VictorJuiz/thesis huggingface dataset:
Role of the Vitamin D Receptor in MDR1/P-glycoprotein Regulation at the Blood-brain Barrier

The blood-brain barrier (BBB) presents a major obstacle for drugs targeting the brain. Drugs that are small or lipophilic enough can penetrate the physical barrier, but are commonly effluxed back into the blood by transporters that are expressed at the luminal membrane, notably P-glycoprotein (P-gp). It has also been shown that amyloid-β (Aβ), a key player in Alzheimer's disease, is a P-gp substrate. We demonstrate that P-gp levels and function are upregulated upon activation by the vitamin D receptor (VDR) via its natural ligand 1α,25-dihydroxyvitamin D

Keywords: blood-brain barrier
P-glycoprotein
regulation
vitamin D receptor
Advisor: Pang, Kim-Ching Sandy
LKB1/AMPK Pathway as a Potential Target for Cancer Treatment and its Role in TGFB Signaling

Although the “Warburg Effect” was reported >50 years ago, in recent years, there has been much greater appreciation for the importance of understanding perturbations in metabolic pathways of cancer cells. Among many key players in cancer metabolism, liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) have been under the spotlight because they function as metabolic switches that regulate several biosynthetic pathways in response to nutrient availability. One of the most highlighted metabolic pathways regulated by AMPK is the mammalian target of rapamycin (mTOR) pathway that controls protein synthesis in cells. Since AKT/PKB activates mTOR to antagonize the effect of AMPK-mediated inhibition of cell proliferation, the balance between AMPK and AKT activation may determine the overall direction of cellular metabolism favoring either growth arrest or proliferation. The first part of this thesis investigated the possible synergy between Metformin-mediated activation of AMPK and MK-2206-mediated inhibition of AKT on cell growth inhibition in vitro. Furthermore, the possibility of using AKT activation level as a molecular marker to predict in vitro sensitivity to Metformin for any given cell line was tested. In the second part, it was hypothesized that LKB1/AMPK pathway may be involved in transforming growth factor β (TGFΒ)-mediated inhibition of cell proliferation as LKB1/AMPK pathway is central in the regulation of general cellular metabolism to inhibit cell proliferation. Consequently, defects in LKB1/AMPK pathway, which occur in a significant portion of lung adenocarcinoma patients, may lead to impaired TGFΒ responses in cancer cells. Therefore, the mechanism of how LKB1 deletion affects the TGFΒ signaling in cancer cells was investigated using three different LKB1-modulated lung cancer cell lines. This study showed that 1) Metformin and MK-2206 exhibit synergy in inhibiting cell growth in vitro, but neither phospho-AKT nor two downstream targets of mTOR signal (phospho-P70S6K and phospho-S6RP) are good predictors of Metformin sensitivity, and that 2) LKB1/AMPK pathway is important for proper TGFΒ signaling and regulates the expression of TGFΒ1, TGFΒ2, TGFΒR2 and SMAD3 as well as the linker phosphorylation of SMAD2. From these results, it was concluded that LKB1/AMPK pathway may play multiple roles in oncogenesis by regulating cell growth in conjunction with AKT/mTOR pathway and by interacting with TGFB signaling.

Keywords: LKB1
STK11
AMPK
Metformin
MK-2206
AKT
mTOR
Cancer Metabolism
Drug Synergy
Combination Treatment
Tumor Suppressor
TGFB
Lung Cancer
Cancer
Advisor: Tsao, Ming-Sound
Mathematical Optimization of Biological Systems

System-level design and optimization of cell metabolism is becoming increasingly important for the renewable production of fuels, chemicals, and pharmaceuticals. Mathematical models of the metabolism of biological systems are improving in terms of their accuracy and scope of predictions, but are also growing in complexity. Consequently, efficient and scalable algorithms are needed for performing simulations and metabolic system design using these models. Such algorithms are being actively developed and are used in industry today. However, many of the existing algorithms scale poorly to the genome-scale, due to an exponential increase in computational effort with model size or design scope. Therefore, there is difficulty in applying these algorithms for the identification of more complex designs using detailed models. This thesis is aimed at meeting these challenges. First, we present EMILiO, a strain design algorithm that identifies individually fine-tuned flux levels with unprecedented speed via successive linear programming. To test the algorithm, we efficiently generate over 100 strain designs for several industrially important biochemicals. We then develop a framework to assess the robustness of strain designs to industrially relevant perturbations and uncertainties. We then explore how metabolomics, an emerging technology for high-throughput measurement of many metabolites, can be used to improve model precision, despite the high variability typically found in these data sets. Accordingly, we develop an algorithm to randomly sample both fluxes and concentrations and use the algorithm to design a sequence of experiments, in which high-variance metabolomics data are used to identify a subset of metabolites needing more precise measurements. Finally, we evaluate some approaches for extending the methods developed in this thesis for strain design to the identification of optimal enzyme manipulations using nonlinear kinetic models of cell metabolism. The methods developed in this thesis should aid metabolic engineers for the efficient design of robust microbial strains.

Keywords: metabolic engineering
systems biology
mathematical optimization
robustness
Advisor: Cluett, William R.
Mahadevan, Radhakrishnan
Canadian Revisionist Drama: Performing Race, Sexuality, and the Cultural Imaginary

My dissertation examines how Canadian revisionist plays adapt popular narratives—national histories, Greek myths, Shakespearean plays, and colonial legends—by changing the identities of marginalized characters and cultural groups. While Linda Hutcheon defines adaptation as repetition with difference, I define revisionist drama as repetition with politicized difference. It is this politicized difference that transforms the identifications of the original marginalized characters, and, as a result, changes their roles in the cultural imaginary. Canadian revisionist plays critique cultural figures such as Philomela, Othello, and Pocahontas as reductive emblems of necessarily complex, layered racial, sexual, and gendered identities. Though this dissertation concentrates on Canadian literature, it also considers European sources (Ovid, Homer, Shakespeare) as well as theories of historiography (Filewod, Salter), speech acts (Austin, Butler), audience reception (Bennett), and publics (Habermas, Warner). My project ultimately outlines a set of twelve literary and dramatic strategies that are repeatedly used to challenge popular conceptions of what it means to be Black, Aboriginal, Canadian, queer, and female. Revisionist adaptation is a leading form of political protest in contemporary Canadian theatre. With attention to eight playwrights—Margaret Atwood, Margaret Clarke, Marc Lescarbot, Monique Mojica, Daniel David Moses, Djanet Sears, Erin Shields, and the collective group Optative Theatrical Laboratories (OTL)—this study examines the shared methodologies of late twentieth-century revisionist dramas. While the first two chapters investigate strategies for identifying groups (“they are” and “we are”), the last two chapters examine self-identificatory utterances (“I am” and “I am not”). Through this twin focus, my project investigates the relationship between individual and collective identities and thereby captures the plays’ fundamental duality as they re-identify individual characters (Othello, Pocahontas, Penelope) in order to challenge collective cultural, racial, and gender stereotypes. While theorists such as Judith Butler, Michel Pêcheux, and José Esteban Muñoz conceive of identity in terms of performance, I invert this theoretical relationship by treating revisionist performance as a mode of identification and as a potentially powerful cultural vehicle for changing the way audiences conceive of and partake in cultural groups. Revisionist drama, I argue, performs disidentification by at once identifying with and against a source-text. This intrinsic doubleness—an embrace and rejection of the source—creates a politicized palimpsest in the minds of the viewers that forever layers the original with the revisionist version.

Keywords: Canadian Literature
Canadian Drama
Adaptation
Advisor: Nyquist, Mary
Speech Perception in Early Childhood: Contending with Speaker and Accent Variation

Understanding spoken language is much more complex than common intuition may suggest. Speaker-related variation in the realization of words due to changes in speaker gender and accent results in myriad possible realizations of the same word. Although adult listeners can easily accommodate such speaker-specific pronunciations, research suggests that children have more difficulty with this variability. In this thesis, I examine when and how children learn to contend with speaker and accent variation. In three lines of research, I test the hypothesis that infants and toddlers may be less challenged by acoustic variability than past research suggests. In Chapter 2, I show that 15-month-old infants, like adults, can readily accommodate an unfamiliar Australian accent after hearing a 2-minute story produced in Australian English. Interestingly, speaker exposure only elicits accommodation when infants are highly familiar with the words in the story. These findings are consistent with the hypothesis that lexical feedback serves as the mechanism inducing accent adaptation. More support for this idea comes from Chapter 3, where even 20-month-olds were found to experience difficulty accommodating a speaker’s unfamiliar accent when the speaker uses hard words that are not consistently known by children this age. Chapter 3 further shows that 28-month-olds, but not 20-month-olds, recognize words produced in sentence frames by a speaker with an unfamiliar accent without any prior exposure to the accent, thereby providing converging evidence that young children are proficient at dealing with accent variability. Chapter 4 subsequently demonstrates that even 7.5-month-olds can contend with some forms of speaker variation when tested under relatively natural listening conditions. Taken together, these three lines of research provide compelling evidence for the view that early speech processing abilities are remarkably sophisticated and that the transition from infant to adult listener may be less abrupt than currently thought.

Keywords: infant speech perception
language development
word recognition
speaker adaptation
Advisor: Johnson, Elizabeth
Merovingian Letters and Letter Writers

This dissertation is a survey of the more than six hundred letters that form the surviving epistolographical output of the Merovingian era, i.e. circa AD 500-750. These pieces of correspondence have been gleaned primarily from the epistolae, auctores antiquissimi, passiones vitaeque sanctorum aevi Merowingici, and formulae Merowingici et Karolini aevi sections in the monumenta Germaniae historica; a few have been taken from the libri historiarum decem of Gregory of Tours. Much of this corpus has never before been translated into English, or indeed into any modern language. It has also been underutilized by scholars. Although work has been done on some of the collections in isolation, no study to date has approached the material as a whole. This study focuses on the letter as a conveyor of personal and private information, and the letter collections as a corpus that contains important historical, sociological, and cultural implications for our understanding of Merovingian Gaul. iii Five chapters discuss various aspects of Merovingian epistolography. Chapter 1 examines letters to and from women. Chapter 2 focuses on the large body of poetic epistles composed by Venantius Fortunatus. Bishops were prolific letter writers and Chapter 3 discusses various aspects of these. Chapter 4 is in two sections: the first examines that shadowy third party in an epistolographical transaction, the bearer, while the second focuses on the gifts that sometimes accompanied letters. Finally, Chapter 5 investigates the role of the Bible in Merovingian epistolography by analyzing the sources, extent, and purpose of the Scripture quotations employed by letter writers. Also included with the chapters are an Appendix of Unusual Poems and carmina figurata with translations, an Appendix of Biblical Quotations, and several charts that serve to quantify the material. The last half of this dissertation consists of a comprehensive Appendix containing summaries of each letter in the Merovingian collections, with historical context. This is followed by an Index of Epistolographical Prosopography that matches each individual with his or her epistolographical output, which can extend over a number of collections.

Keywords: Merovingian
communication
epistolography
Latin
Advisor: Murray, Alexander
History of the Filipino History Book

Studies of Philippine historiography often trace the emergence of history books written by Filipinos--or, more simply, Filipino history books--to the influence of Spanish and American colonialism, and the rise of Filipino nationalism. In most cases, the names of historians and the titles of their works figure prominently in discussions devoted primarily to texts and/or their authors’ backgrounds, while the names of their publishers and other bibliographical details are either relegated to the footnotes or dispensed with altogether. This study proposes an alternative, complementary approach that seeks to enrich the study of Philippine historiography by reconstructing the history of the Filipino history book using the framework of the discipline known as “book history,” and Pierre Bourdieu’s theory of the field of cultural production. The histories of three books, namely, Jose Rizal’s annotated edition of Sucesos de las Islas Filipinas (1890), Leandro Fernandez’s A Brief History of the Philippines (1919), and what is now commonly known as Teodoro Agoncillo’s History of the Filipino People (1960), are presented as case studies through which the evolution of the Filipino history book as a material object and commodity, and not merely as a text to be read or interpreted, may be better understood. Each book represents a different period in the evolution of the study of Philippine history by Filipinos, and was published in multiple editions over several decades. By examining the prevailing conditions throughout each book’s life cycle, the contributions of agents other than their authors, the struggles that accompanied their publication and distribution, and the evidence that may be gleaned from the books themselves, this dissertation shows that Spanish and American colonialism, and Filipino nationalism, did shape the development of Philippine historiography from the late nineteenth century to the twentieth century, but it also reveals that the Catholic Church played an important role in the production and circulation of books regardless of who was in power, and that struggles between agents involved in the historical field have affected the history of the discipline in ways that have yet to be fully acknowledged.

Keywords: book history
historiography
Philippines
history
historians
textbooks
Advisor: Fleming, Patricia
Plasticity of Vagal Origin: Identification and Characterization of a Novel Form of Neural Plasticity in Respiratory Motor Control

In anesthetized, spontaneously breathing adult Sprague Dawley rats I examined the mechanisms by which repeated obstructive apneas trigger a novel form of upper airway respiratory motor plasticity. Based on four specific research aims, the following conclusions were reached: 1. Repeated obstructive apneas elicited plasticity of upper airway motor outflow that was measured as a long-term (> 1 hour) enhancement of inspiratory genioglossus (tongue) muscle tone. Diaphragm muscle activity that served as an index of spinal motor outflow remained unchanged. Airway occlusions triggered upper airway motor plasticity via repeated modulation of vagally-mediated feedback. This form of plasticity required α1-noradrenergic receptor activation at the hypoglossal motor pool. 2. α1-noradrenergic receptor activation at the hypoglossal motor pool was required for both initiation and maintenance (after apneas) of apnea-induced upper airway motor plasticity. 3. Activation of neurotrophin-mediated signalling was necessary for eliciting apnea-induced upper airway motor plasticity. In fact, activation of neurotrophin cellular machinery in hypoglossal motoneurons in turn was sufficient for triggering long-lasting enhancements of genioglossus muscle tone. In addition, neurotrophin-induced motor plasticity requires persistent noradrenergic neuromodulation because it was rapidly reversed by antagonism of α1-noradrenergic receptors at the hypoglossal motor pool. This finding indicates that there exists a cooperative “cross-talk” between neurotrophic and noradrenergic-mediated mechanisms and that the two act synergistically in the manifestation of apnea-induced respiratory motor plasticity. 4. Sleep loss as experienced in disease conditions such as obstructive sleep apnea mitigated the expression of apnea-induced respiratory motor plasticity.

Keywords: Plasticity
Noradrenaline
Motoneuron
Long-term facilitation
Vagus nerve
Hypoglossal
Breathing
Sleep
Serotonin
Neurotrophin
Advisor: Peever, John
Finite Element Simulation of Interfacial Flows on Unstructured Meshes using a Second-order Accurate VOF Method

This thesis consists of two major parts. In the first part a two-dimensional numerical model of interfacial flow phenomena has been developed, consisting of a finite element discretization of the time-dependent Navier-Stokes equations for immiscible, Newtonian, laminar, isothermal incompressible flows, with a volume-of-fluid (VOF) technique for interface capturing. A new formulation of the pressure Poisson equation that requires the discretization of a second-order derivative is used for the flow field on a fixed Eulerian grid. This approach enables us, in particular, to implement equal-order interpolation for the velocity and pressure. Streamline upwind Petrov-Galerkin (SUPG) stabilization is used for convection-dominated flows. Fluid interfaces are reconstructed and advected using a second-order accurate VOF method. An accurate least-squares circle-fit technique has been developed for curvature calculation on triangular meshes, and then used to implement surface tension forces on a single layer of interface elements. A dynamic contact angle model is implemented based on the Kistler correlation, that serves as a means to evaluate the dynamic contact angle as a function of grid-spacing and the contact-line velocity. Two-fluid flows with density ratios ranging from 10 to 106 are simulated, and the performance of the model is evaluated via the static-drop test case and several examples of bubble dynamics. Finally, the model is applied to the coalescence of two bubbles, the merging of a bubble into a free surface, and the impact of a glycerin droplet onto horizontal wax and glass surfaces, and yields good agreement with experimental measurements and other numerical results. In the second part, a second-order accurate three-dimensional VOF method for unstructured tetrahedral meshes has been developed. The method approximates interface geometries as piecewise planar, and advects volume via a forward trajectory remapping method. Two different methods are used to calculate the interface normal: a differential least-squares (DLS) method that is first-order accurate, and a geometric least-squares (GLS) method that is second-order accurate. Second-order accuracy of the VOF algorithm is demonstrated for simple translations and rotations as well as vigorous threedimensional vortex deformation.

Keywords: FEM
Interfacial flow
VOF
Advisor: Mostaghimi, Javad
Paraschivoiu, Marius
Compositional and Performance Impacts of the Innova MIDI Flute

This dissertation explores the background of the Innova MIDI flute, as well as the design, build, and compositional/performance impacts of the radically new design. Through the creation and introduction of a true MIDI-capable flute, my research addresses a need which currently exists within the field of contemporary performance. While MIDI capabilities have been used with piano, guitar, percussive instruments, and others, the flute has been neglected in the field of performance research. It is my desire to provide flutists with the opportunity to be at the forefront of an evolving art form, and to create music with MIDI functions on stage during live performance, with access to the acoustic flute tone, extended techniques, and MIDI-infused music. This research will not only affect performers, particularly flutists, but also composers. The introduction of this new instrument will provide an innovative tool for the contemporary field of music composition. In designing and developing the Innova MIDI Flute, my primary objective was to fill a need for both performers and composers. From the onset of my research, I have worked with prominent MIDI experts, composers, and flutists to ensure my final product would fulfill all requirements. Feedback from Dennis Patrick, and Bruno Degazio, leaders in the Electroacoustic field; Christos Hatzis and Russell Hartenberger, highly respected contemporary composers, both familiar with MIDI technologies; and Robert Aitken and Douglas Stewart, both professional flutists, has served to ensure the final design reflects the needs of both performers and composers. To date, an instrument has not been available for flutists, or composers, which is able to access all three forms of musical repertoire: classical, contemporary, and MIDI, on one instrument. The dissertation looks at how and why this new design for the MIDI flute evolved, and why its introduction is so significant in the music community.

Keywords: Flute
MIDI
Innova
NoaNoa
Praescio VI
Sequitor I
Electroacoustic
Flute and Electronics
Saariaho
Essl
Pennycook
Electronic
Advisor: Patrick, Dennis