VictorJuiz/thesis huggingface dataset:
Hybrid Plasmon Waveguides: Theory and Applications
Keywords: Surface plasmon
Plasmonics
Integrated optics
Hybrid plasmonic waveguide

The study and applications of surface plasmon polaritons (SP) – also known as plasmonics – has attracted the interest of a wide range of researchers in various fields such as biology, physics, and engineering. Unfortunately, the large propagation losses of the SP severely limit the usefulness of plasmonics for many practical applications. In this dissertation a new wave guiding mechanism is proposed in order to address the large propagation losses of the plasmonic guides. Possible applications of this guiding scheme are also investigated. The proposed hybrid plasmonic waveguide (HPWG) consists of a metal layer separated from a high index slab by a low index spacer. A detailed analysis is carried out to clarify the wave guiding mechanism and it is established that the mode guided by the HPWG results from the coupling of a SP mode and a dielectric waveguide mode. A two dimensional HPWG is proposed and the effects of various parameters on the HPWG performance are analyzed in detail. This structure offers the possibility of integrating plasmonic devices on a silicon platform. The proposed waveguide supports two different modes: a hybrid TM mode and a conventional TE mode. The hybrid TM mode is concentrated in the low index layer, whereas the conventional TE mode is concentrated in the high index region. This polarization diversity is used to design a TM- and a TE-pass polarizer and a polarization independent coupler on a silicon-on-insulator (SOI) platform. Moreover, the performance of a HPWG bend is investigated and is compared with plasmonic waveguide bends. The proposed devices are very compact and outperform previously reported designs. The application of HPWG for biosensing is also explored. By utilizing the polarization diversity, the HPWG biosensor can overcome some of the limitations of plasmonic sensors. For example, unlike plasmonic sensors, the HPWG biosensor can remove the interfering bulk and surface effects.
Topology and Dynamics of Macromolecular Aggregates Studied by Pressure NMR
Keywords: nuclear magnetic resonance spectroscopy
membrane proteins
membrane topology
protein dynamics
paramagnetic NMR
oxygen solubility

The topology and dynamics of biomolecules are intricately linked with their biological function. The focus of this thesis is the NMR-based measurement of topology and dynamics in biomolecular systems, and methods of measuring immersion depth and orientation of membrane-associated molecules. In detergent micelles and lipid bilayers, the local concentrations of hydrophobic and hydrophilic molecules are a function of their bilayer immersion depth. For paramagnetic molecular oxygen or metal cations, the magnitudes of the associated paramagnetic isotropic contact shifts and relaxation rate enhancements (PREs) are therefore depth-dependent. NMR measurements of these effects reveal the immersion depth of bilayer- or detergent-associated molecules. This work first explores transbilayer oxygen solubility and thermodynamics, as measured from contact shifts and PREs of the constituent lipid molecules in the presence of 30 bar oxygen. Contact shifts revealed the transmembrane O2 solubility profile spans a factor of seven across the bilayer, while PREs indicated that oxygen partitioning into bilayers and dodecylphosphocholine (DPC) micelles is entropically driven. Next, this work describes how paramagnetic effects from molecular oxygen and Ni(II) cations may be employed to study the immersion depth and topology of drug and protein molecules in DPC micelles. In one study, the positioning of the amphipathic drug imipramine in micelles was determined from O2- and Ni(II)-induced contact shifts. A second study, relying solely on O2-induced PREs, determined the tilt angles and micelle immersion depths of the two alpha helices in a monomeric mutant of the membrane protein phospholamban. A third study utilized 19F NMR to explore the importance of juxtamembraneous tryptophans on the topology of the membrane protein synaptobrevin, via O2-induced contact shifts and solvent-induced isotope shifts of a juxtamembraneous 19F-phenylalanine. Comparison of synaptobrevin constructs with zero, one, and two juxtamembraneous tryptophans revealed that while one tryptophan is sufficient to ‘anchor’ the protein in micelle, the addition of a second tryptophan dampens local dynamics. These solution state NMR studies demonstrate how paramagnetic effects from dissolved oxygen, complemented with measurements of local water exposure, provide detailed, accurate descriptions of membrane immersion depth and topology. These techniques are readily extended to the study of a wide range of biomolecules.
Molecular Mechanisms of Aryl Hydrocarbon Receptor Transactivation and Crosstalk with Estrogen Receptor alpha
Keywords: breast cancer
AHR

The aryl hydrocarbon receptor (AHR) and estrogen receptor alpha (ERα) are ligand-activated transcription factors. Reciprocal crosstalk between these two receptor systems has been previously established but the exact molecular mechanisms of their interactions remain incompletely understood. Using chromatin immunoprecipitation followed by DNA microarrays (ChIP-chip), I assessed the role of ERα in AHR signalling after dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) treatment in the T-47D human breast cancer cell line. I determined that ERα is recruited to a subset of AHR target genes suggesting that it is a gene-specific modulator of AHR activity. Transcription factor binding site analysis of our data set also revealed that forkhead motifs were over-represented, implying that they may be important in AHR signalling. To address this, I focused on the regulation of cyclin G2 (CCNG2) to determine the importance of FOXA1 (forkhead box A1) in AHR signalling. CCNG2 is a negative regulator of cell cycle and known to be repressed by ERα. Using ChIP, Co-IP, CCNG2 reporter gene constructs and RNA interference targeting FOXA1, I demonstrated that FOXA1 was important for the AHR-mediated and TCDD-dependent induction of CCNG2. Another finding from the ChIP-chip study was that AHR was recruited to estrogen target genes. To determine the importance of this I used zinc-finger nuclease mediated knockout of AHR and studied ERα signalling as well as the role of AHR in the cell cycle using breast cancer cell lines. Focusing on the regulatory regions of trefoil factor 1 (TFF-1) and gene upregulated in breast cancer 1 (GREB1) I determined that AHR had an inhibitory effect. Cell cycle analysis indicated that AHR facilitated cell cycle progression with cells accumulating in both the G¬1 and G2/M phases in the absence of AHR. My novel findings demonstrated the complexity of AHR-ERα crosstalk, its importance in the cell cycle, and the need for further study.
Towards Real-time Simulation of Ultrasound Systems
Keywords: simulation
ultrasound
real-time

Diagnostic ultrasound is a non-invasive image modality commonly used to diagnose multiple diseases. Sonographers and physicians have to devote a substantial amount of time learning how the combination of the various parameters of the ultrasound system affects the resulting ultrasound information among its different modalities. The primary objective of this thesis is to create a mechanistic ultrasound simulation method that could achieve near real-time performance to teach and train sonographers and physicians. A major bottleneck for achieving real-time performance with available tools was the transducer field simulation method that uses the impulse response technique. To address this problem a new simulation approach was developed. This project was realized in a three-phase approach, specifically to simulate spectral Doppler. In first place, it was shown that is possible to mechanistically simulate the sample volume power distribution using a novel method based on an array of point sources to represent the transducer geometry. Secondly, by comparison with the Field II results, it was demonstrated that the time-domain signal could be closely reproduced using point sources. Finally, by treating the array of point sources as point receivers, the received signal was compared with the results from Field II, and again, good agreement was achieved. Simulation results were compared against the standard simulation method for a number of examples involving steady and pulsatile flow, for which the spectrograms were compared against Field II. Also presented are preliminary results obtained using the point source approach to simulate B-mode images. As well, methods are described for generating Doppler spectrograms from the results of computation fluid dynamics velocity fields obtained in realistic arterial geometrical models. It is pointed out that the successful simulation of the time domain signal opens the possibility for real-time simulation of other ultrasound modes.
Measurements of Atmospheric Ozone, NO2, OClO, and BrO at 80°N using UV Visible Spectroscopy
Keywords: Atmospheric composition
UV-visible spectroscopy

The motivation for this thesis was to study chemical and dynamical processes in the Arctic stratosphere, using data from two ground-based spectrometers (GBSs). The GBSs took atmospheric trace gas measurements at the Polar Environment Atmospheric Research Laboratory (PEARL), which is located at Eureka, Nunavut, Canada (80.05°N, 86.42°W) and operated by the Canadian Network for the Detection of Atmospheric Change. The University of Toronto GBS took measurements at Eureka on a campaign basis from 1999 2011. The PEARL GBS was installed permanently at Eureka in 2006 and has taken measurements during the sunlit part of the year since then. GBS and other ground based ozone and NO2 column measurements were compared with Atmospheric Chemistry Experiment (ACE) and Optical Spectrograph and Infra Red Imaging System (OSIRIS) satellite measurements above Eureka. Ozone from all instruments agreed within 9.2%, while NO2 from most instruments, including the GBS, agreed to within 20%. On 1 August 2008, a solar eclipse of 98% totality passed over Eureka. GBS NO2 increased to 1.84 times normal levels. This agrees with a ratio of 1.91 that was calculated using a photochemical model, adjusted for reduced sunlight during the eclipse. In spring/winter 2011, up to 47% (250 DU) ozone loss was calculated using GBS and modeled passive ozone. This was the largest ozone loss in the 11 year GBS measurement record. GBS OClO was elevated, indicating chlorine activation and NO2 was low, suggesting denitrification. GBS, satellite, and chemical transport model data were used to investigate the 2011 vortex breakup. NOx transport led to middle stratosphere ozone loss within an anticyclone. Furthermore, isolated, or “frozen-in”, vortex and lower-latitude airmasses were observed following the vortex breakup. Stratospheric BrO was retrieved from spring 2008 GBS zenith sky measurements, using an optimal estimation technique. GBS BrO was compared with OSIRIS and Ozone Monitoring Instrument (OMI) satellite data. Discrepancies are partly attributed to bromine explosions in the boundary layer. New off axis GBS measurements taken in spring 2010 are sensitive to boundary layer bromine. The combination of GBS stratospheric and tropospheric BrO measurements will be useful for future estimates of the Arctic bromine budget.
Reconsidering Similarity in an Agent-oriented Account of Scientific Modeling
Keywords: scientific representation
scientific modeling

In this thesis, I present a novel account of scientific modeling that achieves the stability and generalizability of static approaches with the flexibility and practical relevance of diachronic approaches. In this account, modeling is characterized by the use of a similarity relation for the purpose of surrogate reasoning. Many criticisms of similarity are based on the fact that there is no way to objectively assess similarity between two things that share some, but not all, features. This account does not rely on the inherently flawed notion of objectively assessing similarity. Instead, the focus is on subjective assessment of similarity, within the specific context of an agent using the similarity for surrogate reasoning. This account captures the diversity of models while providing coherence among common features and functions, as evidenced by application to a series of interrelated examples in a case study from mid-twentieth century cognitive psychology. The similarity/difference account advocated in this thesis is particularly significant because its demonstrated success, evidenced by the case study, dispels several misconceptions about the study of scientific models. Advocates of static approaches claim that a diachronic approach cannot provide the generalizability necessary for a unified account, but the functional and agent-oriented similarity/difference account proves otherwise. Advocates of practice-based approaches often suggest that imilarity is too restrictive to capture the diversity of scientific models, but the similarity/difference account demonstrates that this concern only applies to a radically naturalized concept of similarity. As part of an agent-oriented account, a non-naturalized concept of similarity can be flexible enough to capture the full range of scientific models. Combining a diachronic approach with the similarity relation usually associated with static approaches results in an account that can circumvent the issues usually associated with either diachronic approaches or similarity alone.
Pencil Grasp Pattern: How Critical is it to Functional Handwriting?
Keywords: children
handwriting

This thesis reports the results of a large study to evaluate the kinetics of pencil grasp patterns in terms of speed and legibility of handwriting of children in Grade 4. Current clinical practice as recent as 2008 suggests that teachers identify the dynamic tripod pencil grasp as an optimal pencil grasp for handwriting. Research findings had suggested that three other pencil grasps may be functional for handwriting, though there was still inconclusive evidence upon which to base clinical practice. The purpose of the present study was to: assess the impact of pencil grasp on the speed and legibility of handwriting; to determine the effect of grasp on speed and legibility following a 10-minute copy task intended to induce fatigue; and to describe the axial and grip forces of the four pencil grasps. 120 children were assessed, completing a standardized handwriting assessment before and after a 10-minute copy task. The participants utilized an instrumented pen and wrote on a digitizing tablet, which measured, respectively, the axial and grip forces associated with their grasp patterns. Pencil grasp was not found to impact the speed or legibility of the written product in either short or long duration copy tasks. Fatigue decreased the legibility of the product across all pencil grasps but increased the speed across all pencil grasps equally. Grip and axial forces were only different in grasps with an adducted thumb and mainly during the initial assessment. Collectively, these results suggest that four mature grasps are equally functional for handwriting in children of this age. These findings contradict common clinical impressions that the dynamic tripod pencil grasp is optimal.
Regulation of Adult Neurogenesis: Factors Affecting the Production and Development of New Neurons
Keywords: adult neurogenesis
GABA

In the mature dentate gyrus (DG) new neurons are continuously produced in a process known as adult neurogenesis. These neurons are thought to contribute to learning and memory processes, but their precise function is still not fully understood. The rate of neuronal production and the development of young neurons are affected by stimuli such as physical exercise and learning events. The neurotransmitter γ-aminobutyric acid (GABA) has recently emerged as a possible key mediator of this activity-dependent regulation. My study examined the role of a subtype of GABAA receptors that contains the δ subunit (δGABA(A)R) in the regulation of adult hippocampal neurogenesis. Mice lacking the δ subunit (Gabrd−/− or δ-null mice) displayed decreased maturation, migration and dendritic complexity of adult-born neurons. Conversely, following treatment with a selective δGABA(A)R agonist, neuronal maturation was promoted in wild-type, but not δ-null mice. These results indicate a key role for δGABA(A)R in activity-dependent regulation of adult neurogenesis. When administered to rats, δGABA(A)R agonists promoted neuronal survival as well as maturation. The effect on maturation was blocked by the N-Methyl-D-aspartate (NMDA) blocker AP-5, suggesting that some aspects of δGABA(A)R-mediated regulation require the activation of NMDA receptors. To further understand the contribution of adult born neurons to memory function, neurogenesis in rats was alternatively suppressed using ionizing radiation, or enhanced by allowing the rats to engage in running. The rats were then trained and tested in a behavioral paradigm designed to assess their susceptibility to memory interference, a phenomenon which occurs when similar memories are not sufficiently distinguished from one another. Irradiated rats exhibited increased susceptibility to memory interference, indicating an important role for adult-born neurons in the encoding and/or retrieval of distinct memories. Remarkably, irradiated rats that engaged in running exhibited increased neuronal growth and a complete reversal of the memory impairment,emphasizing the beneficial effects of physical exercise on cognitive functions. Taken together, the findings reported in this dissertation offer novel information about the process of adult neurogenesis and its physiological significance.
Mobilization of Procollagen and Lysosomes during Osteoblast Stimulation with Ascorbic Acid
Keywords: Bone cells
collagen

Despite advances in investigating functional aspects of osteoblast (OB) differentiation, especially studies on how bone proteins are deposited and mineralized, there has been little research on the intracellular trafficking of bone proteins during OB differentiation. Collagen synthesis and secretion is the major function of OBs and is markedly upregulated upon ascorbic acid (AA) stimulation, significantly more so than in fibroblast cells. Understanding the mechanism by which collagen is mobilized in specialized OB cells is important for both basic cell biology and bone disease studies. Cellular organelles and vesicles in the exocytic and endocytic pathways have a distinctive spatial distribution and their trafficking is aided by many molecules, Rab GTPases being a master regulator. In this work, I identified the Rab GTPases that are upregulated during OB differentiation using microarray analysis, namely Rab1, Rab3d, and Rab27b, and investigated their role in regulating the trafficking of collagen from the site of synthesis in the ER to the Golgi and ultimately to the plasma membrane (PM) utilizing their dominant negative (DN) expression. The experimental halting of biosynthetic trafficking by these mutant Rabs initiated proteasome-mediated degradation of procollagen and ceased global protein translation. Acute expression of Rab1 and Rab3d DN constructs resulted in impaired ER to Golgi trafficking of procollagen. Similar expression of Rab27b DN constructs resulted in dispersed collagen vesicles which may represent failed secretory vesicles sequestered in the cytosol. A significant and strong reduction in extracellular collagen levels also was observed showing roles of Rab1, Rab3d and Rab27b in the specific function of these major collagen producing cells in the body. I further observed that a fraction of procollagen colocalized with lysosomes which was markedly increased when procollagen was experimentally misfolded. Lysosomes, essential organelles for intracellular degradation, are generally sequestered near the cell centre to receive vesicles with contents targeted for destruction. During AA-induced differentiation of OB cells, I saw a marked increase in total degradative lysosome organelles in addition to an enhanced endocytic rate. Interestingly, lysosomes were dispersed toward the cell periphery in differentiating OBs without being secreted. This required intact microtubules for long range transport and was kinesin motor-dependent but did not involve cytosolic acidification. Moreover, impairment of lysosome dispersion markedly reduced AA-induced OB differentiation. Taken together, this study provides an important general mechanism for cell secretion phenomena that may ultimately lead to clinical targets for treatments of diseases driven by aberrant collagen processing and secretion including Osteogenesis Imperfecta (OI).
Role of the Rho GEF, Lfc, in Macrophage and Neutrophil Function
Keywords: immunology
neutrophil
macrophage
gout
septic shock

Lfc is a Rho specific guanine nucleotide exchange factor (GEF) that is bound and inhibited by the microtubule (MT) cytoskeleton. In epithelial cells, Lfc promotes actomyosin contractility in response to MT depolymerization; however, its role in leukocytes has not been assessed. Through genetic ablation, we generated an Lfc knockout mouse (Lfc-/-) and tested biochemical and cell biological responses to MT depolymerization in bone marrow derived cells. Lfc was necessary for characteristic actomyosin based contractile behaviours of neutrophils and macrophages, in response to MT depolymerization. Gout is a painful arthritic inflammatory disease, caused by buildup of monosodium urate (MSU) crystals in the joints. Colchicine, a MT-depolymerizing agent that is used in prophylaxis and treatment of acute gout flare, blocks neutrophil infiltration to sites of MSU crystal-induced inflammation. We found that Lfc was necessary for the ability of colchicine to inhibit MSU-induced neutrophil infiltration in two in vivo models of gout-like inflammation. Efficient recruitment of leukocytes from the vasculature is a critical step in the immune response to infection. Leukocyte extravasation, which includes rolling, crawling, and diapedesis across the endothelial barrier, is enhanced by fluid shear stress. Through comparison of Lfc+/+ and Lfc-/- mice, we found that Lfc was necessary for in vivo leukocyte crawling and emigration out of the vasculature. Lfc-/- mice also showed defective neutrophil infiltration in response to acute inflammatory insults, and increased mortality in response to polymicrobial infection. In vitro, we found that Lfc was necessary for neutrophil responses to shear stress.