltaic reverse osmosis systems. The World Health Organization estimates that 760 million people worldwide lack access to clean drinking water. The regions with the highest water scarcity are usually off-grid, remote and have high solar insolation. Therefore, the use of solar powered reverse osmosis water treatment systems is a viable solution. However, to minimize the costs, these systems are configured with minimal battery storage and operated intermittently with extended shutdown periods. Literature lacks an experimental characterization of the effect of this intermittent operation on membrane fouling and an associated design optimization framework. This research work on reverse osmosis water treatment systems is divided into two main parts: (1) the experimental characterization of membrane fouling under intermittent operation, and (2) the development of an analytical membrane fouling model and a design optimization framework for these systems. A new fully-instrumented experimental lab-scale system was designed, built, commissioned and operated with triplicate measurements of membrane permeability and membrane salt rejection for the experimental characterization. A new pilot-scale experimental system was also designed, built and operated. The membrane fouling was characterized experimentally for intermittent and continuous operation. The effect of anti-scalant and rinsing was also investigated. Two types of experimental water was tested: an experimental MilliQ-based matrix and an experimental groundwater-based matrix. The groundwater was from Nobleton, Ontario. In addition, membrane autopsy was performed using scanning electron microscopy. An analytical membrane fouling model was developed based on the experimental results. Furthermore, a novel design framework was developed using this new analytical membrane fouling model. This design optimization framework can be used for the configuration of community-specific solar photovoltaic reverse osmosis systems that are reliable throughout the system life at a minimal cost. The design optimization framework can be adapted for other modular systems such as renewable power systems for off-grid communities, remote First Nations, Métis, and Inuit communities, or remote mining sites.

Keywords: Desalination
Design Optimization
Experimental
Membrane Autopsy
Renewable powered
Reverse osmosis
Advisor: Bilton, Amy M
The Role of Empowerment on the Relationship between Flexible Work Arrangements, Work-Life Balance, and Job Satisfaction in the Canadian Public Sector

Some studies have shown strong support for positive outcomes related to flexible work arrangements such as improved performance and productivity (Bloom, Liang, Roberts, Ying, 2015; Laschinger, Finegan, Shamian, Wilk, 2001; Laschinger, Leiter, Day, Gilin, 2009), while others have found detrimental effects including negative impacts on managing and separating work, life, and family demands (Cohen Single, 2001; Yuile, Chang, Gudmundsson, Sawang 2012). The typical approach to studying flexible work arrangements is to examine outcomes at the individual level among employees, assessing the relationship with performance and work-life, or work-family balance. This study examined the relationship between flexible work arrangements and job attitudes and work-life balance, simultaneously at both the individual and organizational unit level of analysis in the Federal public sector in Canada. The data is from responses captured five times over the span of 12 years within the public-sector workforce. The findings provide further contributions to the body of research on the job demands-resources model (Bakker Demrouti, 2007) and support the idea that some types of flexible work arrangements are positively related to work-life balance and job satisfaction, while also being positively mediated by structural empowerment of employees. These findings hold both at the individual and organizational level. Certain flexible work arrangements, namely flextime and telework, show consistent and positive relationships with work-life balance at both the individual and organizational unit level. Compressed work weeks, and income averaging, however, show signs of negative relationships and require further study. A critical finding of this study is that empowerment consistently fosters improved work-life balance and job satisfaction, providing strong evidence for practitioners to prioritize employee structural empowerment as part of strategic human resource plans.

Keywords: Empowerment
Flexible Work Arrangements
Job Demands Resources
Job Satisfaction
Work-Life Balance
Advisor: Latham, Gary P
DNA methylation alterations associated with tumorigenicity in germline TP53-mediated cancer susceptibility

Aberrations in the epigenome, including DNA methylation alterations, are known to play an important role in tumor initiation and progression. However, the extent of interplay between constitutional mutations as a molecular driving force, and epigenetic dysregulation in relation to cellular transformation of cancer predisposition syndromes specifically, is relatively unexplored. Li-Fraumeni Syndrome (LFS) is an autosomal dominant inherited disorder predisposing individuals harbouring a germline TP53 mutation to a spectrum of tumors. TP53 mutant carriers harbor distinct methylation patterns in peripheral blood lymphocytes, further validating genetic aberrations alone to be insufficient in explaining the heterogeneous clinical phenotype of LFS. In this thesis, I describe the association between DNA methylation aberrations and tumorigenicity in the context of cancers arising in germline TP53 mutation carriers, and demonstrate the feasibility of using circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) as a non-invasive diagnostic technique complementing current surveillance strategies, to better stratify and detect occult cancer in asymptomatic LFS patients. I have identified a highly robust and reproducible DNA methylation signature associated with replicative senescence in serially passaged LFS primary fibroblasts. I have also identified hypomethylation of an enhancer region mapping to the oncofetal gene, insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), in LFS tumors to be associated with enhanced tumorigenic potential. Tumor specific differential methylation of IGF2BP3 in relation to paired blood renders this a potentially attractive epimolecular marker for future ctDNA studies in LFS. Finally, I demonstrate there to be an association between cfDNA concentrations and LFS patients with a positive clinical history, rendering this the first study to explore the feasibility of using liquid biopsy modalities for early cancer detection in the context of cancer predisposition. Future studies should consider tumor-specific markers for ctDNA analysis, including epimolecular markers identified from this thesis, for accurate and sensitive detection of occult cancer in asymptomatic LFS patients in clinic. Taken together, these studies are the first to provide a comprehensive genome-wide methylation analysis associated with germline TP53 mutated tumorigenicity, and in exploring the utility of ctDNA as a surveillance tool for early cancer detection in LFS.

Keywords: cancer pre-disposition
circulating DNA
early cancer detection
epigenetics
Li-Fraumeni syndrome
methylation
Advisor: Malkin, David
Therapeutic Monoclonal Antibodies to Detect and Halt ATTR Cardiac Amyloidosis and Neuropathy

Transthyretin (prealbumin, TTR) is an abundant serum protein which transports vitamin A and thyroid hormone T4 throughout the body. Although TTR normally forms stable soluble homotetrameric complexes, point mutations and unknown pathological conditions can favour the dissociation of the TTR tetramer into misfolded monomers which can aggregate and accumulate as transthyretin amyloid (ATTR) throughout the body, particularly in the heart and peripheral nerves. Cardiac ATTR deposition leads to cardiomyopathy, heart failure, and death; nerve deposition causes neuropathy. At present, endomyocardial biopsy is the only method for conclusively diagnosing ATTR amyloidosis and no FDA-approved pharmacotherapies exist. The only treatment option is organ transplantation (heart and/or liver) for a subset of eligible patients. This thesis focuses on the development of conformation-specific polyclonal/monoclonal antibodies which can potentially diagnose/treat both hereditary and wild-type ATTR amyloidosis, through their ability to specifically recognize and bind to disease-associated forms of TTR via a cryptotope (an epitope normally buried and inaccessible in the native protein, but exposed in its altered conformation). These monoclonal antibodies (mAbs) were demonstrated in vitro to specifically bind misfolded TTR, inhibit fibril formation, induce phagocytic clearance of non-native and aggregated TTR, and specifically recognize TTR amyloid in diseased heart tissue. We further investigated the mechanism of mAb-mediated inhibition of fibrillogenesis using immunogold transmission electron microscopy (IGEM). This high resolution imaging technique confirmed this cryptotope to be an effective antibody target due to its exposure within both pathological TTR misfolding intermediates and end-point insoluble TTR fibrils. In addition to their ability to recognize TTR aggregates in vitro, these monoclonal antibodies demonstrated the ability to specifically recognize soluble, misfolded TTR aggregates in vivo in the plasma of transgenic ATTR mouse models. These results further support the use of monoclonal antibodies to target pathological protein conformations as potentially effective immunotherapies for ATTR amyloidosis.

Keywords: Amyloid
ATTR Amyloidosis
Cardiac Amyloidosis
Cardiomyopathy
Immunotherapy
Transthyretin
Advisor: Chakrabartty, Avijit
The Effect of Accent Exposure on Social Cognition and Language Acquisition in Early Childhood

It is common in many parts of the world for children to grow up in linguistically diverse communities. Despite this, developmental psychologists have only recently begun to examine the impact of language variation (i.e., hearing multiple languages and accents) on children. In this thesis, I examine aspects of the social and linguistic development of children living in one of the most culturally and linguistically diverse regions in the world (i.e., the Greater Toronto Area). In Chapter 2, I examine how exposure to accent variation shapes children’s friendship preferences. My findings suggest that despite having regular accent exposure, children living in diverse communities show strong social preferences for peers that speak with the locally dominant accent. However, the strength of children’s preferences seems to be modulated by their exposure to accented speakers in everyday life. In Chapter 3, I consider how linguistic diversity could impact infant’s ability to tell apart languages. My results suggest that although 5-month-olds can tell when an L1 bilingual speaker switches from English to Spanish, they have difficulty distinguishing Spanish and Spanish-accented English samples produced by a L2 English speaker. Finally, in Chapter 4, I examine how brief exposure to speakers with different types of accents can influence speech production. More specifically, I examine children and adult’s imitation of model speakers from their own linguistic community and different linguistic communities. Contrary to previous work, I found no evidence that children imitate model speakers more strongly than adults. However, my results suggest that imitation can be influenced by both the accent of the model speaker and the test methodology. In combination, the three studies reported in this thesis advance our understanding of how accent exposure influences children’s speech perception and social behavior, and highlight the importance of considering real-world accent variation in models of social and linguistic development.

Keywords: accents
developmental psychology
infant speech perception
language acquisition
phonetic convergence
social preferences
Advisor: Johnson, Elizabeth K
Multiscale Modeling of Multifunctional Carbon Nanotube Reinforced Polymer Composites

In this thesis, novel multiscale modeling techniques have been successfully developed to study multifunctional nanocomposite polymeric materials. Interfacial, mechanical, electrical, and piezoresistive properties of carbon nanotube (CNT)-reinforced polymer composites were investigated using molecular dynamics (MD), micromechanics, and coupled electromechanical modeling techniques. Additionally, scanning electron microscopy was used to determine the morphology and dispersion state of a typical CNT-epoxy composite. Based on these measurements, realistic nanocomposite structures were modeled using representative volume elements (RVEs) reinforced by CNTs with different aspect ratios, curvatures, orientations, alignment angles, and bundle sizes. At the nanoscale level, the interfacial shear strength was determined via pull-out MD simulations. Additionally, the stiffness constants of a pure polymer, pristine and defective CNTs, and an effective fiber consisting of a CNT and a surrounding layer of polymeric chains were determined using the constant-strain energy minimization method. The obtained atomistic mechanical properties of the composite constituents were then scaled up using Mori-Tanaka micromechanical scheme. Monte Carlo simulations were conducted to determine the percolation and electrical conductivity of RVEs containing randomly dispersed CNTs. An advanced search algorithm was developed to identify percolating CNT networks and transform them into an equivalent electrical circuit formed from intrinsic and tunneling resistances. A solver based on the modified nodal analysis technique was then developed to calculate the effective conductivity of the RVE. Finally, the electrical model was coupled with a three-dimensional finite element model of the RVE to determine the coupled electromechanical behavior of the composite under tensile, compressive, and shear loads from the resistance-strain relationship. The outcome of the developed modeling approach revealed that: the elastic modulus of a nanocomposite reinforced with well-dispersed straight CNTs was found to increase almost linearly with the increase of their volume fraction and double at CNT volume fraction of 5.0 %; the combined effect of CNT waviness and agglomeration results in a significant reduction in the bulk properties of the nanocomposite; CNTs with grain boundaries perpendicular to the tube axis experience 60% reduction in its mechanical strength; and the nanocomposite gauge factor can reach up to 3.95 and is sensitive to loading direction and CNT concentration.

Keywords: Carbon Nanotube
Finite Element Analysis
Micromechanics techniques
Molecular Dynamics Simulations
Multifunctional Nanocomposites
Multiscale Modeling
Advisor: Meguid, Shaker A.
New Approaches to High Efficiency Inductively Coupled Plasma Analytical Atomic Spectrometry

Two new strategies have been proposed for reducing the gas and energy consumption of ICP sources, in the first place, and improving their analytical performance, in the second place, for analytical atomic spectrometry. In the first strategy, a system was designed to collect the exhaust argon from the interface of an ICP-MS system, purify it, and recycle it back to the ICP torch. The experiments showed that the argon collection system was capable of withstanding the extreme temperatures of the plasma and collect most of the exhaust gas without disturbing the plasma. In the first stage of purifying the gas, a metal-foam heat exchanger coupled with a Peltier cooler was used to freeze the water content of the exhaust gas. In the second stage, a titanium-based heated filter was used to capture the other contaminants. The purification system was shown to be capable of purifying the exhaust argon for several hours of operation. In the second strategy, a new ICP torch was developed with significant reduction in gas and power consumption, but better analytical performance. Computer simulations were used extensively to design and optimize the torch based on the flow patterns, heat transfer, and electromagnetic field. This approach led to a new generation of ICP torches with a “conical” geometry. The new torch could work with up to 70% reduction in gas/energy consumption, at least 4 times higher power density, and a more stable plasma in comparison with the conventional “cylindrical” torches. Based on spectroscopic measurements, in comparison with the common Fassel-type torches, the new torch exhibited 1000–1700 K higher excitation/rotational temperature, 3 times higher robustness, 5 times higher electron density, less interference from easily-ionizable elements, and equal/better detection limits in multi-element analysis. It was further demonstrated that the whole vaporization/atomization/ionization of sample species could be completed in a shorter time using the new torch. Analyzing metal-tagged beads/cells with a commercial CyTOF2 mass cytometer showed that 50% reduction in event length and 2 times higher sensitivity could be achieved using the new torch. These improvements can potentially lead to higher sample throughput and shorter time of analysis per sample.

Keywords: Analytical Chemistry
Argon Recylcing
ICP-MS
ICP-OES
Inductively Coupled Plasma Torch
Mass Cytometry
Advisor: Mostaghimi, Javad
The Effects of Surface Anisotropy on Reaction Dynamics

Reaction dynamics of meta-diiodobenzene (mDIB) and trifluoromethyl (CF3) was studied on the anisotropic Cu(110) surface at 4.6 K using Scanning Tunneling Microscopy (STM). Both systems were modeled by Density Functional Theory (DFT). The surface anisotropy, given by rows of Cu-atoms along the [11 ̅0] direction, was found to give three previously unreported outcomes: product rotation, bond-selectivity, and ‘surface-molecular-beams’. In the electron-induced reaction of mDIB, iodophenyl product rotation was observed following single C-I bond dissociation in the major pathway. The rotation was shown to be caused by the attraction between the I-atom of the iodophenyl and the raised Cu-rows. In a minor pathway both C-I bonds were broken concurrently to give I-atoms from an un-rotated mDIB attributable to short iodophenyl lifetime. Since the extent of the iodophenyl rotation correlated with its rotational lifetime, the observed rotation could be used with the aid of theory to ‘clock’ the reaction dynamics. Bond-selectivity was observed in the C-I electron-induced dissociation of physisorbed mDIB. The C-I bond directed along the Cu-row was found to dissociate with a hundred-fold greater probability than the C-I directed across the Cu-row. This large bond-selectivity was due to the added electron impulsively propelling the system towards a lower energy barrier when the C-I bond was directed along the Cu-row, in which case C-Cu attraction stabilized the transition state. Novel ‘surface-molecular-beams’ of a difluorocarbene (CF2) ‘projectile’ were generated from the electron-induced dissociation of CF3. In the beams the CF2 projectile traveled unidirectionally along a Cu-row as far as ~50 Å, by translation-rotation coupling analyzed as ‘ratcheting’. In further work the CF2 ‘projectile’ was aimed at a stationary CF2 ‘target’ with selected impact parameter, and collision energy. At zero impact parameter and high collision energy the C2F4 product was formed recoiling ‘forward’, due to retention of translational energy along the direction of the incoming projectile. At low collision energy the C2F4 product recoiled ‘backward’, due to association reaction catalyzed by a raised surface Cu-atom.

Keywords: Density Functional Theory
Reaction Dynamics
Scanning Tunneling Microscopy
Surface Aligned Reactions
Surface Chemistry
Surface Science
Advisor: Polanyi, John C
c-Src Controls Mouse Embryonic Osteogenic Differentiation Through Regulation of Stat1 Stability

The protein tyrosine kinase Src is expressed ubiquitously and is involved in differentiation. However, the role of Src in osteogenic differentiation is complex since it has been reported to function both as repressor and activator. Using the small molecule inhibitor PP2, c-Src specific siRNAs, and tet-inducible lentiviral vectors overexpressing constitutively active c-Src, I confirmed c-Src inhibitory role in mouse embryonic stem cells (mESCs) and mouse preosteoblast MC3T3-E1s osteogenic differentiation. I further predicted that the increased level of osteogenic differentiation is regulated through Runt-related transcription factor 2 (Runx2). Additional analysis revealed that active c-Src (p-Y416-c-Src) lowers Runx2 nuclear localization and transcriptional activity in mESCs without having any effect on Runx2 expression level. I provide the first evidence linking inhibitory role of c-Src to Runx2 subcellular localization through signal transducer and activator of transcription 1 (Stat1), the cytoplasmic anchoring partner of Runx2. I discovered that higher level of active c-Src increases Stat1 protein half-life by inhibiting Stat1 proteasomal degradation. Therefore, by inhibition of c-Src activity, Stat1 protein level is reduced resulting in less of interaction with Runx2. This in turn increases nuclear localization and transcriptional activity of Runx2. Collectively, my study has defined a new mechanism, by which c-Src activity inhibits transcriptional regulation of osteogenesis.

Keywords: Bone
Differentiation
Embryonic stem cells
Runx2
Src
Stat1
Advisor: Opas, Michal