VictorJuiz/thesis huggingface dataset:
The Effects of Aerobic Exercise on the Distribution and Metabolism of Select Xenobiotics

Currently, no drug regulatory agency requires the investigation of how exercise might change the efficacy of a medication, which is unsettling considering the myriad of physiological changes in response to physical activity, many of which have the potential to influence pharmacology. Thus, this dissertation involves a series of studies to assess that potential with specific reference to the pharmacokinetics (PK) of several different drugs over various timelines. In Study 1, we examined if the increase in core body temperature (Tc) and decreases in blood pH affect the plasma protein binding of caffeine and its metabolite, paraxanthine, since a greater ‘free’ fraction would likely translate to greater pharmacodynamic effects, distribution, and clearance (CL). A convenience sample of 6 men and 4 women ingested 3 mg/kg of caffeine and a wireless temperature capsule before entering a sauna for passive heating, followed by low intensity cycling (55% V̇O2max, 20 min), and then high intensity intervals (90% V̇O2max, 20s sprint/40s rest, 10 min) to modulate Tc and blood pH. We found that Tc was elevated by 1.37  0.27 C and blood pH decreased by 0.12  0.051, but unbound fractions of caffeine and paraxanthine, along with their CL, were unchanged. In study 2, we determined whether the decrease in hepatic blood flow (Qh) during aerobic exercise limits the CL of the popular antidepressant, sertraline. Ten male participants ingested 50 mg of sertraline before running on a treadmill at 65 or 75% V̇O2max for 1 h. The exercise stimulus was associated with a 33% reduction in Qh and 5.74% decrease in plasma volume. Through our compartmental PK model, we deduced that the acute hemoconcentration elevated the concentration of sertraline immediately post-exercise, which we successfully modeled by adding another compartment that mimics quickly perfused tissues. In study 3, we evaluated whether the well-established exercise-mediated immune response affected regulation of CYP450 drug metabolizing enzymes during the subacute period after exercise. We found that in 10 male participants, 1 h of treadmill running at a moderate intensity resulted in elevations in IL-6, IL-8, and IL-10; however, the PK-modeled CL of 5 drugs ingested as microdoses were unaltered.

Keywords: CYP450 enzymes
Exercise immunology
Exercise pharmacokinetics
Exercise pharmacology
Hepatic flow and drug metabolism
Microdose probe cocktail
Advisor: Jacobs, Ira
Two Redundant Ubiquitin-dependent Pathways of BRCA1 Localization to DNA Damage Sites

The tumor suppressor BRCA1 accumulates at sites of DNA damage in a ubiquitin-dependent manner, and coordinates DSB repair. The phosphopeptide-binding activity of the BRCA1 C-terminal (BRCT) domains is essential for ubiquitin-dependent recruitment and it is through these domains that BRCA1 indirectly interacts with RAP80, a ubiquitin-interacting protein. RAP80 targets BRCA1 to DSBs but whether or not RAP80 is the sole targeting subunit of the BRCA1 complex is a subject of debate. In my thesis, I generated somatic RAP80-/- cell lines and found that RAP80 is dispensable for the initial recruitment of BRCA1 to DSBs. I observed that the isolated tandem BRCT domain absolutely requires RAP80 to localize at DSBs, but the full-length protein does not. I found that the BRCA1 RING domain acts redundantly to promote BRCA1 recruitment to DNA damage sites. I show that that RNF8 E3 ligase acts upstream of both the RAP80- and RING-dependent activities whereas RNF168 acts uniquely upstream of the RING domain. BRCA1 RING mutations that do not impact BARD1 interaction, such as the E2-binding deficient I26A mutation, renders BRCA1 unable to accumulate at DNA damage sites in the absence of RAP80. Cells that combine BRCA1 I26A and mutations that disable the RAP80-BRCA1 interaction are hypersensitive to PARP inhibition and are unable to form RAD51 foci. Our results suggest that in the absence of RAP80, the BRCA1 E3 ligase activity is necessary for recognition of histone H2A Lys13/Lys15 ubiquitylation by BARD1 although I cannot rule out the possibility that the BRCA1 RING facilitates ubiquitylated nucleosome recognition in other ways.

Keywords: BARD1
BRCA1
DNA damage
RAP80
ubiquitin
Advisor: Durocher, Daniel
Identifying Radiosensitizers in Radioresistant HPV-negative Squamous Cancers of the Aerodigestive Tract

Radiotherapy is a mainstay of curative treatment for squamous cell carcinomas (SCC) of the aerodigestive tract and is frequently combined with radiosensitizing drugs to improve efficacy. Outcomes for HPV-negative SCCs remain heterogeneous, in part due to variable resistance to ionizing radiation (IR) and modest benefit of existing radiosensitizing drugs. There is a thus a clinical need for additional novel radiosensitizers that cause less toxicity as a result of their use. Hypothesis driven testing of novel radiosensitizing drugs has previously been limited due to a lack of robust, efficient, and reproducible methods to assess drug radiation combinations. This is largely due to the limitations of the clonogenic assay – the gold standard for measuring radiation response –first developed in 1954 by Puck and Marcus. The introduction of a viability assay amenable to high throughput that can act as a surrogate for the clonogenic assay has resulted in the publication of a dataset with radiosensitivity data and matched gene expression data (Yard et al, Nat. Commun., 2016). I have aided in the development of a computational platform for the analysis of radiogenomic data and have examined features related to radiation response, providing a valuable resource for further investigation. I developed an extension of the viability assay to investigate drug/radiation combinations, validated using the known radiosensitizing compound cisplatin in six radioresistant cell lines. Moreover, I developed a novel analytical framework for assessing radiosensitization from the viability assay output and applied it to evaluate the radiosensitizing potential of two putative radiosensitizing compound classes: cell cycle inhibitors and a NRF2 inhibitor. Finally, I used an ensemble approach to generate 84 signatures of radiation response. Together, these signatures were compared to perturbation signatures within the connectivity map to identify compounds who induce gene expression changes that mimic a radiosensitive phenotype. Future work will validate this method for unbiased radiosensitizer discovery. The knowledge gained from this thesis provides confidence in the utilization of the 9-day viability assay for evaluation of putative radiosensitizers. Our tests of putative radiosensitizing drugs in a cohort of radioresistant cell lines have identified CDK4/6 inhibitors to be of interest for further investigation.

Keywords: CDK4/6
NRF2
Radiobiology
Radiosensitizers
Squamous Cancer
Advisor: Bratman, Scott V
Examining Nurse Educator Experience and Understanding of Simulation Pedagogy within the Practical Nurse Curriculum

Simulation-based nurse education provides a way to foster skill development, decision making, and the ability to think critically when faced with rapidly changing situations in the clinical setting. Utilizing simulation as an effective teaching and learning strategy requires the careful orchestration of instructional methods and the appropriate application of simulation technologies. It should involve educational experiences that are reflective of the healthcare industry’s best practices. The aim of this qualitative research study was to examine and understand how nurse educators experience and understand the various dimensions of simulation pedagogy as a teaching and learning strategy within the practical nursing curriculum. Eight nurse educators who work in a practical nursing program at a community college in Ontario, Canada participated in semi-structured interviews. The major findings include: i) Participants said they were initially unsure how to teach with simulations and it took time and practice before they felt proficient; ii) Participants with simulation-based certifications reported that this form of professional development improved both their self-confidence and their teaching practices; iii) Participants who were not certified were unfamiliar with the INACSL Simulation Standards of Best PracticeTM relied on their own intuitions and past instructional practices when implementing simulation experiences; iv) Part of their discomfort in teaching in a simulated nurse environment was related to technology hesitancy; v) None of the participants felt that they had received necessary support from administrators; vi) Participants felt that receiving training through certification was necessary to fully understand the pedagogy and to be an effective simulation educator; and vii) creating opportunities for peer mentorship and coaching would be a productive step to further strengthen their understanding and implementation of simulation pedagogies. Recommendations are identified not only for the educator, but also administrators and postsecondary institutions that offer simulation education. This study sheds new light on the professional development needs of nurse educators. It is hoped that the study’s findings will ultimately lead to the improved use of simulation pedagogies in schools of nursing.

Keywords: Curiculum
Nurse Educator
Nursing Education
Pedagogy
Practical Nurse
Simulation
Advisor: Hewitt, Jim
Electoral Games, Frames, and Ethnic Party Moderation: The Limited and Selective Moderation of the Bharatiya Janata Party

This dissertation seeks to explain how and why ethnic parties like the Hindu nationalist party in India, the Bharatiya Janata Party (BJP), moderate in the electoral arena while also examining the constraints on their electoral moderation. Questioning the restricted range of outcomes offered in extant literature, I argue that parties like the BJP can moderate in some ways while remaining radical in others. In short, electoral moderation can be limited and selective. I trace the limited and selective moderation of the BJP in the late 1990s and early 2000s to key changes in India’s party system including the decline of the historically dominant Congress Party, the rise of regional and caste-based parties, and the increased fragmentation of the party system that necessitated electoral alliances to govern. While analyzing key changes to the broader political and institutional context in which the BJP competes, I demonstrate that parties have a significant amount of agency to maneuver, pivot, and reposition themselves in their new institutional environments. In the case of the BJP, this meant limited and selective moderation that expanded its appeal among intra-Hindu identities, without substantive changes to the party’s approach to other religious groups. The second half of the dissertation focuses on explaining the limited and selective moderation of the BJP. A comparative analysis of the 2004 and 2014 elections reveals that two sets of relationships can constrain and incentivize limited and selective electoral moderation. One set emanates from within the party organization itself in the form of intraparty dynamics between the party, its workers, and other organizations within the Hindu nationalist movement. Second, the party is also constrained by the strategic interaction with its primary electoral rival, the Congress Party, to control the election narrative. A qualitative content analysis demonstrates how the Congress Party had an incentive to remind the electorate of the party’s ethno-religious strategies of mobilization from the past, even when ethnic parties like the BJP attempt to present a more ‘moderate’ face. These dynamic relationships within the BJP itself as well as its relationship to other electoral competitors can influence the party’s electoral strategies.

Keywords: Bharatiya Janata Party
Elections
ethnic politics
Hindu nationalism
Party strategy
Political parties
Advisor: Bertrand, Jacques
Brightside for Orchestra

Brightside is a thirteen-minute piece for symphony orchestra (woodwinds by twos plus piccolo, four horns, two trumpets in C, two tenor trombones, one bass trombone, one tuba, timpani, xylophone, vibraphone, and strings) inspired by my life on Brightside Drive in Baton Rouge, Louisiana. The different compositional materials used in the piece reflect different aspects of my life.I see life as an interplay between steadiness and contrast and the search for balance between the two. This view of life reminds me of the rondo-like structures seen in ritornello forms of the Baroque era, and this is the basis of the form of Brightside. In the ritornello sections (which I designate as A1, A2, A3, and A4) I sought to depict the idea of gradual transition in the context of overall stability. The harmony is principally derived from minor and diminished triads with common notes, but other notes are added as the piece develops. The episodes (B, C, and D) which represent starker contrasts in my life, are built from contrasting materials including twelve-tone collections and octatonic scales. I also used timbral contrast to enhance the form, reworking ideas from the Baroque concerto grosso. The ritornellos generally make use of the orchestral tutti and the episodes focus on particular families of the orchestra. (B: strings and percussion; C: woodwinds and two horns; D: brass and percussion.) However, I have allowed periodic deviations from this plan, based on my intuition, to avoid the emergence of undesirable predictability. The harmonic plan aims at a long line of development by organizing tonal centers of the sections. The ritornellos work their way through the tonal centers C, Eb, Gb, and A. The episodes and the coda are comparatively unstable, beginning with C#, E, G, and Bb and ending with D, F, Ab, and C. So, the harmonic plan is based on three diminished seventh chord axes, except for the "correction" applied in order to end on C.  The dramatic arc of the piece is fairly "standard" with a climax approximately at the two-thirds mark.

Keywords: Composition
Music
Orchestra
Advisor: Rapoport, Alexander
Joint Action and Communication, with a Focus on Demonstratives

This dissertation develops a view of human communication according to which it is the joint activity of making sense of one another, as fellow agents, in virtue of our actions. I consider the relationship between communication and joint attention in order to show how my view provides a superior successor to orthodox Griceanism. I also motivate my view by using it to explain how there can be successful communication, involving a demonstrative, despite the interlocutors not settling on one or another object as referent. Finally, I address a challenge, which arises for any Gricean view of communication, of explaining what is special about linguistic communication. My answer is based on a formal semantics for demonstratives and related expressions, and draws upon the tradition of dynamic semantics.

Keywords: communication
demonstratives
formal semantics
joint attention
pragmatics
Advisor: Dickie, Imogen
Charlow, Nate
From Structure to Function: Social and Cognitive Networks in Children Born Very Low Birth Weight

Infants born very low birth weight (VLBW, <1500 g) have an increased risk of social and cognitive impairments, which can affect their social and academic success at school. However, little is known about the functional and structural underpinnings of these impairments at preschool-age, an important transitional period in development, as well as the early modifiable predictors of outcome, such as postnatal nutrition. The present thesis used a multi-modal approach to investigate altered white matter microstructure and functional connectivity in five-year-old VLBW children. Using multi-shell diffusion imaging, studies 1 & 2 assessed white matter microstructure in VLBW compared to full-term (FT) children and associations with early nutrition (during postnatal days 9-29) and developmental outcome. Fractional anisotropy (FA), radial diffusivity (RD), neurite orientation dispersion index (ODI) and density index (NDI) were estimated using diffusion tensor and NODDI models. Using magnetoencephalography, social and cognitive networks were assessed during a resting-state (Study 3) and an emotional face processing task (Study 4). Studies 1 & 2 demonstrated disrupted white matter maturation in VLBW compared to FT children. These findings suggest that lower FA in VLBW children may be partly due to increases in axon dispersion, reflecting less coherent organization of axons. We also found that among the macronutrients studied, greater protein intake contributed most to the beneficial effect of nutrition, showing increases in FA and reductions in RD at preschool-age. Study 3 demonstrated increased resting-state functional connectivity in VLBW compared to FT children in the gamma (65-80 Hz) frequency band, anchored in frontal regions known to underlie social-cognitive functions. Further, significant associations between macronutrient/energy intakes with functional connectivity at preschool-age were found. Study 4 demonstrated that VLBW compared to FT children show atypical recruitment of emotional face processing networks in theta (4–7 Hz), specific to angry faces. This hypo-connected network involved key emotion face processing regions with links to inhibitory control. In conclusion, VLBW children showed alterations in structural and functional connectivity underlying social and cognitive functioning at preschool-age. Most importantly, our study relates these findings to early postnatal nutrition, demonstrating the long-term impacts of nutrition on preterm brain development.

Keywords: cognition
functional connectivity
nutrition
preterm
very low birth weight
white matter
Advisor: Taylor, Margot J
Validity and Utility of Theta-Gamma Coupling as a Marker of Ordering of Information in Older Adults

Ordering of information is a critical component of many everyday tasks, such as remembering a phone number or following directions. Prefrontal cortex theta phase-gamma amplitude coupling (TGC) is a neurophysiologic measure associated with ordering of information during the N-back, a working memory task. Prefrontal cortex TGC could be a target for intervention to improve ordering of information, as past research in both humans and animals suggests there is a strong association between TGC and ordering information of multi-item messages. However, further research is needed confirm this relationship in humans. The overall aim of this thesis is to further examine the relationship between prefrontal cortex TGC as recorded by scalp EEG and ordering of information. We began by determining if the relationship between TGC and ordering exists independent of cognitive task and clinical condition. We then examined the association between changes in TGC and changes in working memory performance over time. Lastly, we examined the utility of using a TGC cut-off to create distinct groups with regards to their cognitive function. The results of the first study demonstrate that TGC is associated with performance on ordering-based cognitive tasks that were completed outside of TGC measurement. In addition, there was no interaction between TGC and diagnosis. These results suggest that the relationship between TGC and ordering exists independent of task and clinical condition. The results of the second study demonstrate a longitudinal relationship between change in TGC and change in working memory performance over 6 to 12 weeks, which suggests that TGC is a stable marker of working memory performance over time. The results of the third study indicate that using a TGC cut-off creates more distinct groups with respect to global cognition compared to diagnosis. Individuals with MCI and MCI+MDD have similar, overlapping cognitive profiles, however, those with low TGC have distinct global cognition compared to those with high TGC. Taken together, these findings provide support for using TGC as a potential marker of intervention to improve cognitive function, and potentially slow or prevent cognitive decline.

Advisor: Rajji, Tarek K
Levi Decomposable Subalgebras of Classical Lie Algebras With Regular Simple Levi Factor

This thesis describes and characterizes a significant class of subalgebras of the classical Lie algebras, namely those which are Levi decomposable with regular and simple Levi factor, with select exceptions. Such subalgebras are entirely determined by their Levi factors and radicals. The possible Levi factors are well-established in the literature and so the contribution of this thesis is a characterization of the radicals. The radicals naturally decompose into nontrivial and trivial components. The nontrivial component is found to be fully classified by subsets of the parent root system and Weyl group. However, a classification of the trivial component requires solving the open problem of classifying solvable subalgebras of classical Lie algebras. Nonetheless, this thesis establishes a criterion on the trivial components for determining when two such subalgebras are conjugate. This thesis also briefly explores the ramifications of relaxing simplicity of the Levi factor to allow for semisimplicity.

Keywords: Levi decomposition
Lie algebras
Representation theory
Advisor: Repka, Joe
Electrochemical TiO2 Semiconductor Analysis by Square Wave Voltammetry

With the push for renewable energy to manage greenhouse gas emissions, or the demand for efficient photocatalytic abatement of organic pollutants, titanium dioxide (TiO2) has been at the forefront of these applications for many years. However, the efficiency is a key determinant in its economic viability, and this depends on interface charge exchange properties as dictated by the available energy states in TiO2 electrodes. Current techniques used to understand the electronic state spectrum as a function of energy in an electrochemical setting are limited. Extracting electronic information - such as the density of states, donor concentration, trap state capacitances - electrochemically typically requires a combination of these techniques, with AC methodologies requiring expensive equipment and complex analysis. As an electrochemical characterization technique, square wave voltammetry (SWV) can provide significantly less background current and greater sensitivity than its linear counterpart as a result of sampling the current at the end of each pulse. This is beneficial for the accurate measurement and calculation of electronic properties from electrochemical semiconductor current-voltage data. By varying the frequency and pulse size of the applied square wave, one can probe electronic processes of various time scales. This work presents square wave voltammetry as a high sensitivity alternative for the electrochemical characterization of anodized TiO2 films, with a custom real-time SWV measurement system requiring only an open-source potentiostat to extract the current decay behaviour of each voltammetric pulse.

Advisor: Ruda, Harry E