VictorJuiz/thesis huggingface dataset:
13C PEG as an In Vivo Macromolecular Probe for MRI and Biophysical Studies of Detergent-Peptide and Detergent-Detergent Interactions using NMR
Keywords: HMQC
molecular imaging
MRI
PEG
poly(ethylene glycol)
quantitative

In the first part of this thesis, a new platform technology is demonstrated for the direct in vivo observation and quantification of macromolecular constituents, such as proteins and drug delivery systems, using 1H MRI. To overcome sensitivity challenges, a 28 kDa non-immunogenic tag is employed, consisting of 13C-enriched polyethylene glycol (PEG), whose spectroscopically equivalent 1H nuclei provide a signal amplification of 2500. Passing the 1H PEG signal through the directly coupled 13C nuclei enables the removal of background water and fat signal. Imaging capabilities are demonstrated by monitoring the real-time clearance of PEG and pegylated albumin in the hind leg of a mouse. Improvements to the initial imaging methodology are subsequently proposed, which increase the sensitivity and extend the imaging capabilities to abdominal and cranial regions. Ex vivo detection of pegylated constituents is also possible using NMR spectroscopy. Using blood as a sample biological fluid, clearance profiles of both unlabeled and 13C labelled PEG, as well as a pegylated protein were determined in rats. The second part of this thesis describes biophysical interactions of detergents with either peptides or other detergent molecules. Firstly, the effects induced by a single polar substitution on the structure and topology of model α-helical transmembrane segments were investigated. Upon substitution of a central isoleucine for an asparagine, diffusion NMR measurements revealed that the asparagine-containing peptide bound ~ 20% less detergent. Secondly, NMR was used to investigate the micellization process. A rapid method to determine thermodynamic and volumetric parameters, which relies on a single subtle change in the 1H chemical shift, was developed. The thermodynamic quantities were then related to spectroscopic studies of topology and micelle structure.
Investigating Controls on Variation in Isotopic Fractionation during Biodegradation of Chlorinated Ethenes and Ethanes
Keywords: Biodegradation
Bioremediation
Chlorinated ethanes
Chlorinated ethenes
Compound specific isotope analysis

Kinetic isotope effects occur due to different reaction rates for light and heavy isotope-containing molecules, and are controlled by the bonds broken during degradation. For many primary pollutants, stable carbon, hydrogen, and chlorine isotope effects have been found to fit a Rayleigh model, indicating a single rate-limiting step. This thesis examines biodegradation pathways where additional controls and rate-limiting steps may affect observed isotope fractionation. Two haloalkane dehalogenases catalyzed aerobic 1,2-dichloroethane (1,2-DCA) dechlorination with very different enzyme affinities and turnover rates. However, carbon isotope enrichment factors were the same for both enzymes, reflecting the intrinsic kinetic isotope effect associated with C-Cl bond breakage. Carbon isotope fractionation was also largely constant during anaerobic 1,1,1-trichloroethane (1,1,1-TCA) biodegradation, even when the rate of biodegradation was inhibited by trichloroethene (TCE) co-contamination. This finding provided the basis for carbon isotope-based assessment of 1,1,1-TCE biodegradation at a TCE co-contaminated field site. The wide range of carbon isotope fractionation observed for anaerobic tetrachloroethene (PCE) biodegradation has been a matter of longstanding controversy. This work found the magnitude of carbon isotope fractionation for PCE biodegradation is related to the phylogenetic relationships between PCE-degrading organisms, which may allow for better selection of enrichment factors when assessing PCE biodegradation at field sites. Unexpectedly large variations in carbon isotope fractionation have also been observed for anaerobic TCE biodegradation. During C-Cl bond breakage, slopes of dual element carbon and chlorine isotope effects are typically constant for a given reaction because additional rate-limiting steps affect both elements in a similar way. Hence, characteristic combinations of C/Cl isotope effects can be used to investigate the underlying mechanistic details of a reaction. For TCE biodegradation, C/Cl isotope slopes indicate different reductive dehalogenases may catalyze different reductive dechlorination reaction pathways. This thesis advances the application of compound specific isotope analysis for assessing bioremediation of chlorinated ethenes and ethanes, as well our understanding of the enzymatic degradation mechanisms that catalyze biodegradation.
Time and How to Calculate It: A Study and Edition with Translation of Book 10 of Hrabanus Maurus' De rerum naturis
Keywords: Computus
De rerum naturis
Easter
Encyclopedia
Fulda
Hrabanus Maurus

This study investigates the text and context of book 10 of Hrabanus Maurus' De rerum naturis (DRN) and presents a new edition of the Latin text and an English translation. Chapter one provides an introduction to the topic of computus in the early middle ages, beginning with a definition of the term computus and its cognate disciplines. The chapter continues with a summary of the historical development of the computistical sciences from the early Christian church up to the Carolingian age. In order to contextualize book 10 of DRN, an overview of the encyclopedic genre is offered to lead into the discussions of Hrabanus' computistical and encyclopedic works: De clericorum institutione, De computo, and DRN. Chapter two presents the first modern edition of the Latin text of book 10 of DRN based on the earliest manuscripts and includes descriptions of the sources and textual history, the manuscript witnesses used, and the editorial principles applied. Chapter three provides a commentary on the structure, content, textual sources, and literary traditions of book 10 of DRN. Particular attention is given to the four main source authors: Venerable Bede, Isidore of Seville, Cassiodorus, and the anonymous author of the Clavis Melitonis. As well, previously unidentified passages in book 10 are now attributed to eight new sources including works by Ambrosiaster, Origen, and Paterius. Additional passages which were introduced in the later manuscript and print traditions have also been identified and sourced. Chapter four explores the reception and influence of book 10 of DRN and the story behind the possible twelfth-century additions to the text as well as possible future avenues of study. The three appendices comprise the new English translation of book 10, a glossary of computistical terms, and instructions for calculating the date of Easter.
An Evolutionary Model of the Boy's Quest, 1863-1901
Keywords: Children's literature
Genre studies
Quest-romance
Representations of boyhood
Victorian literature

In tandem with the coming-of-age of children's literature itself, this dissertation explores the growth of the boy's quest-romance, a sub-genre of nineteenth-century boy's adventure literature. Like Franco Moretti, who observes that literary forms evolve according to the "pressure of cultural selection," I posit an evolutionary model of the boy's quest, focusing on the work of George MacDonald, Charles Kingsley, R.L. Stevenson, and Rudyard Kipling as forming a hypothetical branching of this model (Graphs, Maps, Trees 72). By framing close-readings of primary texts within the historical and literary cultural climate of the mid-to-late nineteenth century, I trace how the boy's quest evolves in response to popular tastes: first by disengaging itself from its Evangelical roots, and later by initiating a modernist experimentation with the linear quest structure. While Jacqueline Rose argues that children's writing resists such experimentation, my study challenges this view by demonstrating that children's literature does not simply reflect cultural change but also pioneers this change with its capacity for generic innovation. Focusing on the intersection between gender and genre in these texts, I begin by exploring this model of the boy's quest in MacDonald's Princess books (1872, 82) in order to test its gendered restrictions; by shifting his focus from Irene's search for identity to that of her male companion Curdie, MacDonald reinforces the connective thread between masculinity and quest-romance that my dissertation outlines. I next explore Kingsley's The Water-Babies (1863), in which the male narrator's emphasis on physical courage or "pluck" distances Kingsley's work from that of his Evangelical contemporaries and establishes an important precedent for Stevenson's "a-moral" romances. By highlighting David's ability to manipulate his own representation as a storyteller, I aim both to overturn the caricature of "poor Davie" common in criticism of Kidnapped (1886) and Catriona (1893), and to suggest that Stevenson is introducing metafiction to the quest-romance, a trend that Kipling continues in the Mowgli stories (1893-5) and Kim (1901). In attempting to evade his protagonists' adult roles as imperial agents, Kipling dismantles the linear quest in favour of perpetual childhood, establishing an important precedent for J.M. Barrie into the early twentieth century.
Anti-money Laundering and Counter-terrorist Financing Policy in Canada: Origins, Implementation, and Enforcement
Keywords: banking
banks
Canada
Financial Action Task Force
money laundering
terrorist financing

This thesis outlines and traces the process of reporting transactions that may be related to money laundering or terrorist financing in Canada. First, this dissertation examines the enactment of the Proceeds of Crime (Money Laundering) and Terrorist Financing Act (PCMLTFA). The process of legislating against these activities was one of norm recursivity, in which Canadian parliamentarians increasingly adopted the standards of the Financial Action Task Force--a group of the G8 mandated to standardize and harmonize national anti-money laundering legislation--not because of global hegemonic pressure, but because of an increasing awareness of Canada's own role as a global citizen in the international community. This work then examines the implementation of this legislation by looking at its deployment in Canadian retail banking. It examines at the process of training financial institution employees to engage with the PCMLTFA, and subsequently the use of the PCMLTFA by employees. This study argues that the risk management techniques in the bank responsibilize employees through responsibilization and normalization; however, the presentation of anti-money laundering and counter-terrorist financing (AML/CTF) legislation to employees may be problematic insofar as the stresses on adverse consequences to employees may be overstated, leading to over-reporting by employees in an effort to manage their own risks. Next, it looks at the ways bank employees are trained to use the legislation, how they understand their legal obligations, and how they use the legislation to identify transactions that appear suspicious or unusual. It demonstrates that bank employees are transformed into third party police, engaging in the detection of suspicious financial transactions on behalf of the government, and interrogates the implications of this development in the AML/CTF complex. This study also examines the detection of suspicious transactions by employees, and demonstrates that both factors directly related to the transaction, such as the amount of money and financial instrument presented, and factors related to the client, such as race, age, sex, and gender, can influence an employee's perception of the legitimacy of this transaction. It then concludes by identifying directions for future research and discussing the scholarly contributions of this study.
From causes to Forms: The Phaedo and the foundations of Platonic metaphysics
Keywords: causation
Forms
metaphysics
Phaedo
Plato
Theory of Forms

Plato believed that Forms were causes. Why? Philosophers since Aristotle have contended that Forms cannot be causes in any legitimate sense, and have downplayed the Forms' alleged causal status in making sense of Platonic metaphysics. I show that Forms are causes in a distinctive, pre-Aristotelian sense, and that this sort of causality is fundamental to what Forms are. I begin with a new account of what a cause is for Plato, based on Phaedo 96-107: the cause of something's F-ness is that thing which has been added to it, such that it is now F - what I call the "ingredient cause" (e.g., the ingredient cause of this coffee's sweetness is the sweetener which was added to it). This would have been an intuitive model of causation for Plato, familiar from Anaxagoras and the Hippocratic writers. Furthermore, all of the Phaedo's peculiar causal principles can be derived from this definition (e.g., that a cause of F-ness cannot itself be un-F). Forms are explicitly identified as universal (ingredient) causes at Phaedo 100. I demonstrate that this is because, for Plato, universal causes are, fundamentally, what Forms are. First, I show that universal causes correspond to various "proto-Forms", e.g., Socratic definitions. Second, I show that the Phaedo is a series of hypothetical arguments, all starting from the assumption that there are universal causes, from which different canonical features of the Forms are derived, e.g., imperceptibility at 65, eternality and unchangingness at 78-80. This interpretation illuminates the Forms' most contentious features. Self-Predication - the thesis that each Form of F-ness "is F" - is a consequence of the Forms' being causes, since any ingredient cause of F-ness must itself be F. Furthermore, the Phaedo indicates that a cause of F-ness "is F" specifically in that the definition of F-ness is true of it. This interpretation also illuminates the semantic innovations made in the Parmenides, Sophist, and Aristotle's Categories. Separation - typically understood as the thesis that Forms are not "in" their participants - would seem to run afoul of my interpretation, since ingredient causes are "added to" things. In the Phaedo, however, to be separate is rather to be unqualifiedly what one is. Separate Forms are thus analogous to maximally determinable properties (e.g., 'is shaped', vis-Ă -vis 'is square'), and in this sense their separation can be seen to derive from their being universal causes.
The Design Development of Small Molecule Inhibitors Targeting Unregulated Transcription Factors in Acute Myeloid Leukemia
Keywords: Myeloid Leukemia
Small Molecule Inhibitor
STAT5

Most biological processes including signal transduction via transcription factors are mediated through protein-protein interactions (PPIs). Deregulations of the proteins involved in these interactions have been implicated in contributing to disease progression. It is now well established that cancer can be the result of aberrant PPIs, either through the loss of an essential interaction or, through the overactivation of transcription factors. Thus, targeting transcription factors have become attractive molecular targets. The multi-faceted approach to medicinal chemistry that encompasses synthesis, computational analyses, biophysical and biological evaluations are demonstrated by the invention and production of small molecule inhibitors for two well-known protein targets, the transcription factor STAT5 and the ubiquitin E3 ligase MDM2. A structure based drug design (SBDD) strategy was utilized in the discovery of the first potent and selective inhibitor of the STAT5 protein with optimal metabolic stability. Throughout our efforts in establishing an inhibitor for STAT5, we investigated STAT5 isoforms and their roles in driving several malignancies within the body. A novel STAT5A isoform FP assay was developed and efforts were undertaken to identify an isoform selective inhibitor. A STAT5B selective compound was identified with similar potencies to our first generation lead 13a. With a newly discovered pharmacophore for STAT5, optimizations of the tripodal scaffold were carried out to reduce entropic costs to binding. A new class of benzodiazepines were produced, however, these compounds did not result in a favorable potency/selectivity profile for the STAT5 protein. The class of benzodiazepines was then reevaluated for the MDM2 target with promising preliminary in vitro evaluations. We have identified the first in class and best in class inhibitor for the STAT5 protein reported to date. With a favorable potency/selectivity profile and optimal metabolic stability, two lead compounds have the potential to become candidates for advanced preclinical trials as a STAT5-targeted therapeutic. In addition, these small molecule inhibitors can serve as research tools to investigate the knockdown of STAT5 function at the protein level.
Narrative Medicine in the Native Tongue: The Effect of the L1 as a Moderating Variable of Exam Performance in Experimental Disclosure Therapy
Keywords: Academic Performance
Cognitive Test Anxiety
Experimental Disclosure Therapy
Expressive Writing
Native Language

There is increasing evidence supporting a link between writing about one's emotional experiences and alleviating physical and psychological ailments. Recently, in the academic milieu, studies have focused on relieving test anxiety via experiential disclosure (as it is called); however, relevant studies have only focused on uses of the paradigm in monolingual environments. The role of the native language in an English-only environment has so far been vastly ignored by the literature on this paradigm. This is particularly troubling as studies suggest emotivity is more potent in one's native language than in subsequent languages learned (Schrauf, 2000; Dewaele, 2004; Pavlenko, 2002) and emotivity is integral to the efficacy of the benefits found when writing about ailments (Pennebaker Chung, 2007; 2011). Three hundred and sixty-two undergraduate students were given measures of cognitive test anxiety, optimism, and depression, and randomized to a control or an experimental grouping. They were asked either to think about unemotional topics or express their emotions about an upcoming test in English or in their L1 (native language) before taking a final exam, respectively. Surprisingly, non-native English speakers asked to expressively write in their L1 scored lowest on their final exam, even lower than non-native English speakers asked to write expressively in English. This suggests that stereotype threat may be at play when implementing experimental disclosure therapy, in that L1 speakers may be highly attentive to their environment. The findings of this pilot study suggest that further research into how the L1 affects expressive writing and academic performance in an English-only environment is warranted.
Development of Electrochemical Sensors for the Analysis of Therapeutic Compounds and Proteases related to Alzheimer's disease
Keywords: Alzheimer's disease
antioxidants
electrochemistry
metals
sensors

The development of biosensors has advanced significantly in the past few decades. IUPAC has given the definition of biosensors as a device that employs specific biochemical reactions mediated by enzymes, immunosystems, tissues, organelles or whole cells for the detection of a chemical analyte by electrical, thermal or optical signals. To date, one of the most successful endeavor being the commercialization of the well-known glucose biosensor, now used by many around the world. In 1956, Clark proposed the first oxygen sensor, with the ability to determine oxygen content in a sample independent of the sample composition. In this thesis, we will review the fundamental concepts in electrochemical biosensors with respect to its detection techniques and applications of carbon nanomaterials to enhance signal detection (Chapter 1) in relation Alzheimer's disease (AD) (Chapter 2). Next, we will demonstrate the use of carbon nanotube modified screen-printed electrodes for the detection of disease markers such as homocysteine (Chapter 3). Another prominent disease marker, the Amyloid-β peptide (Aβ), has been implicated in Alzheimer's disease (AD). Under the Amyloid Cascade Hypothesis, the onset and progression of AD has been connected with the formation of toxic Aβ aggregates. However, numerous factors affect this aggregation process and the next few chapters will serve to explore factors that have been shown to increase Aβ aggregation (Chapter iii 4) and potential natural therapeutic compounds that may slow down the progression of Aβ aggregation (Chapter 5 and 6). To showcase the applicability of electrochemical biosensors for the detection of an array of biological processes, we further applied the screen-printed electrodes for the detection of an apoptosis biomarker linked to AD (caspase-3), using a label-free detection platform (Chapter 7) and with assistance from a well-known label, p-nitroaniline, which has a dual function as a fluorescence tag and an electrochemical probe (Chapter 8). The applications presented in this thesis will highlight the utility of electrochemical platforms as a powerful analytical tools, capable of fast detection at a lower cost with future miniaturization and high-throughput analysis capabilities.
Aircraft Landing Gear Thermo-tribomechanical Model Development
Keywords: Bearing overheating
Bingham grease
Lubrication mechanism
non-Newtonian lubricant
Passive control
Tribotopological theory

A transient numerical model for studying the thermo-tribomechanical behavior of an aircraft landing gear is presented. The study reveals the major heat sources and heat sinks that impact the characteristic thermal behavior of the landing gear shock absorber. The severe in-service performance degradation and reported structural damage can be explained as a consequence of the heat generated by the high drag loads induced by rough runways on the bearings, and by the high sliding velocities of the piston. A conclusive model may lead to improved landing gear performance once the transient process of heat generation in a phase-changing grease-lubricated lower bearing is fundamentally understood. A novel tribotopological lubrication theory is derived in order to take into account all distinct physical phases of the non-Newtonian Bingham lubricant. The governing equations are solved using a hybrid numerical solver that is optimized for numerical efficiency and fast convergence. The proposed framework is validated against existing theories and results, and it demonstrates accurate predictions of the thermal performance of the landing gear. Strategies to passively optimize the lower bearing lubrication mechanism are further suggested in order to achieve optimal thermal performance of future aircraft landing gear.