VictorJuiz/thesis huggingface dataset:
Prediction of Patient Outcomes after Traumatic Spinal Cord Injury using Acute Clinical and Radiological Variables

There is a pressing unmet need, in the acute setting after traumatic spinal cord injury (SCI), to predict both short and long-term clinical outcomes for individuals affected. Possessing this ability would not only facilitate improved communication and treatment planning in the clinical realm, but also would allow for enhanced study of SCI patients in the research realm. Presently, there is little available to scientifically guide clinicians and researchers alike with respect to this topic. In this thesis, it is hypothesized that clinical outcomes can accurately be predicted after SCI based on acute patient, injury and radiological features. In order to investigate this hypothesis, a series of investigations have been undertaken, using a combination of two large prospective SCI datasets, to explore the impact of acute clinical and radiological factors on long-term functional outcome, long-term neurological outcome and in-hospital complication occurrence. First, after performing a comprehensive systematic review of existing literature, a clinico-radiographic model was created and internally validated using a combination of pre-specified clinical and magnetic resonance imaging (MRI) variables obtained in the first 3 days after injury, to predict functional outcome at 1 year. Second, the acute radiological finding of facet dislocation (FD) was evaluated and found to predict reduced motor neurological recovery at 1 year, even after adjusting for individuals’ baseline degree of injury severity. Third, a combination of clinical variables predicting in-hospital complication development after cervical SCI were identified and used to develop a model to predict the occurrence of these complication events. Finally, the impact of age as an effect modifier governing the relationship between acute neurologic status and long-term functional outcome was evaluated. This analysis demonstrated older age to have the greatest negative impact on functional outcome in patients with lesions of intermediate severity. Although future validation studies are required, the findings presented in this thesis have provided new insights into relationships between acute predictor and outcome variables in the context of traumatic SCI. Further, these analyses have demonstrated the feasibility, and potential advantages, of using a combination of acute clinical and radiological variables, to predict outcome after SCI.

Keywords: Spinal Cord Injury
Prediction
Advisor: Fehlings, Michael
Molecular Factors that Influence BCG Vaccine Properties

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the only vaccine against tuberculosis (TB). Although in use for nearly a century, it is far from ideal, exhibiting variable protection against pulmonary TB in adulthood and can cause disseminated disease in immunocompromised individuals. Therefore, there is an urgent need to develop more effective and safer TB vaccines than BCG. Understanding molecular factors that influence BCG vaccine properties including safety, immunogenicity, and protective efficacy will help to achieve this goal. This is especially relevant since vaccine candidates designed to boost BCG efficacy have yielded disappointing results in recent clinical trials. Several hypotheses exist for the variable protection of BCG and one of which concerns BCG strain heterogeneity. While it was widely recognized that different BCG strains exhibited varying degrees of virulence and protection in animal models, it has been attributed to quality control issues during the manufacturing process. However, work from our lab suggests that this variability may reflect true biological differences among BCG strains. Notably, we discovered a correlation between the production of the cell wall lipids, phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), and BCG vaccine safety record and between the expression of phoP, the transcriptional regulator in the PhoP-PhoR two-component system, and BCG immunogenicity. Based on these initial observations, the goal of my thesis was to understand the roles of PDIMs/PGLs and PhoP in mediating BCG vaccine clinical properties, including virulence, immunogenicity, and protection. Using mouse models of infection and M. tuberculosis challenge, I found that the loss of PDIMs/PGLs reduces virulence and efficacy of BCG without having an effect on immunogenicity. In examining the role of PhoP, I showed that overexpression of phoP improved protection but also increased virulence of BCG. Taken together, my work has identified two molecular factors that impact BCG vaccine properties and suggests that phoP overexpression may be a novel strategy to improve BCG efficacy. Further, my work suggests that there is an intimate link between BCG virulence and protective efficacy, which provides valuable insight for the selection of BCG strains for current immunization programs and the design of future TB vaccine candidates.

Keywords: BCG
Tuberculosis
vaccine
Mycobacterium
Advisor: Liu, Jun
L'art de la description et la description de l'art dans les Voyages de Théophile Gautier

Le XIXe siècle inaugure une transformation radicale de l’économie du récit de voyage qui grâce à l’intrusion dans son espace de l’homme de lettres devient un genre littéraire à part entière. À la lumière de cette évolution générique notre thèse explore la question de la littérarité des textes viatiques de Théophile Gautier en montrant que cet aspect esthétique s’y manifeste à travers l’image en tant qu’«évènement textuel» que l’on interroge selon deux perspectives complémentaires : l’art de la description et la description de l’art. Notre étude se répartit en quatre chapitres. Afin de mieux expliciter la logique de notre approche binaire de la description, dans le premier chapitre nous nous penchons sur la figure de Gautier écrivain-voyageur, sa façon d’aborder le voyage en tant que genre et les postures énonciatives qu’il adopte face à ses «devoirs de voyageur pittoresque», de littérateur aux ambitions de peintre, mais aussi de critique d’art professionnel. Les chapitres deux et trois étudient l’art de la description en s’attachant à la question du style de Gautier marqué par l’idée de modernité : la libération esthétique de la couleur, dans la peinture comme dans la littérature, et l’avènement dans la littérature de la «nouvelle imagerie». À la lumière d’une étude globale et d’analyses ponctuelles de l’appareil langagier (métadiscours pictural, opérateurs lexicaux et référentiels) qui induit des effets visuels ou picturaux du texte, nous étudions les stratégies descriptives, empruntées aux arts visuels (peinture de coloriste, aquarelle, carte, panorama et diorama). Cette approche stylistique est complétée par la recherche des sources qui alimentent les logiques descriptives correspondantes puisées par Gautier dans son expérience de rapin et de critique d’art. La description de l’art dans le voyage gautiériste fait l’objet du quatrième chapitre thématiquement limité à l’ekphrasis religieuse. Abordée selon une analyse comparative cette dernière étude met en relation la prise de position de Gautier face au tableau occidental à motif religieux avec celle qu’il adopte à l’égard de l’icône gréco-russe. Pour mieux configurer cette problématique, nous la faisons précéder de considérations mettant en lumière les spécificités rhétorique et historique qui différencient l’ekphrasis moderne, imposée par Diderot et dont Gautier hérite, de son modèle antique, exercice d’éloquence des rhéteurs et des sophistes.

Keywords: Littérature de voyage - XIXeme siècle
Théophile Gautier
Advisor: Huenen, Roland Le
Data-driven Modeling of Kinase Networks in TRAIL-induced Apoptosis Inform Combination Therapy

Tumor-necrosis factor Related Apoptosis Inducing Ligand (TRAIL) is a soluble peptide that preferentially induces apoptosis in many solid tumors. Unfortunately, the emergence of resistance in treated cells limits the efficacy of TRAIL or other synthetic receptor agonists as single agent therapeutics. Since adaptation of the underlying signalling network may drive this resistance, we undertook a detailed characterisation of the cellular response to TRAIL to identify compensatory signaling nodes that could serve as candidates for combination therapy. As kinases are intimately linked with the regulation of apoptosis, we systematically evaluated the human kinome in the context of TRAIL-induced apoptosis through RNAi and over-expression screens, protein interaction mapping, and phospho-proteomics in the colon adenocarcinoma cell line DLD-1. We identified 164 kinases that influence TRAIL signaling, mapped out an underlying protein interaction network connecting these kinases to apoptotic regulators, and characterized two kinases (PXK, AAK1) that affect TRAIL sensitivity through modulating receptor endocytosis. Finally, by modeling changes in information flow through the signaling network, we identified novel combinations of kinases whose inhibition act synergistically to augment TRAIL-induced apoptosis.

Keywords: apoptosis
kinases
functional genomics
proteomics
network modeling
Advisor: Pawson, Tony
Cerium Oxidation State in Silicate Melts and the Application to Ce-in-Zircon Oxygen Barometry

Through measurements of cerium redox equilibrium in silicate melts, and an internally-consistent model for zircon-melt partitioning of Ce, a calibration for estimating the redox conditions during zircon crystallization is presented. To quantify Ce4+/Ce3+ in natural magmas, Ce doped silicate glasses ranging in composition from basalt to rhyolite (&plusmn; H2O) at 0.001 and 1 GPa, under fO2 conditions varying from FMQ &ndash;6.0 to +8.4 (where FMQ is the fayalite-magnetite-quartz oxygen buffer), and temperatures from 1200 to 1500&deg;C were synthesized. Samples were analyzed using both synchrotron-based Ce M4,5-edge x-ray absorption near edge structure (XANES) spectroscopy and traditional wet chemical techniques. Based on comparison to potentiometric determinations of Ce4+/Ce3+ in digested portions of our samples, Ce4+ was found to have a greater fluorescence yield (FLY) response to the incident radiation in the M4,5-edge XANES region than Ce3+. A correction to M-edge determined Ce4+/Ce3+ ratios as follows: Ce4+/Cetotal=587.7[Ce4+/Cetotal+/-5%]XANES^A(+/-0.004) (0&lt;Ce4+/Cetotal&lt;0.4) where the exponent A is a function of the number of non-bridging oxygens per tetrahedrally-coordinated cation (NBO/T) for a given glass composition, [Ce4+/Cetotal]XANES is the contribution from Ce4+ to the M4,5-edge area over the total area of the M4,5-edge, and Ce4+/Cetotal is the actual fraction of Ce4+ in the sample. For a given melt composition, the change in Ce4+/Ce3+ with fO2 follows the thermodynamically predicted trend assuming simple oxides as melt species. In addition to fO2, melt composition and water content have been found to be secondary controls on Ce4+/Ce3+, with more depolymerized melts and hydrous compositions favoring the stabilization of Ce3+. The Ce4+/Ce3+ ratio can be expressed through the equation, log(Ce4+/Ce3+)=1/4logfO2+5705(+/-257)/T-0.8694(+/-0.005)NBO/T-3.856(+/-0.049)xH2O-3.889(+/-0.102) where T is in Kelvin, and xH2O is the mole fraction of water in the melt. Using this model, fO2 for samples from the Bishop tuff (USA), Toba tuff (Indonesia) and Nain plutonic suite (Canada), have been calculated and are in excellent agreement (typically within 0.5 log units) with independent estimates. Using the composition of the Jack Hills Hadean zircons, combined with estimates of parental magma composition, the fO2 during zircon crystallization was determined to be between FMQ -1.0 to +2.5, suggesting that relatively oxidized magmatic source regions, similar to 3.5 Ga komatiite suites, existed by ~4.4 Ga.

Keywords: Cerium oxidation state
Silicate melts
Zircon
XANES
Advisor: Brenan, James
Defining the Role of Integrin-linked Kinase in Ureteric Bud Growth and Branching During Murine Kidney Development

The mammalian kidney develops through two major processes: nephrogenesis and renal branching morphogenesis. During branching morphogenesis, precise regulation of growth factor signaling is important for branching, elongation, and differentiation of the developing ureteric bud (UB). Defects in renal branching morphogenesis can lead to the development of kidneys incapable of supporting postnatal life. Despite their critical role in renal branching, the intracellular signaling pathways mediating the response to growth factor signaling in the developing kidney are poorly understood. Herein, I describe the crucial role of an intracellular scaffold protein, Integrin-linked Kinase (ILK), in kidney development. ILK is expressed within the developing UB and the conditional deletion of Ilk from this cell lineage during murine kidney development leads to postnatal renal hypoplasia or hypodysplasia. Characterization of the phenotype of Ilk-deficient kidneys demonstrated a role for Ilk in embryonic renal branching in vivo. At a mechanistic level, whole transcriptome analysis identified downstream gene targets of Ilk-dependent signaling involved in epithelial tube development that are mis-regulated in the absence of Ilk. The downregulated genes that were expressed in the developing UB included: i) known regulators of renal branching (Wnt11, Sox8, CXCR4), and ii) genes with unknown function in the developing kidney (Krt23, Slco4c1, Myb). Furthermore, activation of p38MAPK signaling was decreased in Ilk-deficient kidneys and a subset of Ilk-dependent genes requires p38MAPK activation for their expression in vitro. Loss of Ilk also results in misregulation of MAPK phosphatase activity in embryonic kidneys, with an upregulation of the Dual Specificity Phosphatase 8 (DUSP8). DUSP8 overexpression attenuates the activation of p38MAPK and decreases expression of Wnt11 and Krt23 in vitro. In sum, the combined approach of phenotypic, molecular, and genomic analysis of the role of ILK provided a comprehensive understanding of the role of this important protein in the developing kidney. This research improves our understanding of the regulation of intracellular signaling pathways during kidney development and provides knowledge that can be applied to the understanding and treatment of human renal disease.

Keywords: kidney
developmental biology
Advisor: Rosenblum, Norman
Role of DNA Mismatch Repair in Disease-associated Trinucleotide Repeat Instability

Trinucleotide repeat (TNR) tract expansions in specific genes are known to cause numerous neurological and neuromuscular diseases. The mechanism of DNA instability is believed to involve the formation of slipped-repeat structures, and ongoing expansion requires the presence of functional mismatch repair (MMR) proteins. It is known that MMR efficiency is affected by the structure of the DNA lesion, leading to outcomes such as G-T mismatches being repaired more readily than C-C mismatches. It has also been demonstrated that the structure of slipped TNRs can affect their repair, with CAG slip-outs being repaired with higher efficiency than CTG slip-outs. Here I will show that the length of the slip-out, the number of slip-outs, and the slip-out junction all affect repair; additionally, I show that their formation/processing can occur during DNA replication. While isolated short slip-outs are efficiently repaired (much more efficiently than long slip-outs), clustered slip-outs are poorly repaired. The repair of short TNR slip-outs involves the MMR protein MutSβ, but not MutSα. MutSβ is known to contribute to TNR instability, and my results indicate a potential mechanism: attempts to repair short slip-outs meet with interference due to the presence of numerous adjacent slip-outs, and this leads to errors in the repair process causing mutagenesis. Expansion products can also occur during the processing of longer slip-outs. Long CAG and CTG slip-outs can vary widely at the slip-out junction, and I show that these variations can lead to differences in correct repair, even occasionally leading to repair of the wrong strand and thus the retention of excess repeats. Finally, I show that the processing of slipped-repeats by MMR proteins can occur during DNA replication. Altogether, this thesis reveals the role of mismatch repair proteins in instability during the repair and replication of trinucleotide repeat tracts, and how features of DNA structures in the repetitive tracts affect their processing.

Keywords: Trinucleotide repeat instability
mismatch repair
Advisor: Pearson, Christopher
Losses to Follow-up from an Antiretroviral Therapy (ART) Program in the Zomba District of Malawi

Losses to Follow-Up from Antiretroviral Therapy (ART) programs remain a challenge in Malawi. The objectives of this doctoral project were to explore factors that influence loss to follow-up, to describe patterns of follow-up, to identify a definition of lost to follow-up (LTFU) that predicts whether a patient will return to care and to determine the predictors of becoming and remaining LTFU, among patients receiving ART through Dignitas International (DI) in Zomba, Malawi. DI has been working with the Malawi Ministry of Health since 2004 to deliver comprehensive HIV/AIDS care. In collaboration with DI, this project used a mixed-methods approach to explore losses to follow-up from ART. New data collection in the form of concept mapping with Malawian stakeholders was first used to determine why patients on ART become LTFU. Descriptive analyses involving Generalized Estimating Equations (GEE) was used to describe patterns of follow-up among patients who initiated ART from 1 January 2007 to 1 July 2010. Survival functions were plotted to identify the cut-off that can be used to define LTFU. GEE logistic regression was used to model the predictors of becoming and remaining LTFU at each FU visit. In concept mapping, 90 participants consisting of ART patients, ART providers, Health Surveillance Assistants and Zomba District Health Office team members participated. A nine-cluster concept map solution was generated. In the descriptive analyses, n =7,815 patients with n =76,417 follow-up visits were included. Patients did not show a consistent pattern of follow-up over time (e.g., not always late). Plotted survival functions indicated that a LTFU cut-off of &ge;9 weeks late was relevant in this context. Based on the GEE models, 5 factors that were explored were consistent in predicting both LTFU risk and a return to care within 12 months of an expected visit (transferring in, duration on ART, World Health Organization stage at ART initiation, duration on ART and being in centralized care). Five variables demonstrated statistical differences across models (female gender, being married, cumulative proportion of non-adherent visits, a &ge;10% weight gain and reporting side effects, and being in centralized care). This dissertation points to the dynamic complexities which individuals face during the course of their treatment that affect their ability to return to the clinic for scheduled follow-up. There is a need for a variety of program strategies to adequately address the diverse challenges faced by patients.

Keywords: Epidemiology
Global Health
Advisor: Cole, Donald
Secular Evolution of Compact Triple Systems: The Interplay of Kozai Resonances, Tidal Friction, Gravitational Wave Radiation and Mass Transfer

Ultra Compact X-ray Binaries (UCXBs) consist of a neutron star accreting mass from a white dwarf and are found primarily in globular clusters. Here we focus on UCXBs with orbital periods P 30 min and luminosity variations with periods on the order of hundreds of days. In order to understand, both analytically and via numerical simulations, the dynamics of such triple systems we develop a model that considers three body dynamics in the presence of additional effects such as tidal friction, mass transfer and gravitational wave radiation. First we consider the dynamical state of 4U 1820-30, which is an UCXB located in the globular cluster NGC 6624. Its tight orbit implies that the secondary star is a helium white dwarf. A feature of 4U 1820-30 is its large luminosity variation over a period of 170 days. We demonstrated that the variations in the eccentricity of the inner binary arise from libration around a stable fixed point deep in the Kozai resonance. Taking into account both tidal effects and effects of mass transfer we set a lower limit for the tidal dissipation factor Q for helium white dwarfs. Next, we explore the dynamics of additional three akin globular cluster UCXBs 4U 1850-087, 4U 0513-40 and M15 X-2. Finally, we use the dynamical model developed for UCXBs to examine white dwarf–white dwarf mergers may lead to type Ia supernovae events. But since these mergers are driven by gravitational wave radiation the major issue is how to produce enough binaries that are sufficiently tight to merge in a Hubble time and reproduce the observed rates of these events. We investigate the role of tidal effects and GW radiation in such systems. Our results indicate that tidal effects are important in the regime of moderately high inclinations (85o ≤ i0 ≤ 89o and 97o ≤ i0 ≤ 105o) where, combined with GW radiation they contribute to a dramatic decrease in GW merger timescale. In the regime of high inclinations (90o ≤ i0 ≤ 96o), the inner binary suffers direct collision and tidal effects do not alter the outcome of the evolution.

Keywords: UCXBs
dynamics
Advisor: Murray, Norman
Spaces of the Hispanic Avant-garde: Ultraism & Stridentism in Perspective

This project examines the Hispanic avant-garde’s understanding and representation of space in the first decades of the twentieth century. A close reading of visual works and poems demonstrates that the transformation of urban space brought about by modernity defined the work of the Hispanic avant-garde movements, both in Mexico and Spain. Acceleration, the most prominent feature of modernity, soon entered the avant-garde psyche and manifested in the portrayal of distorted and fragmented spaces across numerous visual and poetic works. Arguing that the transatlantic approach is the most appropriate way to understand the avant-garde phenomenon —due to the extensive transatlantic crossing of materials and ideas that shaped Hispanic modernity— I compare and contrast the cultural production of the Estridentista and Ultraísta movements through the work of their most notable members: Manuel Maples Arce, Guillermo de Torre, Germán List Arzubide, Rafael Cansinos-Asséns, Luis Quintanilla, Humberto Rivas, Ramón Alva de la Canal, Rafael Barradas, Jean Charlot, Norah and Jorge Luis Borges, Francisco Bores, Celso Lagar, among others. I contend that the Hispanic avant-garde was fundamentally concerned with the re-production of changing spaces. It also advanced a renewed understanding and imagining of the city, the cafés, and means of transportation; the three most commonly represented and notable spaces in the ultraist and stridentist production. My study shows that these spaces were perceived and portrayed in remarkably similar ways both in Europe and America, which justifies the notion of a common Hispanic modernity whose cultural production should be studied as a unified transatlantic body of work. Ultimately, my research departs from a purely historical perspective and moves toward new critical interpretations that recognize the Hispanic avant-garde as one of the most coherent and significant artistic movements of the twentieth century.

Keywords: Avant-Garde
Hispanic
Literature
Visual arts
Transatlantic
Space
Ultraísmo
Estridentismo
Vanguardias
Advisor: Sarabia, Rosa