VictorJuiz/thesis huggingface dataset:
The Consequences of Collagen Degradation on Bone Mechanical Properties

The mechanisms underlying the effect of alterations in Type I collagen on bone mechanical properties are not well defined. Clinical tools for evaluating fracture risk, such as dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) focus on bone mineral and cannot detect changes in the collagen matrix. The mechanical response tissue analyzer (MRTA) is a potential tool for evaluating fracture risk. Thus, the focus of this work was to investigate the effects of collagen degradation on bone mechanical properties and examine whether clinical tools can detect these changes. Female and male emu tibiae were endocortically treated with 1 M potassium hydroxide (KOH) solution for 1-14 days and then either mechanically tested in three-point bending, fatigued to failure or fatigued to induce stiffness loss. Computed Tomography scans, DXA, QUS, MRTA and three-point bend testing in the elastic region were performed on emu tibiae before and after either KOH treatment or fatigue to induce stiffness loss. Fracture surfaces were examined to determine failure mechanisms. Bone mineral and bone collagen were characterized using appropriate techniques. Bone mineral-collagen interface was investigated using Raman spectroscopy and atomic force microscopy (AFM). Endocortical KOH treatment does not affect bone mineral however, it causes in situ collagen degradation, rather than removal and may be weakening the mineral-collagen interface. These changes result in significantly compromised mechanical properties. Emu tibiae show significant decreases in failure stress and increased failure strain and toughness, with increasing KOH treatment time. The significant increase in toughness of KOH treated bones is due to structural alterations that enhance the ability of the microstructure to dissipate energy during the failure process, thereby slowing crack propagation, as shown by fracture surface analysis. KOH treated samples exhibit a lower fatigue resistance compared to untreated samples at high stresses only for both sexes. Partial fatigue testing results in similar decreases in modulus for all groups and sexes. The MRTA detected these changes whereas DXA and QUS did not. MRTA detects changes in bone mechanical properties induced by changes in collagen quality and fatigue and could be a more effective tool for predicting fracture risk.

Keywords: collagen degradation
bone mechanical properties
Advisor: Grynpas, Marc D.
Hexokinase 2 is a Key Mediator of Aerobic Glycolysis Promoting Tumour Growth in Glioblastoma Multiforme

Proliferating tissues, including embryonic and tumour tissues, preferentially employ aerobic glycolysis to support cell growth. This reliance on glycolysis even in the presence of oxygen, referred to as the “Warburg Effect”, may confer a proliferative, survival and invasive advantage and be exploited therapeutically. In this thesis, we demonstrate that the glycolytic enzyme Hexokinase 2 (HK2) is crucial for the “Warburg Effect” in human Glioblastoma Multiforme (GBM), the most common and therapeutically resistant malignant brain tumour. In contrast to normal brain and low-grade gliomas, GBMs exhibited a marked increase in HK2 expression, but not HK1, particularly in perinecrotic, hypoxic regions and its expression predicted poor overall survival of GBM patients. Stable loss of HK2 in GBM cells restored oxidative phosphorylation (OXPHOS)-mediated glucose metabolism, with increased oxygen consumption and decreased lactic acid production, an effect not seen with loss of glycolytic enzymes HK1 or PKM2. Furthermore, HK2 depletion resulted in decreased proliferation in vitro and in vivo and increased sensitivity to apoptotic inducers such as radiation and chemotherapy, both common adjuvant therapies of GBMs. Intracranial xenografts of GBM cells with reduced HK2 demonstrated significantly increased survival with decreased proliferation and angiogenesis yet enhanced invasiveness. In contrast, exogenous HK2 expression in GBM cells promoted proliferation, therapeutic resistance and intracranial growth. This was dependent partly on the PI3K/AKT dependent translocation of HK2 to the mitochondrial membrane. Stable loss of glycolytic enzymes HK2, HK1 and PKM2 reduced GBM proliferation but differentially altered the PI3K/AKT/mTOR and AMPK signaling pathways, the extent to which may influence whether a cell preferentially undergoes autophagy or apoptosis as the primary mode of cell death. Collectively, targeting enzymes employed by the tumour to modulate its energy metabolism, such as HK2 in GBMs, may favourably alter its therapeutic sensitivity to radiation and both classical and novel chemotherapeutic agents.

Keywords: Glioblastoma Multiforme
aerobic glycolysis
Hexokinase 2
Advisor: Guha, Abhijit
Preoperative Internal Medicine Consultation for Elective Intermediate-to-high Risk Noncardiac Surgery in Ontario

This dissertation uses population-based administrative healthcare data to evaluate the outcomes, processes-of-care and practice variation associated with preoperative medical consultation in Ontario, Canada. First, a multicentre cross-sectional study was conducted to develop a novel algorithm for identifying preoperative medical consultations using administrative data. The optimal claims-based algorithm was a physician service claim for a consultation by a cardiologist, general internist, endocrinologist, geriatrician, or nephrologist within 120 days before the index surgery. This algorithm had a sensitivity of 90% (95% confidence interval [CI], 86 to 93) and specificity of 92% (95% CI, 88 to 95). Second, we conducted a population-based cohort study to evaluate the association of preoperative medical consultation with outcomes and processes-of-care. After adjustment for measured confounders using propensity-score methods, consultation was associated with increased preoperative testing, preoperative pharmacological interventions, 30-day mortality [relative risk (RR) 1.16; 95% CI, 1.07 to 1.25], 1-year mortality (RR 1.08; 95% CI, 1.04 to 1.12), and mean hospital stay (difference 0.67 days; 95% CI, 0.59 to 0.76). These findings were stable across subgroups, as well as sensitivity analyses that tested for unmeasured confounding. Third, temporal trends and practice variation in consultation were evaluated within the population-based cohort. The proportion of patients undergoing consultation remained relatively stable over the study period, at approximately 39%. Although patient-level and surgery-level factors did predict consultation use, they explained only 6.8% of variation in consultation rates. By comparison, inter-hospital differences in rates were substantial (range, 1.9% to 86.8%), were not explained by surgical volume or teaching status, and persisted after adjustment for patient-level and surgery-level factors. Overall, this dissertation highlights the need for research to identify interventions for safely decreasing perioperative risk, define mechanisms by which consultation influences outcomes, examine factors that influence practice variation in medical consultation, and identify patients who benefit most from preoperative medical consultation.

Keywords: Perioperative medicine
Preoperative consultation
Surgery
Internal medicine
Advisor: Laupacis, Andreas
The Difference between Ecological Context and Treatment Progress of Young Girls with Comorbid Externalizing and Internalizing Disorders and Young Girls with Only Externalizing Disorders

Many children and their families who seek assistance for childhood behaviour disorders experience comorbid disorders, namely the presence of two or more disorders. Although comorbid disorders are recognized as a frequent clinical complication, minimal direction exists within the literature about the risk factors for comorbid conditions and how best to provide intervention services. In this study an ecological framework was used to compare the individual, family, and community environmental contexts of young girls who presented at intake at a children’s mental health centre with comorbid externalizing and internalizing disorders, and girls who presented at intake with externalizing disorders only. The treatment response to a cognitive-behavioural intervention for externalizing behaviour disorders was examined, by comparing externalizing scores over time between girls with comorbid externalizing and internalizing disorders and girls with externalizing disorders only. Additionally, internalizing scores over time for girls with comorbid disorders were examined. Results indicated that a history of abuse and a cluster of individual characteristics placed girls at higher risk to present with comorbid conditions. The results also indicated that girls with comorbid disorders experienced a reduction of both externalizing and internalizing symptoms. Only 1 in 7.4 girls, however, scored below the clinical range for both externalizing and internalizing disorders at the end of the treatment phase, in comparison to 1 in 5 girls scoring below the clinical range for externalizing disorders in the noncomorbid group.

Keywords: comorbid externalizing and internalizing disorders
girls
risk factors
treatment outcome
Advisor: Stern, Susan
Beyond Geometric Models: Multivariate Statistical Ecology with Likelihood Functions

Ecological problems often require multivariate analyses. Ever since Bray and Curtis (1957) drew an analogy between Euclidean distance and community dissimilarity, most multivariate ecological inference has been based on geometric ideas. For example, ecologists routinely use distance-based ordination methods (e.g. multidimensional scaling) to enhance the interpretability of multivariate data. More recently, distance-based diversity indices that account for functional differences between species are now routinely used. But in most other areas of science, inference is based on Fisher's (1922) likelihood concept; statisticians view likelihood as an advance over purely geometric approaches. Nevertheless, likelihood-based reasoning is rare in multivariate statistical ecology. Using ordination and functional diversity as case studies, my thesis addresses the questions: Why is likelihood rare in multivariate statistical ecology? Can likelihood be of practical use in multivariate analyses of real ecological data? Should the likelihood concept replace multidimensional geometry as the foundation for multivariate statistical ecology? I trace the history of quantitative plant ecology to argue that the geometric focus of contemporary multivariate statistical ecology is a legacy of an early 20th century debate on the nature of plant communities. Using the Rao-Blackwell and Lehmann-Scheffé theorems, which both depend on the likelihood concept, I show how to reduce bias and sampling variability in estimators of functional diversity. I also show how to use likelihood-based information criteria to select among ordination methods. Using computationally intensive Markov-chain Monte Carlo methods, I demonstrate how to expand the range of likelihood-based ordination procedures that are computationally feasible. Finally, using philosophical ideas from formal measurement theory, I argue that a likelihood-based multivariate statistical ecology outperforms the geometry-based alternative by providing a stronger connection between analysis and the real world. Likelihood should be used more often in multivariate ecology.

Keywords: Ecology
Multivariate statistics
Likelihood
Statistical models
Advisor: Jackson, Donald Andrew
Correlations in the Cosmic Far-infrared Background at 250, 350, and 500 μm Reveal Clustering of Star-forming Galaxies

We demonstrate the application of CMB techniques to measure the clustering of infrared emitting star-forming galaxies. We detect correlations in the cosmic far-infrared background due to the clustering of star-forming galaxies in observations made with the Balloon-borne Large Aperture Submillimeter Telescope, BLAST, at 250, 350, and 500μm. We perform jackknife and other tests to confirm the reality of the signal. The measured correlations are well fit by a power law over scales of 5–25 arcminutes, with ∆I/I = 15.1 ± 1.7%. We adopt a specific model for submillimeter sources in which the contribution to clustering comes from sources in the redshift ranges 1.3≤z≤2.2, 1.5≤z≤2.7,and1.7≤z≤3.2,at 250, 350 and 500 μm, respectively. With these distributions, our measurement of the power spectrum, P(kθ), corresponds to linear bias parameters, b = 3.8±0.6,3.9±0.6 and 4.4±0.7, respectively. We further interpret the results in terms of the halo model, and find that at the smaller scales, the simplest halo model fails to fit our results. One way to improve the fit is to increase the radius at which dark matter halos are artificially truncated in the model, which is equivalent to having some star-forming galaxies at z ≥ 1 located in the outskirts of groups and clusters. In the context of this model we find a minimum halo mass required to host a galaxy is log(Mmin/M⊙) = 11.5+0.4, and we derive effective biases beff = 2.2 ± 0.2, 2.4 ± 0.2, −0.1 and 2.6 ± 0.2, and effective masses log(Meff/M⊙) = 12.9 ± 0.3, 12.8 ± 0.2, and 12.7 ± 0.2 , at 250, 350 and 500 μm, corresponding to spatial correlation lengths of r0 = 4.9, 5.0, and 5.2 ±0.7 h−1 Mpc, respectively. Finally, we discuss implications for clustering measurement strategies with Herschel and Planck.

Keywords: Submillimeter
Clustering
Advisor: Netterfield, Calvin Barth
Rayano: una nueva metáfora para explicar la dominicanidad

Through close readings of various texts that deal with issues of border, identity and the relationship between Haiti and Dominican Republic as well as with the flow of immigrants between Dominican Republic and the United States, this study introduce the trope of the “rayano” (the one that was born, lives or comes from the border) as an apt metaphor to explain the identity of Dominicans in the twenty-first century — an identity that should be viewed as one born out of movements, translations and interstices. The primary texts that this study will focus on will cover the Haitian-Dominican and Dominican-American experiences.  In terms of the former, El Masacre se pasa a pie (1973) by Freddy Prestol Castillo and The Farming of Bones (1998) by Edwidge Danticat are useful for analyzing the defining moment of the relationship between Haiti and Dominican Republic in the twentieth century: the 1937 border massacre of Haitians and Dominican-Haitians ordered by Dominican dictator Rafael L. Trujillo. In the case of the Dominican-American relationship, Dominicanish (2000) by Josefina Báez, and The Brief Wondrous Life of Oscar Wao (2007) by Junot Díaz will be the texts through which it will be analyzed the Dominican diaspora and its relationship with the two defining spaces of Dominicanness in the twenty-first century: Santo Domingo and New York City. In addition to these texts, this study also will engage with the theoretical production regarding the triangular relationship between Dominican Republic, Haiti and the United States through an analysis of the different metaphors used by Lucía M. Suárez in The Tears of Hispaniola: Haitian and Dominican Diaspora Memory, Eugenio Matibag in Haitian-Dominican Counterpoint: Nation, State and Race in Hispaniola, and Michele Wucker in Why the Cocks Fight: Dominicans, Haitians, and the Struggle for Hispaniola.

Keywords: Rayano
Dominican Identity
Latin American Literature
Dominican Republic
Haiti
United States of America
Advisor: Rodríguez, Néstor E
What Happens after Establishment? The Indirect Impacts of the Gypsy Moth on Native Forest Caterpillar Communities

Invasive insects are considered one of the most serious threats affecting forests today; however, surprisingly little research has addressed the impacts of invasive species establishment on native forest insect communities. Such information is lacking for even the most thoroughly studied invasive forest insect, the gypsy moth. Using gypsy moth as a case study, my thesis addresses the questions: What are the ecological impacts of an exotic forest insect upon its establishment in a new community of native species? Does the community shift after the invasive establishes, and if so, what are the drivers in this realignment? I used multivariate analysis to assess native caterpillar communities collected in forest stands with and without a history of gypsy moth outbreak. I found that gypsy moth outbreak history had no significant effects on native caterpillar communities; however, current gypsy moth abundance was related to shifts in the structure of late season caterpillar assemblages. These results suggest that gypsy moth may affect native caterpillar communities through short-term mechanisms but not through long-term ecological changes. I used quantitative food webs to investigate the effects of gypsy moth on native host-parasitoid webs from the same caterpillar communities, and found that food web structure was resilient to both gypsy moth outbreak history and current abundance. The gypsy moth shared few parasitoids with native species in my study sites, none of numerical significance, thus minimizing the opportunity for enemy-mediated indirect interactions. Finally, I conducted a greenhouse experiment and found that early spring feeding by forest tent caterpillar can indirectly influence gypsy moth susceptibility to its virus, demonstrating that the complex interactions that can occur between native and exotic species do not always benefit the invader. Overall, I argue that the establishment of the gypsy moth into North American forests will not cause major changes in native caterpillar communities.

Keywords: gypsy moth
ecological impacts
invasive insects
forest caterpillars
food webs
host-parasitoid
Advisor: Smith, Sandy
Construction of Functionalized Heterocycles by Palladium-catalyzed Domino Reactions with Strained Alkenes

The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate. The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines. In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones. Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.

Keywords: Nitrogen Heterocycles
Palladium
Domino Reactions
Strained Alkenes
Catalysis
Advisor: Lautens, Mark
Mechanisms of High Glucose-induced Decrease in β-cell Function

Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo.

Keywords: Glucotoxicity
Oxidative Stress
Type 2 Diabetes
Endoplasmic Reticulum Stress
c-jun N-terminal kinase
Advisor: Giacca, Adria