VictorJuiz/thesis huggingface dataset:
Molecular Mechanisms of E. coli Shiga Toxin Pathogenesis
Keywords: Shiga toxin
endothelium
CXCR4
VEGF
SDF-1
O157:H7
E. coli

Shiga toxin-producing E. coli (STEC) comprise a group of pathogenic organisms that elaborate a family of protein exotoxins known as Shiga toxins (Stxs). Intestinal infection with these organisms may lead to hemorrhagic colitis and hemolytic uremic syndrome, a life-threatening condition characterized by thrombocytopenia, non-immune hemolytic anemia, and acute renal failure. Vascular endothelial damage is believed to be a key initiating event in Stx-mediated diseases. At the molecular level, these toxins depurinate human 28S rRNA and inhibit translation. In addition, at concentrations that only minimally affect global protein synthesis, they have been found to alter expression of specific target genes. To better understand the endothelial damage induced by Stx, we investigated the global effects of Stx on endothelial gene expression, and defined a specific group of genes whose expression was altered by the toxin. Of interest, the CXCR4/CXCR7/SDF-1 chemokine pathway, a pathway central to vascular biology, was activated by Stx. In vitro studies demonstrated that Stx enhanced both transcript levels of these molecules, as well as their association with ribosomes. To define the relevance of these findings in vivo, a mouse model was established and key changes were noted in plasma and tissue content of CXCR4/CXCR7/SDF-1 following Stx exposure. Inhibition of CXCR4/SDF-1 interaction decreased indices of endothelial activation and organ injury and improved animal survival. Importantly, in children infected with E. coli O157:H7, plasma SDF-1 levels were significantly elevated in individuals who progressed to hemolytic uremic syndrome. A second pathway critical to endothelial health and function is VEGF signaling. Of interest, our endothelial gene expression analyses revealed changes in this pathway in vitro. VEGF mRNA association with cellular polyribosomes increased following Stx treatment. Further studies in vivo demonstrated decreased cardiac function and blood pressure, and increased vascular permeability in specific tissues. VEGF, an important inducer of vascular permeability, increased in mouse plasma. Additionally, altered mRNA expression was observed in key organs, such as the kidney and heart, following Stx challenge. Inhibition of VEGF significantly improved survival of animals treated with Stx, indicating that VEGF plays a role in Stx-mediated pathogenesis. Moreover, in vitro studies demonstrated that Stx-mediated endothelial permeability was attenuated in the presence of a VEGF inhibitor. Taken together, these data indicate that E. coli-derived Stxs induce pathological changes in two pathways key to vascular biology. These pathways represent novel targets for the development of preventative and therapeutic strategies for complications associated with Shiga toxin-producing E. coli infection.
Online Learning in the Open University Systems of India and China: A Comparison of Responses to Globalization
Keywords: Open University
Globalization

Since the turn of the millennium the national Open Universities in China and India have been integrating online learning as an additional means of course delivery. Over this period both countries have witnessed exponential growth in Internet access and a commensurate need, mandated by government, to increase enrolments in higher education with one focus placed on using networked technologies. Prevailing arguments suggest there is a growing convergence towards a universal model of higher education based on a western world culture. The question of whether online learning may support, or accelerate, such a convergence by hastening the displacement of national ideas and values is the central question addressed in this investigation. Aspects of online learning in the Open University of China (OUC) and the Indira Gandhi National Open University (IGNOU) are compared: policy, curriculum and students’ experiences and perceptions A comparative case study methodology has been used, incorporating a mixed methods design. Data collection techniques include document analysis, interviews and surveys. The analysis of policy documents, covering the period from 1997 to 2011, and data from interviews with institutional policymakers point to differences in the experience of developing online learning in the two national institutions. The OUC has taken a top down linear approach backed by government oversight, whereas IGNOU has tended to devise policy based on the emerging experiences of instructors and students learning online. A consideration of the content of four courses in each institution, combined with data from interviews with course developers, offers a glimpse of curriculum design for online learning within the larger Open Universities. A rubric is used to quantify the extent of national and foreign content in some of the courses. The findings point to varying degrees of a national representation of knowledge in the presentation of content. The third data set presents findings of a student survey. Results point to general satisfaction with online learning at each Open University, including a positive outlook for future employment as an outcome of learning online. Additional findings indicate that students believe the representation of national knowledge in content may be compromised as the use of online learning grows. Tying these results together, this investigation aims to bring a deeper awareness of the impact of online learning within each Open University. As each institution enrolls approximately three million students, with growth expected, it is valuable for policymakers and curriculum designers to reflect on how national knowledge may be balanced with global learning content in this new and widely used medium. Finally, the fact that the two institutions are similar in infrastructure, enrolments and openness to online learning, results in insights into how each system may learn from the other as it goes forward.
Tiered Pricing for Volume and Priority: Three Problems at the Intersection of Marketing and Operational Policies
Keywords: supply chain
service pricing
mechanism design

This thesis addresses three problems where a focal agent's operational policies (inventory and capacity allocation) interact with marketing decisions. The first chapter studies how wholesale all-unit discounts may lead to products being shifted from authorized retailers to discounted gray market channels. Such discounts lead to discontinuous ordercosts which may induce buyers to order up to a threshold where they receive a greater discount. The buyer in this chapter is a reseller who makes purchasing decisions while taking into account inventory holding costs, how their resale price affects consumer demand and whether or not they divert inventory to the gray market. I analyze factors which determine how the reseller balances between lowering resale prices and diverting to the gray market, both of which lower costs by shortening the time inventory is held. Modelling the decisions as a Stackelberg game, the welfare of the authorized channel participants is analyzed. Of import, consumer welfare may decrease if a gray market emerges when holding costs are low. In the latter two chapters, the supplier sells a congested service. For example, this supplier may be a courier facing stochastic buyer arrivals. Buyers vary in their value for the service and how patient they are, so the supplier may improve outcomes by providing a menu of delay levels and prices. The system is modelled as a priority queue where congestion constrains the arrival rates at each delay level. In the first study, the supplier has aggregate market data. I model the problem as an optimization subject to incentive and congestion constraints. The novel contributions include a precise description of the optimal menu as a function of the supplier's capacity (the rate at which buyers can be served). Findings include existence of distinct capacity regions where the supplier utilizes service pooling and strategic delay. In the final chapter the related welfare maximization problem is considered. Sufficient conditions for optimal pricing are derived which depend only on operational information: the current revenue must be equal to the best-case revenue subject to current prices and congestion constraints. An associated performance measure is shown to bound deviation from maximum welfare and is used as a heuristic within an adaptive pricing protocol. This protocol is shown to converges to near welfare maximizing outcomes.
Chopin's Third Piano Sonata, Op. 58: Late Style, Formal Ambiguity, and Performance Considerations
Keywords: Chopin
Sonata
Late Style
Formal Ambiguity

Chopin’s Third Piano Sonata, Op. 58, is the largest solo work of his late period. Chopin’s successful combination of the Classical and the Romantic aesthetic, which is explored in Chapter 1, results in an effective balancing of structural integrity and emotional fulfillment. Every movement of Op. 58 possesses qualities of movements in a traditional sonata cycle; however, the tendency to blend structural elements, the expansion of thematic material, and the postponement of climaxes contribute to Chopin’s distinctive treatment of the sonata genre. The issue of late style in Chopin’s output has recently garnered considerable attention. Most writers focus on particular compositional techniques such as the blending of musical genres and the increasing importance of counterpoint and chromaticism. New expressive elements include manifestations of a dandified aesthetic as well as emotional lassitude. These discussions are primarily related to works in Chopin’s original genres, neglecting somewhat the Third Piano Sonata, Op. 58. The second chapter of this dissertation examines the elements of Chopin’s late style present in Op. 58, emphasizing the sonata’s first three movements. These aspects of late style include blurring of genres, complex use of chromaticism, intricacy of counterpoint, textural and thematic variety, dandified impertinence, emotional lassitude and polyvalence. The employment of late stylistic features within the sonata model results in formal ambiguities, which are particularly manifest in the first movement. Chapter 3 reconsiders the movement’s thematic boundaries and especially evaluates the juncture between development and recapitulation. In Chapter 4, the last movement’s indebtedness to Chopin’s balladic model is examined. The gradual intensification of the primary theme together with the presence of a characterizing theme and dancelike episode suggest a merging of Chopin’s balladic practice with rondo form to create an end-directed hybrid structure. This study not only encourages further research into the implications of Chopin’s late style for his larger forms but also increases the variety of interpretative choices available to performers through awareness of Chopin’s stylistic features. The final chapter suggests how insights into musical structure, style, and genre might inform performances of this sonata and how these possibilities relate to a selection of recorded performances.
Extraction of Preservative Components from Treated Wood Waste
Keywords: extraction
preservative
treated wood waste
recycle

The preservative concentration difference in treated wood was investigated to understand the component distribution; a study of different chemical extractions of treated wood waste was carried out and certain reagents were realized to be feasible to the preservative component removal. During fixation, the preservative components redistributed between earlywood and latewood and concentration gradients at depths also developed. Different solvent extractions of CCA treated wood were tested and ion exchange, chelation and metal dissolving were all mechanisms for component extraction. The transition of Cr(III) to Cr(VI) by oxidizing reagents (NaClO and H2O2) can make possible the direct reuse of extracted chemicals as a preservative. Different reaction factors in the oxidant extractions were compared and higher pHs significantly improved the oxidizing capability of the reagents and CCA component removal. Fresh and aged CCA treated wood generally responsed similarly to the oxidant extractions. However, arsenic in aged wood was more difficult to be removed by NaClO, while, H2O2 was more efficient to extract CCA components from aged wood than fresh wood. Monoethanolamine (Mea) efficiently extracted copper (above 90%) from ACQ treated wood and the formation of stable neutral Cu(Mea)2 in sufficient Mea solution is the main mechanism for Mea extraction. Little wood structure degradation occurred during the process. Mea (10%~15%) extraction was fast and the effect of temperature was insignificant. Cu diffusion in the longitudinal direction was the most significant compared to other wood directions. To further promote Mea extraction, repeated extraction (batch-based and column-based) was performed and proved to be more efficient, feasible and economical than one-time extraction. Column-based continuous Mea extraction showed both high Cu removal (up to 99%) and Cu accumulation in the extract. After the preservative treated wood waste is decontaminated significantly, the extract solution can be reused by directly mixing with the preservative treating solution, which is the most straightforward procedure for the recycling of chemicals removed from the preservative treated wood.
Values, Conflicts & Value Conflict Resolution: An Investigation of the Experiences of Educational Administrators
Keywords: values
conflicts
value conflict resolution
educational administrators

This dissertation reports on a study of educational administrators and the value conflicts experienced within their schools. The extensive review of literature on values in educational administration has determined very little consensus regarding the influence of values on the practice of educational administrators. A lack of common understanding about the definition of the term values exists along with variations and inconsistencies regarding the pervasiveness of values in educational administration. School leaders frequently encounter value conflicts and their resolution involves considerable degrees of decision making. Participants in this study include members of the cohort of the Ed.D. Program in the Department of Theory and Policy Studies at the University of Toronto, Ontario Institute for Studies in Education (OISE) as well as practising educational administrators with extensive experience in school leadership. As the researcher works within the Catholic school system, the majority of study participants are Catholic administrators who were accessible to the researcher for participation. A qualitative research methodology was employed and fourteen semi-structured interviews were conducted which focused on the three main research questions. The following research questions were addressed in the study: 1. How do educational administrators see the role of values in their work? 2. What types of value conflicts do educational administrators experience? 3. How do educational administrators resolve conflicts that stem from values issues? The findings herein indicate that administrators view values as extremely important and relevant in their work. The influence of values on administrator behavior is evident in how leaders define the term value: as a code/set of rules and fundamental beliefs that guide daily interactions; and a basis for decision making. In terms of conflicts, administrators experience interpersonal conflicts frequently and attribute this type of conflict to differences in stakeholder values. Educational administrators resolve conflicts that stem from values issues by taking a moral stand which allows them to remain committed to their values. The results of this study acknowledge and contribute to the existing field of studies relating to values and value conflict resolution within educational administration while simultaneously suggesting further implications for future research. The adoption of a values-based leadership model and its associated values clarification process is recommended for school leaders as a framework to deal with the existing realities of their complex role. This model has tremendous potential to transform the existing face of educational administration provided it is seamlessly integrated within educational organizations and becomes the new standard of leadership practice.
Sustained Intraperitoneal Chemotherapy via an Injectable Depot Delivery System for the Treatment of Ovarian Cancer
Keywords: Ovarian cancer
Intraperitoneal chemotherapy
Localized drug delivery
Docetaxel
Injectable
Polymer-lipid

Ovarian cancer has the highest mortality rate of all gynecological malignancies, due to inadequate treatment strategies and poor early diagnosis. Intraperitoneal (IP) chemotherapy administered on an intermittent schedule has been pursued for ovarian cancer treatment. However, local toxicities and complications associated with indwelling IP catheters required to deliver the chemotherapeutics have been documented. Furthermore, shortening or completely removing treatment-free periods between each chemotherapy cycle has shown improved efficacy compared to intermittent chemotherapy. The focus of this thesis was to develop and characterize a biocompatible and biodegradable IP injectable depot sustained drug delivery system as a new treatment strategy for ovarian cancer. A polymer-lipid injectable formulation (PoLigel) was developed and used for sustained docetaxel (DTX) delivery. The PoLigel resulted in homogeneous DTX peritoneal distribution and sustained plasma levels in healthy mice, which was in contrast to Taxotere®, the clinically used formulation of DTX. Sustained plasma, tissue, tumor and ascites DTX concentrations were observed in mice bearing IP SKOV3 tumors or ID8 ascites over a 3 week period following IP administration of the PoLigel. The intratumoral distribution and tumor penetration of DTX in subcutaneous (SC) and IP SKOV3 tumors were characterized. DTX distributed more towards the tumor core and diffused 1.5 fold further from blood vessels of the IP tumors compared to the SC tumors. The high efficacy observed in the IP SKOV3 and ID8 models and the SC SKOV3 model was attributed to favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure. Sustained chemotherapy with DTX alone and in combination with a drug efflux transporter inhibitor was investigated in multidrug resistant (MDR) ovarian cancer. In vitro, combination delivery via the PoLigel resulted in more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in MDR ovarian cancer cells. Sustained combination chemotherapy was more than twice as efficacious as intermittent Taxotere® treatment in MDR ovarian cancer. Significant anti-tumor efficacy was also observed in the MDR model following sustained DTX chemotherapy compared to intermittent Taxotere®. Overall, results presented here encourage the clinical investigation of IP sustained chemotherapy for ovarian cancer treatment.
Analysis of Telomere Healing of DNA Double-strand Breaks
Keywords: yeast
DNA repair
telomere
checkpoint
phosphorylation
phosphatase

DNA double-strand breaks (DSBs) are a threat to cell survival and genome integrity. In addition to canonical DNA repair systems, DSBs can be converted to telomeres by telomerase. This process, herein termed telomere healing, endangers genome stability since it usually results in chromosome arm loss. Therefore, cells possess mechanisms that prevent the untimely action of telomerase on DSBs. In this work, I reported the completion of a transposon mutagenesis screen in budding yeast and the identification of five novel genes (RRD1, CIK1, CTF18, RTS1, and IRC6) critical for telomere healing. The characterization of Rrd1 led to the surprising finding that Rrd1 facilitates telomere healing at DSBs with little or no TG-rich sequences but not at DSBs with long tracts of telomeric sequences. Pph3, a PP4 phosphatase, acts in conjunction with Rrd1 to promote telomere healing. Conversely, Mec1, the ATR ortholog, phosphorylates Cdc13 on its S306 residue to suppress its accumulation at DSBs. Rrd1 and Pph3 oppose Cdc13 S306 phosphorylation and are necessary for the efficient accumulation of Cdc13 at DSBs. Next, I found that Cik1 and its kinesin partner Kar3 are both important for telomere healing. Importantly, Kar3 contributes to telomere healing through its motor function. In contrast to Rrd1, Kar3 contributes to telomere healing regardless of telomeric sequence lengths adjacent to the break. Finally, Cik1 and Kar3 have a general role in DNA repair and physically associate with DSBs, which is dependent on the process of anchoring DSBs to nuclear periphery. In conclusion, I identified a mechanism by which the ATR family of kinases enforces genome integrity, a phosphoregulatory loop that underscores the contribution of Cdc13 to the fate of DNA ends, and a kinesin complex critical for the spatial organization of DNA repair.
Variable Selection and Adjustment in Relation to Propensity Scores and Prognostic Scores: From Single-level to Multilevel Data
Keywords: education
psychology
statistics

Through three sets of simulations, this dissertation evaluates the effectiveness of alternative approaches to causal inference that make use of propensity scores. In the setting of single-level data, the first study examines the relative performance of (a) three variable selection methods for propensity score models (i.e., including all the treatment predictors, including all the outcome predictors, or including confounders), and (b) three adjustment methods in outcome models (i.e., adjusting for the propensity score only, adjusting for the propensity score in combination with the prognostic score, and adjusting for the propensity score in combination with strong outcome-predictive covariates). The second study tests the robustness of the alternative approaches under a range of model misspecifications, including omitted covariates, omitted nonlinear terms, and omitted interaction terms in a propensity score model, a prognostic score model, or an outcome model. The third study extends the evaluation to multilevel data by additionally examining another dimension unique to multilevel data. The study compares random intercept and slopes models, random intercept models, and single-level models for the propensity score and prognostic score estimations. The impact of omitting cluster-level covariates is also examined under each type of model specification. Evaluation criteria include bias, precision, mean squared error, remaining sample size after stratification, and confidence interval coverage percentage. The main findings are: (1) in general, adjustment methods in outcome models have more important consequences than variable selection for propensity score models for bias reduction, precision, and MSE; (2) the robustness against model misspecifications under alternative approaches depends on the type of misspecifications; (3) multilevel propensity score models show advantages over their single-level counterparts especially when combined with prognostic score adjustment; (4) omitting cluster-level information is not highly consequential once the multilevel structure has been accounted for by using multilevel outcome models.