VictorJuiz/thesis huggingface dataset:
Chemical Genomic Analyses of Plant-pathogen Interactions
Keywords: plant-pathogen interactions
chemical genomics
high-throughput screening
molecular biology

The recently-emerged field of chemical genomics is centered on the use of small molecules to perturb biological systems as a means of investigating their function. In order to employ this approach for the study of plant-pathogen interactions, I established an assay in which Arabidopsis thaliana seedlings are grown in liquid media in 96-well plates. Inoculation of these seedlings with a virulent strain of the bacterial phytopathogen Pseudomonas syringae resulted in macroscopic bleaching of the cotyledons of these seedlings. This symptom was used as the basis for high-throughput chemical genomic screens aimed at identifying small molecules that protect Arabidopsis seedlings from infection. One of the first chemicals identified through this screen was the sulfanilamide compound sulfamethoxazole (Smex). This compound was later shown to also reduce the susceptibility of both Arabidopsis and wheat to infection by the fungal pathogen Fusarium graminearum, suggesting a broad spectrum of activity. More detailed investigations of Smex indicated that the protective activity of this compound did not derive from antimicrobial effects, and that this activity was not executed through common defence-related signalling pathways. The folate biosynthetic pathway enzyme dihydropteroate synthase is a known target of sulfanilamides, and it does appear to contribute to Smex-induced disease resistance, albeit in a folate-independent manner. In order to identify downstream mediators of Smex activity, I initiated two forward genetic screens intended to recover mutants with altered sensitivity to Smex in a seedling growth assay. Interestingly, while these screens yielded mutants with striking Smex sensitivity phenotypes, disease resistance phenotypes were not altered. Gene expression profiling of Arabidopsis tissues treated with Smex prior to bacterial inoculation suggested that this compound generally affects lipid signalling. Altogether, it is evident that Smex elicits a complex set of responses in Arabidopsis with apparently non-overlapping phenotypic outputs.
Non-invasive Cardiac Output of Children in Health and Disease: Respiratory Gas Techniques
Keywords: cardiac output
children
exercise physiology

Cardiac output (Q) is an important determinant of the cardiovascular system‟s ability to meet the oxygen needs of the body. This dissertation addresses the non-invasive measurement of Q, in healthy children and those with heart and lung disease. 1) The correction factors for collision broadening, downstream difference and end tidal CO2 (PetCO2), used in the CO2 rebreathe (equilibrium) method, were evaluated. In lung disease, one is unable to assume a normal dead space to estimate arterial CO2 (PaCO2), and the use of any of these correction factors alone should be used with caution as they each exert a profound effect on the Q measurement. 2) A new equation to predict PaCO2 from PetCO2 in patients with CF was derived via multiple regression analysis, taking into account disease severity. 3) The validity and reliability of Q measures via the inert gas rebreathing technique (InnocorTM device) were evaluated. The highest intraclass correlation coefficients were attained during exercise (0.7-0.98), indicating excellent reliability of the device. Comparisons of Q measures from the InnocorTM (QInn) to the AMIS mass spectrometer system (QAmis) were made to assess validity. The bias (QInn-QAmis) and limits of agreement (±2SD) were 0.45 ± 1.9 L.min-1 and 0.27 ± 2.1 for children with congenital heart disease and healthy controls respectively, with no systematic differences between the two methods. 4) Assessment of cardiac output in Fontan patients demonstrated that an individualized, atrioventricular (AV) delay optimization was required. Moreover, there was a small but significant improvement in heart function with AV synchronized pacing (DDI) versus ventricular pacing (VVI), suggesting that further study with a larger sample of patients is warranted. The limitations and strengths of the measurement of non-invasive cardiac output in children, primarily via respiratory gas analysis, were delineated and recommendations were made for their use.
Supporting Public Health Policy Decision-making through Economic Evaluation: Applications and Methods
Keywords: health economics
public health
economic evaluation
decision-analysis
infectious diseases
mathematical modeling

The extent to which economic evaluations of public health programs in Ontario are conducted and used by decision makers is currently very limited. This thesis supports public health decision-making through applied and methodological work. The applied work demonstrates different methods to evaluate the cost-effectiveness of public health interventions using the examples of seasonal and pandemic influenza immunization programs. The methodological component explores whether time horizon choice, one methodological consideration in economic evaluations, introduces bias. The economic evaluation of Ontario’s universal influenza immunization program (UIIP) uses primarily provincial health administrative databases to assess the impact of UIIP on health outcomes (quality-adjusted life years (QALYs), mortality), health care resource use (physician office visits, emergency department visits, and hospitalizations), and costs due to seasonal influenza. Ontario’s UIIP was found to be cost-effective compared to a targeted program. The economic evaluation of Ontario’s H1N1 (2009) mass immunization program uses a mathematical modeling approach to describe the pandemic as observed in Ontario. By removing immunization from the simulation, the impact of the program was evaluated. Outcome measures include health outcomes (attack rate, deaths, QALYs), resource use, and cost (physician office visits, emergency department visits, hospitalizations). The analysis found Ontario’s mass immunization program to be highly cost-effective despite high program cost. The methodological component investigates whether time horizon choice, a major methodological choice, introduces bias to economic evaluations. The existence, magnitude and direction of time horizon bias are demonstrated using a formal model. This work supports current guidelines in recommending a lifetime time horizon and provides a framework to discuss bias in economic evaluations. This thesis demonstrates different approaches to evaluate the cost-effectiveness of public health interventions, informs decision-making, and establishes the groundwork to guide future economic evaluations of public health interventions.
Flaxseed and Lower-dose Estrogen: Studies on Their Protective Actions and Mechanisms in Bone Using the Ovariectomized Rat Model
Keywords: Flaxseed
Lower-Dose Estrogen Therapy

Flaxseed (FS) is a rich source of lignans and n-3 polyunsaturated fatty acids (PUFA), compounds that may help preserve normal bone cell function during aging. Understanding the effect of FS alone or combined with lower doses of estrogen therapy on bone and other estrogen-responsive tissues (e.g. uterus) is of particular interest to postmenopausal women who combine dietary bioactives (e.g. FS) with pharmacological agents (e.g. estrogen monotherapy) to attenuate postmenopausal bone loss. The overall objective of my research was to determine the effects and mechanisms of FS, alone or combined with lower doses of estrogen therapy, on bone and uterus health by measuring a comprehensive set of outcomes in the ovariectomized rat model of postmenopausal osteoporosis. The results demonstrated that FS enhances the protective effect of low-dose estrogen therapy (LD) on vertebral bone mineral density (BMD), three-dimensional microarchitecture and strength in ovariectomized rats. Moreover, FS exerts a stronger effect on bone outcomes when combined with LD than when combined with ultra-low-dose estrogen therapy (ULD). These studies also showed that FS feeding results in higher lignans and n-3 PUFAs in vertebrae, tibias and femurs. Histological analyses at the lumbar vertebra (LV) showed that there were no differences in TRAP-5β, CTX, or OPG/RANKL ratio between the FS+LD and LD groups. FS+LD did however result in lower protein expression of osteocalcin, a marker of bone formation and overall bone turnover, and higher expression of OPG compared to the negative control (NEG), while LD did not. While these findings suggest that FS+LD results in greater attenuation of deterioration of bone tissue compared to LD due to a reduction in bone turnover, significant differences between FS+LD and LD were not observed. Elucidating these specific mechanisms of action require further investigation. In the uterus, FS+LD did not induce greater cell proliferation or differences in qualitative indices of uterine morphology compared to LD. These findings suggest that there may be no increase in the risk of endometrial hyperplasia and carcinoma with FS+LD compared to LD. These findings may lead to the development of strategies that combine food bioactives and current pharmacological agents to more effectively normalize bone turnover during aging.
Axisymmetric Drop Shape Analysis (ADSA) and Lung Surfactant
Keywords: Surface Thermodynamics
Surface Tension
ADSA
Lung Surfactant

The objective of this thesis was to further develop a methodology for surface tension measurement called Axisymmetric Drop Shape Analysisn(ADSA) and to adapt it to studies of lung surfactants, i.e. the material that coats and facilitates the functioning of the lungs of all mammals. The key property of a functioning lung surfactant is its surface tension, which can reach extremely low values. Such values are difficult to measure; but a certain configuration of ADSA, using a constrained sessile drop (ADSA--CSD), is capable of performing such measurements. Clinically, lung surfactant films can be altered from both sides, i.e. from the airspace as well as from the bulk liquid phase that carries the film. Therefore, being able to access the interface from both sides is important. Here, ADSA--CSD was redesigned to be used as a micro film balance allowing access to the interface from both gas- and liquid-side. This allows deposition from the gas side as well as complete exchange of the bulk liquid phase. The new design was used to study lung surfactant inhibition and inhibition reversal. A dynamic compression-relaxation model (CRM) was developed to describe the mechanical properties of lung surfactant films by investigating the response of surface tension to changes in surface area. The model evaluates the quality of lung surfactant preparations -- beyond the minimum surface tension value -- and calculates the film properties, i.e. elasticity, adsorption and relaxation, independent of the compression protocol. The accuracy of the surface tension measurement can depend on drop size. A detailed analysis of drop shapes and accuracy of measured surface tension values was performed using a shape parameter concept. Based on this analysis, the design of ADSA--CSD was optimized to facilitate more accurate measurements. The validity analysis was further extended to the more conventional pendant drop setup (ADSA--PD). An overall upgrade of both hardware and software of ADSA--CSD, together with extensive numerical work, is described and applied to facilitate a more efficient operation. Finally, it is noted that the ADSA--CSD setup developed here can be used for a wide range of colloid and surface chemical applications.
Systematic Genetic Analysis of Dimorphism in Saccharomyces cerevisiae
Keywords: Genomics
Yeast

Deletion mutant collections allow for the systematic study of gene function by linking a genotype to a phenotype. Furthermore, these collections permit the parallel and quantitative study of phenotypes, which is the foundation of functional genomics. I begin by summarizing the methods used and data derived from the field of functional genomics using the Baker’s yeast Saccharomyces cerevisiae, and provide important background information on the origins of the filamentous growth-competent S.cerevisiae strain Σ1278b, and the developmental process of fungal dimorphism. I describe my efforts in creating a complete deletion mutant collection in the filamentous growth-competent S.cerevisiae strain Σ1278b, and the subsequent phenotypic analysis of that deletion mutant collection. By quantitatively measuring mutant phenotypes of cells undergoing haploid invasive growth, biofilm mat formation and diploid pseudohyphal growth, I studied the clinically relevant developmental process of fungal dimorphism. I present the first genome-wide and quantitative phenotypic analysis of fungal dimorphism and identify a novel transcription factor encoded by the open reading frame YDL233W, which I named FMR1for Filamentation Master Regulator 1. By performing genetic, cell biological, biochemical, and expression analysis, I demonstrate that Ydl233w acts by forming a protein complex with the DNA-binding transcription factors Flo8 and Mss11 and this complex binds to a specific element within the promoter of the surface adherence mediating gene FLO11. I directly compare the essential gene sets between the Σ1278b deletion collection and the reference deletion collection made in the S288c genetic background completed by the Yeast Deletion Consortium in 2002. I find that most essential genes are shared between these two strains but a number of genes are essential for viability in only one genetic background, a phenomenon termed conditional essentiality. I describe the genetic basis of conditional essentiality as a consequence of the complex inheritance of background-specific alleles. Lastly, I summarize the scientific advancements of my research using the Σ1278b deletion collection, and highlight some potential applications for both the data derived from my research and the deletion mutant collection itself. The Σ1278b deletion collection provides a valuable resource for yeast geneticists, evolutionary biologists, researchers of fungal disease, and researchers interested in modeling the genetics that underlie complex traits and diseases.
Zelter, Goethe and the Emergence of a German Choral Canon
Keywords: Zelter
Goethe
Choral
Bach

This thesis examines the dialogue between Carl Friedrich Zelter (1758-1832) and Johann Wolfgang von Goethe (1749-1832) on choral music and the role they envisioned for it within a national German repertory. The primary source for this examination is the voluminous correspondence between the two men, which spans almost 900 letters and over thirty years. In the correspondence, they discuss choral music both as an abstract and practical art. In addition, Zelter’s descriptions of concerts that he performed in and attended form a valuable record of musical life in Berlin in the early nineteenth-century. To show the importance of choral music within the correspondence, this thesis is divided into three parts: an examination of Zelter and Goethe’s engagement with (choral) music; their respective choral organizations; and two musical case studies that show the application of their discussions. The first segment allows for a fuller understanding of how choral music fit in Zelter and Goethe’s larger artistic endeavours. This context is especially important given their marginal musical legacies, which have contributed to the scholarly neglect of their discourse on choral music. The second segment examines Zelter’s work with the Berlin Sing-Akademie in detail, focussing on its performance practice, membership, and audience. This examination shows that contrary to the oft-repeated claim that the Sing-Akademie did not regularly perform in public until 1829, the chorus in fact sang for a wide audience on a regular basis from the early 1800s on. The third segment provides case studies on the music of J.S. Bach and G.F. Handel. Goethe and Zelter’s dialogue about the two composers is considered, along with their practical engagement with the repertoire. Further, the Sing-Akademie’s performance history of both composers is examined. In sum, this thesis demonstrates the central role of historical choral music in the correspondence of Goethe and Zelter; their interest in older German choral music is shown to have had a profound impact on the music performed by similar organizations across Germany.
Labour Force Participation and Health-related Quality of Life in People Living with HIV
Keywords: employment
health-related quality of life
HIV

This dissertation consists of four papers aimed at understanding the complex relationship between employment and health. One paper is a systematic review of the return to work literature, while the other three papers used secondary data from three cohorts of people with HIV to examine the association between employment and health-related quality of life. The systematic review looked at longitudinal studies that reported health outcomes associated with return to work in relation to other employment trajectories. This review supported the beneficial effect of return to work on health in a variety of populations, times, and settings, and also found evidence that poor health interferes with the prospects of returning to work. Two other papers looked at the association between employment and health-related quality of life in people with HIV; one paper used a cross-sectional sample of people with HIV, while the other paper used a longitudinal sample of men who have sex with men. These two studies found evidence to support the association between employment and both physical and mental health-related quality of life. They also found that employment had a stronger relationship with physical than mental health, suggesting an adaptation process to the experience of unemployment. Finally, another paper examined the cross-sectional association between job security and quality of life in men and women living with HIV. This study found that job security offered additional mental health quality of life benefits, over and above participation in employment alone, for men living with HIV. On the other hand, women benefited from the availability of work, but the perception of job security failed to offer additional health benefits. The current level of evidence on the relationship between work and health in HIV needs to be strengthened by further research to develop and support practical clinical and policy recommendations.
Role of the Intestinal Epithelial Insulin-like Growth Factor-1 Receptor in Glucagon-like Peptide-2-mediated Small Intestinal Growth Responses
Keywords: intestine
proliferation
insulin-like growth factor
glucagon-like peptide-2

The gut hormone glucagon-like peptide-2 (GLP-2) has numerous beneficial effects on the intestinal epithelium, including increased mucosal growth and proliferation. GLP-2 is also necessary for the adaptive intestinal re-growth that occurs upon re-feeding after fasting. Although insulin-like growth factor (IGF)-1 and the IGF-1 receptor are known to be required for GLP-2-induced crypt-cell proliferation, the precise cellular localization of the IGF-1 receptor through which the intestinotrophic actions of GLP-2 are mediated remains unknown. I hypothesized that small intestinal growth responses to GLP-2 occur through an intestinal epithelial IGF-1 receptor-dependent pathway, through the use of an inducible, intestinal epithelial-specific IGF-1 receptor knockout (IE-igf1rKO) mouse. Intestinal growth and proliferative responses were examined in IE-igf1rKO and control mice following treatment with GLP-2, as well as in animals that were fasted and re-fed to induce GLP-2-dependent adaptation. In Chapter 3, it was demonstrated that IE-igf1rKO mice, as compared to control littermates, had normal small intestinal weight, morphometric parameters, proliferative index and differentiated epithelial cell lineage distribution. Administration of GLP-2 for 30 minutes increased nuclear translocation of !-catenin in non-Paneth crypt-cells, and stimulated the crypt-cell proliferative marker c-Myc 90 minutes following GLP-2 treatment, in control littermates but not in IE-igf1rKO mice. In Chapter 4, adaptive re-growth was studied by fasting IE-igf1rKO and control animals for 24 hours, or by fasting and then re-feeding mice for 24 hours. Small intestinal weight, crypt depth, villus height and crypt-cell proliferation were decreased in both control and IE-igf1rKO mice after 24 hour fasting. While re-feeding in control mice restored all of these parameters, re-fed IE-igf1rKO mice displayed abrogated adaptive re-growth of the crypt-villus axis as well as reduced crypt-cell proliferation. In Chapter 5, control mice responded to chronic GLP-2 with increased small intestinal weight, mucosal cross-sectional area, crypt depth, villus height and crypt-cell proliferation. However, the GLP-2-induced increase in crypt-cell proliferation was absent in IE-igf1rKO mice, in association with impaired growth of the crypt-villus axis. Taken together, these results indicate that the proliferative responses of the intestinal epithelium to exogenous GLP-2 administration and during conditions of GLP-2-dependent adaptive re-growth are dependent on the intestinal epithelial IGF-1 receptor.
The Left Regular Representation of a Semigroup
Keywords: Operator Theory
Semigroups

As with groups, one can study the left regular representation of a semigroup. If one considers such representations, then it is natural to ask similar questions to the group case. We start by formulating several questions in the semigroup case and then work towards understanding the structure of the representations given. We present results describing what the elements of the image under the representation map can look like (the semigroup problem), whether or not two semigroups will give isomorphic representations (the isomorphism problem), and whether or not the representation of a semigroup is reflexive (the reflexivity problem). This research has been funded in part by a scholarship from the Natural Sciences and Engineering Research Council of Canada.