VictorJuiz/thesis huggingface dataset:
Endogenous Chemical Exchange Saturation Transfer: Quantitative Modelling and Application in Cancer

This work describes the origins of the contrast mechanism chemical exchange saturation transfer (CEST) and methods for proton magnetic resonance imaging (MRI), with application in cancer. It focuses on endogenous techniques, which do not require the injection of a contrast agent, and the experimental and analytic techniques which allow quantitative metrics to be obtained. The theory behind CEST is presented, and it is modelled using a three pool system of Bloch equations which are a function of magnetization relaxation parameters, CEST pool concentration, and hydrogen exchange rate constant. A platform is created for optimization and parameter fitting, which is used to obtain parameter values and for pulse sequence experimental design. The contribution of semi-solid macromolecules to the CEST spectrum is determined, and evidence given that the CEST parameters (in particular, the exchange rate constant) can be obtained independently of this additional pool. It is shown that there is a linear relationship between the log of the exchange rate constant and pH. CEST spectra are obtained in cancer xenografts in mice, exhibiting features from amide, amine and aliphatic protons as well as from magnetization transfer. Semi-quantitative CEST parameter maps are derived, showing the distribution of CEST features in tumours and in contrast with the surrounding normal-appearing muscle. Several exploratory experiments are performed in protein-containing phantoms and cell pellets in order to validate the origins of CEST spectra and their behaviour in conditions of changing pH and temperature. Cell pellet experiments support the hypothesis that CEST is sensitive primarily to intracellular conditions, and furthermore that the cell nucleus is a concentrated source of CEST-contributing proteins. These validation experiments are supportive of the assumptions made in the next section, in which a ratiometric method of determining intracellular pH from CEST spectra is proposed and proof-of-concept experiments are performed. Ultimately, the work contained herein supports the hypothesis that the endogenous CEST experiments provide new information not obtainable from other MRI experiments, leading to quantitative absolute intracellular pH mapping. This has potential for predicting the effectiveness of treatment regimens based upon the relationship between intracellular pH and drug uptake, establishing regions of tumour which are actively proliferating or which may be resistant to therapy.

Keywords: CEST
chemical exchange saturation transfer
magnetization transfer
MRI
pH
Advisor: Stanisz, Greg J
Knowing and Trusting: The Medieval Social Epistemologies of Augustine and Aquinas

This dissertation is an introductory exploration of two influential medieval thinkers, Augustine and Aquinas, on the topic of testimony. I explain how Augustine's view that testimony is a source of knowledge (notitia) developed through four stages, and argue that on Augustine's view testimonial belief is justified inferentially. I argue that Aquinas thinks some testimonial belief is justified inferentially, and some is justified by adhering to the speaker as the formal object of one's belief, on the grounds that the speaker is truthful. I argue that they provide knowledge when they provide "cognitio". And I argue that Aquinas's view can be developed into a plausible account of testimonial trust and trustworthiness.

Keywords: Aquinas
Augustine
knowledge
testimony
trust
Advisor: King, Peter
Hybrid Passive Component for High Frequency and High Efficiency Power Conversion

This thesis proposes a hybrid passive power component that provides dielectric isolation and load-source matching capability, and is a viable alternative to the classical magnetic transformer at high operating frequencies. The hybrid passive power component is comprised of a multi-layer dielectric device denoted as the Multi-Layer Ceramic Isolation Device, which is used for isolated power transfer, and a high frequency air core coupled inductor topology denoted as the Mutual Branch Topology, which provides load-source matching. The Multi-Layer Ceramic Isolation Device is realized based on a four terminal multi-layer ceramic structure with barium strontium titanate and alumina layers. Some key advantages of this device are a reduction in losses over conventional decoupling techniques, high power density and ease of manufacturing due to the planar design. The Mutual Branch Topology is an air-core inductor network which can achieve improved efficiencies over an equivalent two winding classical transformer. The multi-layer ceramic device and air core coupled inductor topology were tested separately and together within a resonant converter topology. A design procedure for each component is presented, along with simulation results that have been experimentally verified. The hybrid passive power component has been shown to have a higher efficiency compared to a classical transformer design in the MHz operating range.

Keywords: air core coupled inductors
high frequency passive device
magnetic transformer
multi layer ceramic isolation device
mutual branch topology
resonant converter
Advisor: Dawson, Francis P.
Ruda, Harry E.
Air, Disease, and Improvement in Eighteenth-century Britain: Sir John Pringle (1707-1782)

The Scottish-born physician John Pringle (1707-1782) achieved remarkable fame as a natural philosopher, eventually becoming a physician to King George III and President of the Royal Society of London. He did so largely on the basis of a single major work. The Observations on the Diseases of the Army (1752), founded on his experience as an Army physician during the War of the Austrian Succession and the Jacobite Rebellion, was a guide to the diseases facing soldiers in Northern Europe. It also examined the nature, prevention, and treatment of epidemic fevers that afflicted large groups living in close proximity. Pringle believed, like many in his day, that epidemic fever was associated with the process of putrefaction taking place within the body. A member of the Royal Society, he performed a series of experiments on putrefaction which were subsequently appended to his Observations. These investigations earned him the Society's Copley medal in 1752, were widely emulated across Europe, and established him as a natural philosopher of note. They represented, I argue, a promising approach to a problem of significant concern to early modern European society. This thesis examines both the nature of Pringle's claims and the manner in which they shaped his reputation as a natural philosopher. Particular attention is paid to Pringle's Scottish education and early career among the medical community at Edinburgh. The first two chapters discuss, respectively, the observational and the experimental foundation of his medical claims. The final two examine his contribution within the context of eighteenth-century British society, especially its relation to the culture of British natural philosophy and the interests of his Hanoverian patrons. A prominent figure within the royal court, the Royal Society, and the military, Pringle became a patron to others whose work furthered his interests. He consequently played a significant role in the emergence of the Chemical Revolution.

Keywords: Chemical Revolution
Enlightenment
Great Britain
History of Medicine
History of Science
John Pringle
Advisor: Levere, Trevor H
Dacome, Lucia
Ethics Experience: Toward a Pragmatist Metaethics

Abstract for Ethics Experience: Toward a Pragmatist Metaethics Submitted for the Degree of Doctor of Philosophy By Diana Beverley Heney, 2014 Graduate Department of Philosophy, University of Toronto This project develops a strain of pragmatist thought arising from the work of Charles Sanders Peirce, carried on by William James, John Dewey, and Clarence Irving Lewis, which is developed for the purpose of intervening in contemporary debates concerning truth and principles in metaethics.

Keywords: Lewis
Metaethics
Peirce
Pragmatism
Advisor: Misak, Cheryl J
The Role Of ECT2 In Astroctyoma Invasion and Stress Granule Formation

In this thesis, the oncogenic role of the cytokinetic RhoA guanine nucleotide exchange factor, ECT2 in astrocytoma is studied. ECT2 is overexpressed in astrocytoma cells, and correlates with poor patient prognosis and increasing astrocytoma grade. ECT2 is a nuclear protein in non- cancerous cells. Here, it is demonstrated that ECT2 is aberrantly located in the cytoplasm of astrocytoma cells at the leading edge of the cell where it activates Rac1 and Cdc42 but not RhoA. Interestingly, ECT2 overexpression results in mesenchymal-amoeboid transition with ECT2 localizing to the retraction bleb in amoeboid cells. Using ECT2 immunoprecipitation followed by mass spectrometry, I identified the novel ECT2 interactor, RASAL2. RASAL2 is a RasGap know to be an inhibitor of breast cancer growth and metastasis. SiRNA-mediated loss of RASAL2 leads to highly invasive astroctyoma cells with an amoeboid phenotype and increased RhoA activity. This suggests that RASAL2 may modulate ECT2 specificity toward critical Rho GTPases. I also demonstrate that ECT2 has a novel role in stress granule formation. Stress granule formation results in translational reorganization that allows cells to survive acute stress such as hypoxia and radiation. ECT2 colocalizes with stress granules and co-immunoprecipites TIAR under stress. SiRNA-mediated silencing of ECT2 results in increased sensitivity to cellular apoptosis and stress granules in a less mature peri-nuclear location, however stress granule number and size are unchanged. The upstream activator of the ECT2 pathway, AurkB, was then examined. I demonstrate for the first time that AurkB and its downstream target phospho- Histone 3 are phosphorylated with cellular stress. Chemical and siRNA mediated interference with AurkB phosphorylation leads to the formation of fewer stress granule of a smaller size and with less TIAR aggregation. Using RNA immunoprecipitation of stress granules, I show that iii mRNA from multiple cellular pathways are contained in astrocytoma stress granules. These pathways include those subserving cellular migration, cellular metabolism, cell death and post translational and transcriptional modifiers. Utilizing a doxycycline-inducible expressing siRNA system, I show that mice injected with ECT2 siRNA live longer, with fewer tumours and decreased invasion than mice injected with NS siRNA controls. Taken together, these data suggest that ECT2 is a putative astrocytoma oncogene that warrants further investigation as a therapeutic target in astrocytoma.

Keywords: ECT2
Glioblastoma
Invasion
mesenchymal Amoeboid Transition
Stress granules
Advisor: Rutka, James T
Functional Properties of Monomers and Oligomers of the M2 Muscarinic Receptor

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and mediate signaling for a host of neurotransmitters, hormones and other stimuli from light to odorants. Despite their ubiquity and importance, their mechanism of action remains unknown. That uncertainty derives in part from uncertainty over their oligomeric status and the origin of a characteristic, efficacy-correlated heterogeneity revealed in the binding of agonists. If GPCRs signal as monomers, the heterogeneity could be induced by the G protein; if they signal as oligomers, it can be attributed to a mix of cooperativity and asymmetry among orthosteric sites within the oligomeric array. A related question concerns the relevance, if any, of a topographically distinct allosteric site known to interact with the orthosteric site. To examine these questions, M

Keywords: aggregation
cooperativity
G protein-coupled receptors
membrane reconstitution
monomers
oligomers
Advisor: Wells, James W
Virtuous Action, Inside and Out

This dissertation states and defends a novel view of virtuous action, motivated by a desire to do justice to the internal and external aspects of evaluating action. I argue that virtuous action is a complex notion, consisting in internal and external success. Acts are internally successful when they issue from admirable motivation, and externally successful when they achieve worthwhile or at least permissible ends. Virtuous action is well-motivated permissible success. I motivate the view by arguing that well-motivated permissible acts constitute organic wholes--entities whose value as wholes is greater than the value of their parts in isolation--and that the resultant view allows us to capture plausible ideas about the relation between virtue and benefit. I then defend the account from three rivals: (i) views on which subjective rightness supplies conditions on virtuous action; (ii) consequentialist theories on which virtue is a function of goodness produced; and (iii) views on which facts about virtue determine facts about rightness. I end by defending two claims about virtuous motivation. The first is variantism about the evaluative valence of individual motives: the fact that an individual motive is good (bad, neutral) in one context does not entail that it is good (bad, neutral) in other contexts. The second is that Aristotelian and Kantian accounts of virtuous motivation do not provide necessary, but may provide sufficient, conditions on all-things-considered good motivation.

Keywords: Action
Motives
Right
Virtue
Virtuous Action
Advisor: Hurka, Thomas
Effect of Genetic Variation on Salt, Sweet, Fat and Bitter Taste

Background: Taste is one of the primary determinants of food intake and taste function can be influenced by a number of factors including genetics. However, little is known about the relationship between genetic variation, taste function, food preference and intake. Objective: To examine the effect of variation in genes involved in the perception of salt, sweet, fat and bitter compounds on taste function, food preference and consumption. Methods: Subjects were drawn from the Toronto Nutrigenomics and Health Study, a population of healthy men (n=487) and women (n = 1058). Dietary intake was assessed using a 196-item food frequency questionnaire (FFQ) and food preference was assessed using a 63-item food preference checklist. Subsets of individuals were phenotyped to assess taste function in response to salt (n=95), sucrose (n=95), oleic acid (n=21) and naringin (n=685) stimuli. Subjects were genotyped for Single Nucleotide Polymorphisms (SNPs) in candidate genes. Results: Of the SNPs examined in putative salt taste receptor genes (SCNN1(A, B, D, G), TRPV1), the rs9939129 and rs239345 SNPs in the SCNN1B gene and rs8065080 in the TRPV1 gene were associated with salt taste. In the TAS1R2 gene, the rs12033832 was associated with sucrose taste and sugar intake. The rs1077242 SNP in the bitter taste receptor gene TAS2R19 was associated with naringin taste and both grapefruit intake and preference. In the putative fat taste receptor CD36 the rs1761667 and rs1984112 SNPs were associated with intake of total, polyunsaturated and monounsaturated fats as well as oleic acid taste. Conclusions: Our findings demonstrate that genetic variation is associated with differences in taste function, food preference and intake across a number of taste modalities.

Keywords: Bitter
Fat
Genetics
Salt
Sweet
Taste
Advisor: El-Sohemy, Ahmed
Covariation Methods in Proteomics

Covariation is a commonly observed process that can occur in biological systems where two characteristics experience change as influenced by their mutual feedback. This phenomenon occurs at varied biological scales, from macroscopic to molecular, and suggests an interaction between the evolving characteristics. Increasing availability of sequence data affords the material for examination of molecular covariation. This thesis examines molecular covariation using different elements of proteomic data and applies computational methods to infer protein functional pathway membership, protein-protein interactions and protein structure. We examine molecular covariation using stratified units of proteomic information - entire proteomes, comparison between (inter-) protein sequences and finally comparison within (intra-) protein sequences. Using entire proteomes, phylogenetic profiling assists in understanding the loss of the essential chaperonin GroEL in some species of Mycoplasma, and suggests a role for the chaperonin in adhesion-invasion. Diving further into the proteomic detail, we probe distances between protein sequences, using our MMM algorithm to detect covariation between phylogenetic trees as in indication of protein-protein interaction. In the Human co-evolution network, we find two subnetworks divided on the basis of evolutionary age. Finally, we introduce multi-dimensional mutual information (mdMI) as a means to detect intra-protein contact points through correlated mutation analysis and show that mdMI's accuracy is comparable to leading methods despite low computational time. Additionally, we also explore evidence that the physiochemical environment can unilaterally influence covariation score. The covariation methods applied and analyzed here represent a general approach to solving broad biological problems.

Keywords: bioinformatics
coevolution
molecular evolution
protein
Advisor: Tillier, Elisabeth R M
Activating Neural Stem and Progenitor Cells to Enhance Neural Repair

The discovery of neural stem cells in the adult brain has led to the promise of utilizing these cells to promote neural repair after injury or disease. Stroke is one of the leading causes of death and disability worldwide and there are currently no interventions that repair the brain following stroke. While neural stem cells and their progeny (together termed precursor cells) are activated following brain injury, this response alone is not sufficient to promote tissue repair or functional recovery. In order to enhance neural repair, it is important to characterize the neural stem cell pool, factors that stimulate neural precursors, and induce their proliferation, migration, and differentiation following injury. Herein, I have shown that adult neural precursor cell behaviour can be modulated throughout life using a number of different methods of stimulation. In considering strategies to activate endogenous neural precursor, I have elucidated the mechanism by which the pro-survival factor Cyclosporin A (CsA) affects enhanced neural precursor survival, specifically by inhibition of mitochondrial permeability transition pore formation. Furthermore, I considered the limitations of aging in the brain and have demonstrated that the old age brain can, in fact, respond to CsA in the same manner as was shown to enhance tissue regeneration and functional recovery in young adult mice. Subsequently, given the pro-survival effects of CsA, I have explored endogenous survival factors present in the developing brain to determine whether the adult neural precursor population can be modified by activating signaling pathways seen in development. I have shown that adult neural stem cells remain responsive both in vitro and in vivo to stromal cell-derived factor -1α (SDF-1α) and stem cell factor (SCF) released from embryonic neurons during development. Finally, I have identified a novel population of stem cells that retain characteristics of primitive neural stem cells, which were thought to disappear during development. I have characterized this rare population of primitive neural stem cells in the adult brain showing they are responsive to leukemia inhibitory factor (LIF); they express the pluripotency marker Oct4, and they give rise to the definitive, well characterized neural stem cell in the adult brain. Significantly, these adult primitive neural stem cells respond to stroke injury by proliferating to effectively increase the size of the primitive neural stem cell pool, further suggesting that this cell population may be a target for regenerative strategies. Together, these findings provide insights into the factors that modify neural precursor pools towards the goal of developing novel stem cell based strategies for neural repair.

Keywords: CsA
LIF
neural stem cells
SCF
SDF-1
stroke
Advisor: Morshead, Cindi M
The Response of Individual Microbubbles to High Frequency Ultrasound

The majority of studies investigating the physics of ultrasound-triggered microbubble behaviour have been conducted at low frequencies (<5 MHz), motivated by imaging applications for the heart, liver and pancreas. There is gaining interest, however, in employing contrast imaging strategies to higher frequency applications where microbubble behaviour is less well understood, including imaging of the breast, carotid and intravascular imaging. It has been recently recognized that the assessment of individual microbubbles, as opposed to bubble populations, is a powerful approach to gain physical insight into the response of microbubbles to ultrasound. This thesis investigates the response of individual microbubbles in the 5-25 MHz range, motivated by high-frequency imaging applications. It was shown that there exists heterogeneity in nonlinear response between microbubbles of similar encapsulation materials in terms of active bubble size, signal amplitude, disruption threshold and bubble state (bound versus unbound). Furthermore, it was determined that microbubbles exhibit “expansion-dominated” radial oscillations, the opposite asymmetry to that which has been observed at lower frequencies. In addition, microbubbles were shown to exhibit nonlinear resonance phenomena at low acoustic pressures, and the encapsulation material was determined to exhibit “strain-softening” rheology. Finally, the effect of boundary proximity on the frequency (fMR) and amplitude (AMR) of maximum response was assessed. In proximity to a polystyrene layer, the scattered emissions exhibited an interference-pattern based response due to the large mismatch in acoustic impedance. For a more biologically relevant boundary, the influence of the boundary is greatest in close proximity (< 10 µm), and results in changes of approximately 10% for fMR and AMR when in physical contact with the boundary as compared to their responses in an unbounded liquid, a behaviour not completely captured by modeling efforts. The insights gained from this thesis can aid in optimizing agent design, improving bubble-specific detection strategies and contrast image quantification.

Keywords: Contrast Imaging
High Frequency
Microbubbles
Nonlinear
Subharmonic
Ultrasound
Advisor: Goertz, David E