VictorJuiz/thesis huggingface dataset:
Novel PMOs: Studies in Periodic Mesoporous Organosilicas
Keywords: mesoporous
silica
organosilica
PMO

The field of mesoporous materials has been expanding rapidly in recent years, and has come to include a wide variety of different types of materials from organic to inorganic, as well as hybrid materials that encompass both worlds. The following account explores one type of mesoporous materials, specifically those consisting of silica with an attached organic group that have come to be known as periodic mesoporous organosilicas (PMOs). Much of the work here involves incorporating new types of organic groups into a mesoporous framework for the purpose of adding a useful functionality, either chemical or physical, to the material. Firstly it is shown that a borazine moiety can be successfully incorporated into a mesoporous material with a very high loading. It was further shown that once incorporated into the material many of the borazine moieties are available for further chemical reactions with acids and transition metals. Next, a new class of materials termed hybrid periodic mesoporous organosilicas (HPMOs) was developed that was able to circumvent many of the problems associated with PMO self-assembly. Now, using very simple techniques, virtually any type of silsesquioxane can be incorporated into a PMO, and the organic group can be specifically at the surface of the pores, thereby maximizing its accessibility. And finally, a PMO is made that incorporates buckyballs, and it is shown that, given the right synthetic conditions, the buckyballs are homogeneously distributed throughout the material.
Characterization of Shadoo and DPPX: Two Proteins of Potential Relevance to Prion Biology
Keywords: prion
biochemistry
neurodegenerative disease
protein folding
Shadoo
DPPX
PrP
Doppel
protein-protein interaction
mouse models
DPP6
Sprn
neuroscience
DPP10

Prion diseases are fatal neurodegenerative disorders of humans and animals. The prion hypothesis states that PrPSc, a misfolded conformational isoform of the cellular prion protein (PrPC), is the sole component of the infectious particle. Many open questions exist in prion biology including the cellular role of PrPC, the potential involvement of auxiliary factors in prion replication, and the mechanism of PrPSc-induced toxicity in prion disease. The identification of novel prion-like proteins and authentic in vivo prion protein-interacting proteins would certainly assist the process of demystifying these unsolved mysteries. Accordingly, two newly-identified proteins with potential relevance to prion protein biology, Shadoo and DPPX, were selected for biochemical and functional characterization. Shadoo, a hypothetical prion-like protein, is revealed as being a glycoprotein which possesses many overlapping properties with PrPC including neuronal expression, C1-like endoproteolytic processing, and the ability to protect against apoptotic stimuli in cerebellar neurons. Shadoo loosely resembles the disordered N-terminal domain of PrPC and consistent with this notion, Shadoo appears to lack a well-defined structure. Remarkably, Shadoo levels in the brains of mice with clinical prion disease are significantly decreased suggesting that Shadoo may be inherently linked to prion replication or prion disease pathogenesis. These experiments define Shadoo as the third member of the prion protein family and, because of its functional similarities to PrPC, Shadoo may be a useful tool for deciphering the in vivo function of PrPC. DPPX, a neuronal type II transmembrane protein, is demonstrated to be the first protein capable of interacting with all three members of the prion protein family (PrPC, Doppel, and Shadoo) in vivo. Complex formation between prion proteins and DPPX appears to be mediated by multiple binding sites. When coupled with high levels of DPPX expression in cerebellar granular neurons, DPPX is a strong candidate for mediating phenotypic interactions between prion proteins in cerebellar cells. Thus, Shadoo and DPPX comprise two new entry points for studying prion proteins. Further investigation of the roles of Shadoo and DPPX in both the cell biology of prion proteins and prion disease may yield important clues to these enigmatic topics.
Targeting Inflammation to Reduce Secondary Injury after Hemorrhagic Stroke
Keywords: intracerebral hemorrhage
stroke
microglia
astrocytes
neutrophils
cytokines
neuroinflammation
aging

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from rupture of a blood vessel in the brain. Tissue inside the hematoma is irreversibly damaged soon after ICH onset and when this thesis research began, there was a dearth of information regarding pathological changes outside the hematoma. Inflammation is often proposed as a mechanism of injury, but very little information was available to show that inflammatory cells were in the right place at the right time to cause secondary brain injury. Using the collagenase-induced model of ICH, this work sought to better define spatial and temporal relationships between secondary brain injury and the inflammatory response after ICH. To test the hypothesis that reducing inflammation can protect the brain from secondary injury, minocycline, an antibiotic with established anti-inflammatory effects, was administered 6 hours after ICH onset. A small number of neurons die in the parenchyma bordering the hematoma between 6 hours and 3 days after ICH onset. This area was not associated with neutrophil infiltration, and most activated microglia/macrophages did not accumulate until after most neuron death had occurred. Despite a pronounced microglial response and prolonged increase in expression of many inflammatory genes, including complement receptor-3, interleukin-1 beta, interleukin-6, and interleukin-1 converting enzyme, no dying neurons were observed further outside the hematoma at any time. Interestingly, less early neuron death was observed in aged than in young animals, without a concomitant difference in the amount of tissue lost at 28 days. However, aged animals had less early microglial activation and a larger residual lesion, which might have resulted from impaired phagocytosis by activated microglia/macrophages. Minocycline was less effective in reducing microglial activation in aged animals, and did not reduce neuron death in either young or aged animals. Edema and BBB disruption was associated with degradation of the basal lamina protein, collagen type IV, and that damaged vessels are associated with tumor necrosis factor-alpha (TNFα)-positive neutrophils and active matrix metalloprotease-12 (MMP-12), all of which were reduced by delayed minocycline treatment. In contrast to ischemic stroke, there is a limited ‘penumbra’ outside the hematoma. Nevertheless, BBB damage in this region appears to be a potential target for protection. Furthermore, the prominent inflammatory response that continues for days after ICH does not appear to be associated with damage to other areas of the brain. Minocycline appears to protect the BBB by reducing neutrophil infiltration and the MMP-12 mediated basal lamina degradation. Future studies should investigate other targets for protection (i.e., white matter injury), and seek drugs that modulate the inflammatory response in aged animals and promote lesion resolution.
A Quest for High-performance Peer-to-peer Live Multimedia Streaming
Keywords: Peer-to-Peer multimedia streaming
Network Coding

Demands for multimedia content, one form of digital content, are continuously increasing at a phenomenal pace, as video features are commonly available on personal devices, such as iPod, cell phone, laptop, PDA, and Blackberry. The streaming service poses unique bandwidth and delay challenges to application designers. The size of a typical video content is usually orders of magnitude larger than that of any other type of content, resulting in high demands for bandwidth contribution from the content providers. Even more challenging, the content must be delivered to end hosts in real time to maintain smooth playback, i.e., the content must be transmitted at a satisfactory rate. In this thesis, we present our research towards a high-quality peer-to-peer live streaming system that utilizes network coding, a novel technique that permits coding at every peer, which has proven benefits in file dissemination applications. To ensure the practicality of our work, it is our imperative objective to conduct all experiments under realistic settings.
Malta, Motherhood, and Infant Mortality: Integrating Biological and Sociocultural Insights
Keywords: Infant mortality rate
Malta
Mothering
Historical demography
Colonial Discourse Analysis
Overpopulation
Social history
Critical Medical Anthropology

Because infants are the most vulnerable members of a community, their deaths – and the resulting infant mortality rate (IMR) – are said to signal more fundamental problems that are likely to affect the general health of a community. However, a focus on proximate- and intermediate-level risk factors in epidemiological analyses presents a decontextualized picture and ignores the role of larger forces on health, disease, and illness. In response to this trend, this project will contribute to a revitalization of the use of infant mortality as an index of larger social problems by tempering statistical analyses with critical reflection regarding the effects of the liminal position of Malta within the British imperial system, prior to the Second World War. In addition, by bringing together several analytic approaches which often proceed in parallel, rather than in dialogue – historical epidemiology, social history, and the analysis of colonial discourse – this dissertation highlights the problematics of knowledge production at both the theoretical and methodological level. As a result, my work is not just about Malta, one moment in history, the calculation of infant mortality rates, or the disentanglement of various determinants of infant mortality in this context; it is about the dynamics and repercussions of power differentials and of social, economic, and political inequalities, as they define and structure health outcomes and experiences. Specifically, I will show that fluctuations in international tensions affected Malta’s population on a number of levels because of the island’s importance as a British military and naval base and its location in the middle of the Mediterranean. I will demonstrate how Malta’s “strategic position” restricted political and economic development in the island and articulated with colonial perceptions of the Maltese as “Other” and Malta as “overpopulated.” Finally, I will argue that international tensions, Malta’s location within Empire, and perceptions of the island and its inhabitants in the early twentieth century affected the ways in which infant deaths were explained and understood and the strategies of intervention initiated in the island to curtail infant mortality – all of which had a tremendous impact on the rates at which infants in Malta died.
Knowledge-based Vertical Integration: The Nature of Knowledge and Economic Firm Boundary Location
Keywords: Strategic Management
Knowledge-Based View of the Firm
Organizational Structure
Mutual Funds

This research extends the knowledge-based view of the firm as it relates to organizational structure. In particular, this research provides evidence that fundamental classifications of knowledge are measurable, in relative terms, as factors of production. It then relates differences in relative quantities of these classifications of knowledge to the presence or absence of inter-firm boundaries. Finally, this study provides evidence that financial performance may be related to the alignment of organizational structure with knowledge-based factors of production. This study contributes to strategic management theory by offering a potential solution to the difficulties of measuring knowledge as a factor of production. The research was motivated by the belief that it is the cost and value of knowledge that determines economic efficiency (Simon, 1999). By surveying professionals in the mutual fund industry for their relative reliance on three classifications of knowledge, this study suggests a set of measures of knowledge-based factors of production. These measures in turn support the testing of hypotheses related to the vertical integration (or de-integration) of adjacent stages of production. Researchers have typically categorized organizational knowledge as either tacit or explicit. This research develops the concept of encapsulated knowledge as a fundamental classification of knowledge. Encapsulated knowledge is neither tacit nor explicit, because it is externalized and implicit. Progress in measuring knowledge is made by distinguishing between knowledge that resides in human minds (tacit), knowledge that is codified as information (codified), and knowledge that is embodied in the design and functionality of physical artefacts (encapsulated). Relative reliance on the fundamentally different knowledge-based factors of production was found to vary between adjacent stages of production, despite the essential overlap of jointly held substantive knowledge. Portfolio managers are generally less (more) reliant on tacit (encapsulated) knowledge than other investment management professionals in the mutual fund complex. In addition, portfolio managers whose firms are de-integrated from the mutual fund management firms were found to be more (less) reliant on tacit (encapsulated) knowledge than their integrated counterparts. Finally, alignment between mutual fund structure and reliance on knowledge-based factors of production was found to affect performance of mutual funds.
Biomimetic Aminoacylation
Keywords: Aminoacylation tRNA
non-natural amino acids

Abstract “Biomimetic Aminoacylation” Svetlana K. Tzvetkova Doctor of Philosophy, 2008 Graduate Department of Chemistry University of Toronto The accuracy of ribosomal protein synthesis depends on the fidelity of highly specific enzymes, aminoacyl tRNA synthetases, towards amino acid – tRNA pairs. These biological catalysts are responsible for activating the amino acids as aminoacyl adenylates and for their subsequent attachment to the 2’- or 3’-OH at the 3’-terminal of the correct tRNA to give aminoacyl-tRNA. Extended diversity in protein structure and function could be achieved if non-natural side chains can be introduced in protein synthesis. This requires that the acceptor stem of a tRNA molecule be synthetically aminoacylated. The most widely used methods for charging tRNA with non-natural amino acids involve multi-step synthesis of an aminoacyl-pCpA and its consequent enzymatic ligation to truncated tRNA. No direct route to these species has been reported. We have developed a method for direct biomimetic aminoacylation of the 3’-terminal hydroxyls of tRNA. Our approach shows to be promising in reactions leading to direct 2’- or 3’-O-aminoacylation of not only nucleosides and nucleotides but also RNA in general and tRNA in particular. The system we have developed provides: 1) efficient activation of the amino acids as aminoacyl phosphates, analogues of the enzymatic intermediates, and 2) specific recognition of the 3’-terminal of tRNA by lanthanide ions present in the reaction. The aminoacylating reagents used in our studies were carefully selected to provide handles to follow the reaction: UV absorbance, fluorescence spectroscopy and 19F NMR. Lanthanide (III) ions can play a role similar to a key part of the aminoacyl tRNA synthetases – they bring the aminoacyl close to the 3’-terminal of tRNA, in this case by forming a bis-bidentate complex with the aminoacyl phosphate and the 2’,3’-diol functionality of the 3’-terminal adenosine. This process relies on the specificity towards the unique 3’-terminal diol on tRNA, provided by the metal ion and the simultaneous complexation of the aminoacyl phosphate.
Investigating the Impact of Diffuse Axonal Injury on Working Memory Performance following Traumatic Brain Injury Using Functional and Diffusion Neuroimaging Methods
Keywords: fMRI
TBI
Working Memory
Frontal Lobe

Traumatic brain injury (TBI) is a leading cause of disability globally. Cognitive deficits represent the primary source of on-going disability in this population, yet the mechanisms of these deficits remain poorly understood. Here functional and diffusion-weighted imaging techniques were employed to characterize the mechanisms of neurofunctional change following TBI and their relationship to cognitive function. TBI subjects who had sustained moderate to severe brain injury, demonstrated good functional and neuropsychological recovery, and screened positive for diffuse axonal injury but negative for focal brain lesions were recruited for the project. TBI subjects and matched controls underwent structural, diffusion-weighted and functional MRI. The functional scanning paradigm consisted of a complex working memory task with both load and executive control manipulations. Study one demonstrated augmented functional engagement for TBI subjects relative to healthy controls associated with executive control processing but not maintenance operations within working memory. In study two, multivariate neuroimaging analyses demonstrated that activity within a network of bilateral prefrontal cortex (PFC) and posterior parietal regions was compensatory for task performance in the TBI sample. Functional connectivity analyses revealed that a common network of bilateral PFC regions was active in both groups during working memory performance, although this activity was behaviourally relevant at lower levels of task demand in TBI subjects relative to healthy controls. In study three, diffusion-imaging was used to characterize the impact of diffuse white matter pathology on these neurofunctional changes. Unexpectedly, decreased white matter integrity was not correlated with working memory performance following TBI. However, markers of white matter pathology did inversely correlate with the compensatory functional changes observed previously. These results implicate diffuse white matter pathology as a primary mechanism of functional brain change following TBI. Moreover, reactive neurofunctional changes appear to mediate the impact of diffuse injury following brain trauma, suggesting new avenues for neurorehabilitation in this population.
Development, Evaluation and Application of a Pediatric Ulcerative Colitis Index (PUCAI)
Keywords: PUCAI
Validity
Responsiveness
Minimal important difference
Reliability
Ulcerative colitis
Pediatric
Acitivity index
Outcome measure

This thesis uses the methods of sychometrics and clinimetrics to develop and evaluate a Pediatric Ulcerative Colitis Activity Index (PUCAI). The initial phases of item generation and reduction were performed previously. This thesis comprises five main studies. Study one: the weighting and formatting of an initial draft PUCAI using a cohort of 157 children with ulcerative colitis, enrolled prospectively in five pediatric IBD centers. Study two: the validation of the final draft on a separate prospective cohort of 48 children undergoing complete colonoscopy. The PUCAI was highly correlated with physician global assessment (PGA) (r=0.91), Mayo score (r=0.95) and colonoscopic appearance (r=0.77). The PUCAI was able to differentiate the different categories of disease activity, and cutoff points were defined. Study three: Assessment of the responsiveness of the PUCAI. The index demonstrated excellent responsiveness on 75 children seen twice during the study period (effect size=1.9, standardized response mean=2.2, responsiveness statistics=2.6, correlation with PGA of change=0.84, and area under the ROC curve=0.97 95%CI 0.93- 0.99). Study four was aimed at evaluating the predictive validity of the PUCAI, on a retrospective cohort of 99 children with severe ulcerative colitis admitted for intravenous corticosteroid therapy. The PUCAI, calculated on the third and fifth day of therapy was highly predictive of therapy failure at discharge and one year post discharge (area under the ROC curve 0.84 (95%CI 0.76-0.92). Study five: a methodological study evaluating the preferred way to determine the minimal clinically important difference (MCID) of health-related outcome measures. This study was conducted using the PUCAI and three other well established instruments. It was concluded that the MCID should be determined primarily by the anchor-based approach using the ROC curve method on the entire cohort, supplemented by calculating the minimal detectable difference beyond statistical error using the standard error of measurement. Small, moderate and large MCID values could be presented based on the degree of expected relevant change. Together, these studies have contributed to the rigorous development and thorough evaluation of a novel, non-invasive tool for assessing disease activity in pediatric ulcerative colitis clinical studies and practice.
Physiology of Potassium Nutrition in Cereals: Fluxes, Compartmentation, and Ionic Interactions
Keywords: Potassium
Compartmental analysis
Nitrogen
Plant physiology
Efflux
Influx
Electrophysiology
Barley
Rice
Ammonium
Nitrate
Cellular Ion Exchange
Low-affinity transport system
High-affinity transport system

Potassium (K+) is an essential nutrient and the most abundant cation in plant cells. Plants possess two transport systems for K+ acquisition: a high-affinity system (HATS), operating at external K+ concentrations ([K+]ext) below 1 mM, and showing reduced transport activity in the presence of ammonium (NH4+); and, a low-affinity system (LATS), operating at [K+]ext above 1 mM, that is not affected by NH4+. K+ transport and compartmentation were investigated in barley (Hordeum vulgare L.) and rice (Oryza sativa L.) using the non-invasive technique of compartmental analysis by tracer efflux (CATE), to simultaneously determine unidirectional membrane fluxes, ion concentrations, and exchange characteristics in subcellular compartments. These studies revealed striking differences in unidirectional K+ fluxes between HATS and LATS. It was found that flux measurements, using traditional direct influx (DI) protocols, accurately represented HATS influx, but underestimated LATS influx by as much as seven-fold. In both barley and rice, LATS K+ fluxes were found to undergo rapid, futile cycling, with the ratio of efflux:influx 3 to 5 times greater, and the cytosolic exchange rate 2 to 3 times faster than under HATS. Based upon plasma-membrane electrical potential measurements, efflux was found to be active under LATS conditions. LATS-mediated conditions for K+ were found to provide relief from NH4+ toxicity in barley by immediately reducing NH4+ influx by more than 50%, and significantly reducing NH4+ futile cycling. Employing the K+ channel inhibitors cesium, lanthanum, and tetraethylammonium, NH4+ was shown to have both K+-sensitive and –insensitive influx pathways at high [NH4+]ext. Based on current models of flux energetics, the combined uptake of K+ and NH4+ was found to utilize 60% of root oxygen consumption. Barley and rice both showed signs of NH4+ toxicity at low [K+]ext, but rice recovered at much lower [K+]ext, suggesting a crucial role of K+ in the NH4+-tolerance of rice. These experiments address fundamental aspects of K+ fluxes, and help provide a physiological framework for future studies of K+ transport and mineral nutrition.