VictorJuiz/thesis huggingface dataset:
Investigation of the Mechanisms of Aromatic Amine-induced Idiosyncratic Drug Reactions

Drugs with the primary aromatic amine structure are notorious structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). The toxicity of aromatic amines has been attributed to the formation of reactive metabolites common to this functional group that can form antigenic substances and redox cycle to induce oxidative stress. To date, there has not been a systematic study to investigate the mechanisms of aromatic amine-induced IDRs. Therefore, in the first part of my thesis, the danger hypothesis was tested through a global screen of hepatic gene expression in rats treated acutely with the aromatic amine drugs sulfamethoxazole (SMX), dapsone (DDS), and aminoglutethimide (AMG). Although one gene, Eiih, was up-regulated by all drugs tested and could be a general biomarker to drugs that induce IDRs, few changes were found that are likely to represent danger signals. To confirm this, a more comprehensive study was performed on the liver with AMG after longer treatment intervals. Despite substantial changes in apoptotic and mitochondrial pathways, there were few immune changes and no histological evidence of damage. These findings suggest that the liver is not a direct target of aromatic amine drugs or, if it is, the default response may be immune tolerance. The presence of myeloperoxidase in neutrophils and antigen presenting cells provides a more plausible mechanism of aromatic amine toxicity through direct activation of the immune system, and this was tested in the second part of my thesis research. A significant increase in activated neutrophils was observed in AMG-treated rats, which was attributed to an increase in granulocyte progenitors in the bone marrow. This effect is opposite to the agranulocytosis that is observed with AMG clinically, but it may have important implications to the early effects preceding the pathology. In the spleen and lymph nodes, T-cell proliferation was found with simultaneous indications of immune modulation through differential intracellular cytokine expression. Moreover, down-regulation of immune activation may be why the AMG-treated rats do not develop hypersensitivity. Further investigations into tolerogenic mechanisms may have broader implications into why IDRs only develop in a subset of patients.

Keywords: idiosyncratic drug reactions
aromatic amine drugs
immunotoxicity
biomarkers
Advisor: Uetrecht, Jack
Clients' Productive Processing in Cognitive-behavioural Therapy and Emotion-focused Therapy for Depression

The primary objective of the current study was to examine clients’ in-session cognitive-affective processing in relation to therapeutic outcome in order to determine whether productive versus unproductive processes differentiated between good and poor outcome clients. The study examined archival data from cognitive-behavioural therapy (CBT) and emotion-focused therapy, the process-experiential approach (EFT-PE), in a 16-week treatment for depression (Watson et al., 2003). Participants consisted of 66 clients, primarily Caucasian, 44 females and 22 males, ages 21 to 65 (M = 41.52). In order to capture clients’ in session processing activities the middle 20 minutes of sessions 3, 9 and 12 were coded using a newly development instrument, the Measure of Clients’ Productive Processing (MCPP; Watson & McMullen, 2008). This measure consists of 11 mutually exclusive, nominal categories and brings together a number of generic cognitive and affective processing activities that clients’ may engage in while in psychotherapy, as well as processes indicating mini outcomes, and processes referring to how clients’ evaluate or treat themselves. The productive processes for the MCPP included describing (vivid, concrete, specific), organismic experiencing (inner experience), asserting (need, limits), validating self and others, exploring (actively inquiring, scrutinizing), and statements of new understanding. Unproductive processing included describing (vague, general), exploring (static uncritical, rambling), and making meaning (intellectual, rehearsed, explaining). Clients’ negative self-treatment included avoiding inner experience, hopelessness, pressuring oneself, and self-criticism. Using the MCPP this study investigated the relationship between the way clients processed their experiences and problems in therapy and (a) clients’ pre-treatment characteristics including attachment style, capacity to regulate affect, and coping style; (b) clients’ change as indicated in self-reports post-session; and (c) clients’ level of symptoms at the end of treatment. Results demonstrated that pre-treatment variables predicted in-session processing, and in-session processing predicted post-session change and post-therapy outcome, verifying that how clients processed their experiences and problems in therapy was important. Engagement in productive processing differentiated the good outcome clients from the poor outcome clients. Similar and different processing activities were noted across CBT and EFT-PE. This study provides preliminary support for construct and predictive validity of the MCPP.

Keywords: emotion focused therapy, process experiential therapy, cognitive behavioural therapy, productive processing, psychotherapy, process research, Measure of Clients' Productive Processing, mechanisms of change, cognitive processing, emotional processing
Advisor: Watson, Jeanne C.
Lanthanide-containing Microgels Intended for Bead-Based Bioassays by Mass Cytometry

This thesis describes the synthesis and characterization of functional polyelectrolyte copolymer microgels intended for bioassays based upon mass cytometry. The microgels are based upon copolymers of N-isopropylacrylamide (NIPAm), N-vinylcaprolactam (VCL) and methacrylic acid (MAA), crosslinked with methlene-bis-acrylamide, poly(NIPAm/VCL/MAA). The microgels were loaded with Ln(III) ions, which were then converted in situ to LnF3 or LnPO4 nanoparticles (NPs). Very specific conditions were required for confining the NPs to the core of the microgels. I used mass cytometry to measure the number and the particle-to-particle variation of Ln ions per microgel. By controlling the amount of LnCl3 added to the neutralized microgels, we could vary the content of individual microgels from ca. 106 to 107 Ln atoms, either in the form of Ln3+ ions or Ln NPs. Leaching profiles of Ln ions from the Ln-containing microgels were measured by traditional ICP-MS. Under neutral or basic conditions, the leakage of Ln ions into the aqueous medium was not significant. In acidic buffer solutions, however, the leakage of metal from Ln3+ ion-containing microgels was prominent. On subsequent exposures to buffers, the microgels underwent continuous loss of metals. For LnF3-containing microgels, there was much smaller extent of metal leakage and very small of continuous loss of metal upon subsequent exposures to buffers. For LnPO4-containing microgels, there was very little detectable leakage of metals to the acidic buffers. In order to test the use of Ln nanoparticle as reagents of enhanced sensitivity in mass cytometry, we employed TmF3 encoded microgels as model cells. In one sample, Tm-encoded poly(NIPAm/VCL/MAA) microgels were coated with streptavidin (SAv) and used as model biomarkers, in quantitative mass cytometric bioassays. The sensitivity of different reagents (including a biotinylated metal cheating polymer, containing 50 Tb3+ ions per probe and a biotinylated NaHoF4 NP, containing 15,000 Ho atoms per probe) was examined for detecting and quantifying the number of SAv per microgel by mass cytometry. By using the Bi-PAsp(Tb)50 probes, a biomarker level at ~104 per cell was detected. By using the Bi-NaHoF4 NP probes, a biomarker level as low as ~102 per cell was quantified.

Keywords: microgel
mass cytometry
Advisor: Winnik, Mitchell
Race, Gender, Youth, and Urban Space: Young Men of Colour and Homelessness in the Greater Toronto Area

What are the relationships between race, gender, homelessness, and urban space? This research explores these relationships through the experiences of Canadian-born young men of colour in the Greater Toronto Area. Foregrounding their lived experience through ethnographic methods, I ask how does homelessness affect the lives of young men in different spaces of a large city and in relationship to race and gender? How do these young men&rsquo;s experiences of the city help us understand the city? This research draws upon diverse bodies of theory in urban, cultural, feminist, and anti-racist geographies. I expand these literatures to illustrate connections between systems of socio-spatial domination such as racism, sexism, and classism. Through 40 interviews and 8 of what I call &lsquo;Where-I-Live-Tours&rsquo;, a tour of urban space I conduct with the participant, I explore the material and affective dimensions of space in the lives of these young men. By paying attention to the material and affective dimensions of homelessness, I illustrate how relationships between race, gender, homelessness, and urban space emerge in everyday experiences. In investigating the non-conscious affective dimensions of urban life, I combine representational and material understandings of the city to afford an understanding of the complex micro-geographies of urban space. I investigate the affective forces that shape how people live in the city, moving them through some spaces and attracting them and repelling them from others. Research findings indicate micro-geographic racial &lsquo;vibrations&rsquo; that see race emerge differently around the GTA. Young men of colour also negotiate a variety of (in)visibilities in their lives in the city, including physical, imagined, political, and social. Their homelessness means they have atypical experiences of &lsquo;home&rsquo; and they create multiple alternative forms of home or belonging. This research follows in feminist and anti-racist research traditions that examine marginalization and oppression to critique dominance and privilege. It allows us to see how marginalized actors can enact resiliencies and resistances and be creative and productive of identity and urban space. This research illustrates the multifarious relationships people have with city space and how an accumulation of forces shapes people&rsquo;s everyday lives in the city.

Keywords: Race
Gender
Youth
Homelessness
Urban
Cultural
Advisor: Ruddick, Susan
Walks, Alan
Investigating photoinduced structural changes in silicon using femtosecond electron diffraction

This thesis reports on developing a femtosecond electron diffraction technique and its application in following the structural changes associated with photoexcited Si. Time resolved electron diffraction is capable in principle of capturing transient structures of photoinduced phenomena with femtosecond time resolution. In practice, however, the time resolution is severely limited by the broadening of electron pulses due to space-charge forces. Another technical difficulty lies in that diffraction in transmission geometry requires samples that are semi-transparent to electrons. These experimental challenges were dealt with using innovative engineering and software development, and novel nanofabrication methods. Subsequently, a robust highly automated experimental setup was established, and 50 nm free-standing membranes of polycrystalline Si were nanofabricated. These membranes were first excited below damage threshold with 387 nm light, at an absorbed fluence of 5.6 mJ/cm 2 . The observed loss of intensity and associated dynamics under these conditions are related to the Debye-Waller effect as the lattice heats up through electron-phonon processes. At high excitation levels, greater than ∼6% of the valence electron density, the crystalline structure of the lattice was lost in <500 fs. This observed time scale is indicative of an electronically driven order-to-disorder phase transition due to an abrupt change in the potential-energy landscape of the lattice. In addition, it was discovered that the high sensitivity of the electron diffraction process to shear-type deformation in single crystals makes the technique ideal to the generation and detection of coherent acoustic phonons. Longitudinal and shear acoustic phonons were subsequently resolved in (001)-oriented Si crystals. This study constitutes the first direct observation of shear phonons in symmetrically cut crystals, in sharp in contrast to the all-optical methods that rely on crystals asymmetrically cut at >20° to enhance the amplitude of the shear mode in order to detect its displacements.

Keywords: Applied sciences
Pure sciences
Femtosecond
Electron diffraction
Polycrystalline
Shear phonons
Advisor: Miller, Dwayne
Advancing Dynamic Imaging for Microfluidic Stimulated Tissues: Biology, Techniques, and Applications

Using quantitative fluorescence microscopy imaging of cellular activities in intact tissues stimulated in a microfluidic device creates opportunities for studying major diseases such as diabetes and cancer. Despite a number of documented phenotypic traits of these diseases, the underlying pathophysiological mechanisms remain to be elucidated. Conventional biochemical assays have been used to probe mechanistic information; however, these techniques often lack the biological context of the living sample and offer limited spatiotemporal resolution. Here, we show that dynamic imaging of intact ex vivo pancreatic islets and three-dimensional in vitro tumor spheroids on a custom microfluidic platform provides real-time physiological and biological information with subcellular resolution. Using this microfluidic stimulated tissue platform, we developed a novel imaging method relating the redox-associated changes in electron transfer flavoprotein (ETF) autofluorescence to fatty acid oxidation in living pancreatic islets. We found that elevated glucose (&gt;10 mM) decreases the ETF redox state within 20 minutes in islets when presented with a mixed nutrient condition associated with glucolipotoxicity. This observation suggests a glucose-mediated shift in lipid partitioning away from fatty acid oxidation. Furthermore, we found that excess branched-chain amino acid leucine prematurely turns off fatty acid oxidation despite the fasted state and reduces the dynamic glucose response leading to a condition termed metabolic inflexibility. Finally, we imaged the nanoparticle-tissue interactions in tumor spheroids and found that incorporating affinity ligands onto nanoparticles and enhancing convective interstitial fluid flow through the tissue increased the uptake efficiency of nanoparticles by spheroids despite the limitation imposed by diffusion. Overall, our results demonstrate the effectiveness of ETF autofluorescence imaging in monitoring mitochondrial fatty acid oxidation in intact pancreatic islets and the efficiency of a custom microfluidic platform as the pre-animal model for probing nanoparticle-tissue interactions. Future experimental efforts to study other tissue types, physicochemical properties of nanoparticles, imaging techniques, and microfluidic technologies could lead to the development of more sophisticated and effective platforms for medical tissue biopsy or high-throughput rapid screening of nanoparticles to accelerate the clinical translation of nanoparticles.

Keywords: Microscopy Imaging
Autofluorescence
Microfluidics
Nanoparticles
Pancreatic Islets
Tumor Spheroids
Advisor: Rocheleau, Jonathan
Iron Complexes for the Catalytic Reduction of Polar Double Bonds

A series of new iron complexes featuring multi-dentate ligands containing phosphorus and nitrogen donor atoms were synthesized using a multi-component metal template synthesis. This was achieved by using convenient air-stable phosphonium dimers, [cyclo-(PR2CH2CH(OH)-)2][Br]2, which upon addition of base are cleaved to produce useful phosphino-aldehyde synthons. The phosphonium dimers were versatile in the template synthesis with KOtBu, [Fe(H2O)6][BF4]2 and the appropriate amine of iron(II) complexes bearing mertridentate P-N-N or P-N-S or P-N-Pʹ ligands and tetradentate P-N-N-P ligands. Crude solutions of trans-[Fe(NCMe)2(P-N-N-P)][BPh4]2 were stirred with KBr under a CO atmosphere overnight to produce pre-catalysts trans-[Fe(CO)(Br)(P-N-N-P)][BPh4]. The complexes were tested for the catalytic transfer hydrogenation of acetophenone in basic isopropanol. Only catalysts with R = Et and a CO ligand were found to be active. Examination of the role of base in pre-catalyst activation, revealed a five-coordinate iron(II) complex in which the tetradentate P-N-N-P ligand has been doubly deprotonated specifically at the carbons adjacent to the phosphorus atoms. These iron(II) ene-amido complexes were used in the transfer hydrogenation of acetophenone in isopropanol in base free conditions and had identical catalytic activity to that of the pre-catalysts with added base. A new iron pre-catalyst, [Fe(CO)(Br)(P-NH-N-P)][BPh4], was synthesized that features an imine-amine moiety on the tetradentate ligand such that this pre-catalyst produces intermediates even closer to the actual catalytic cycle. New iron complexes mer-trans-[Fe(Br)(CO)2(P-N-Pʹ)][BF4] were prepared by the template synthesis under a CO atmosphere using a phosphino-amine followed by reaction with AgBF4. These complexes were then reacted with LiAlH4 and alcohol to form mono-hydride iron pre-catalysts. The iron pre-catalysts that had alkyl or phenyl substituents on the phosphorus atoms of the P-N-Pʹ ligand were active for the H2 hydrogenation of ketones, aldehydes and imines under mild basic conditions (T = 50 °C, p(H2) = 5 atm). Catalytic activities of TOF up to 2000 h-1, TON up to 4000 and enantioselectivity up to 85% (S) were observed.

Keywords: transition metal catalysis
hydrogenation
Advisor: Morris, Robert H.
High Performance Inverted Pyramidal Texture for Silicon Photovoltaics

An inverted pyramidal grating texture is known to reduce both surface reflection and to promote light trapping in crystalline silicon (c-Si) solar cells. However, these textures are not used in commercial solar cells mainly because of high fabrication costs, limited scalability of conventional fabrication techniques to thin wafers, and insufficient knowledge of the optimum grating parameters for silicon of different thicknesses. These issues become even more important as industry makes a transition to thinner Si wafers to reduce device cost. The objective of this this thesis is to address all of these issues. Firstly, a new process for inverted pyramidal texturing of c-Si has been developed that is compatible with thin silicon wafers and foils. Secondly, a theoretical study of the optimum inverted pyramidal grating parameters has been done for a wide range of Si wafer thicknesses. Finally, the optical performance of the optimal textures has been experimentally verified. The laser assisted texturing method produces high quality inverted pyramids in a non-cleanroom environment and is potentially scalable to mass production. Because of the contactless fabrication, the method can be used to texture fragile, ultra-thin Si foils. This approach also offers precise control of the patterned areas, which can exclude areas for front surface contacts on PV devices. The wave-optical study of the size dependent performance of inverted pyramidal textures identifies a 1000 nm period as being universally optimal for silicon thicknesses ranging from 2-400 microns. As a point of comparison, inverted pyramidal textures were also fabricated by electron beam lithography. The measured reflectances show that textures with micron scale periodicity outperform a submicron periodic texture, in agreement with trends predicted by the wave-optical simulations. Finally, a novel phenomenon of internal structuring within an optically transparent thin film is described that was discovered in the course of optimizing the laser processing parameters for making apertures in the hard mask layer for PV surface texturization. This phenomenon shows promise for varied applications such as marking of surfaces, and the production of buried channels within a thin film for lab on chip architectures.

Keywords: Photovoltaics
Silicon
Femtosecond Laser
Dielectrics
Quantized Structuring
Thin Films
Advisor: Nogami, Jun
Kherani, Nazir
Scanning Tunneling Spectroscopy Studies of Multiband and Unconventional Superconductivity

Scanning tunneling spectroscopy at low temperature and in a magnetic field has been used to study multiband superconductivity in 2H-NbSe&#8322;, superconductivity in iron chalcogenides and pnictides, and the superconducting proximity effect between a high-Tc cuprate and a half-metallic manganite. In superconductors with complex band structures, pairing can involve multiple bands with multiple superconducting gaps. To search for new phenomena, a scanning tunneling microscope that operates at 300 mK was specially designed for a magnetic field of up to 9 T to be applied parallel to the sample surface. In the mixed state, field-induced supercurrents give the Cooper pairs a finite superfluid momentum, enabling the study of the quasiparticle density of states spectrum using the Doppler energy shift as a perturbation. This technique was applied to 2H-NbSe&#8322;, a layered s-wave superconductor with a multi-sheeted and anisotropic Fermi surface. We identify spectral features that evolve with field, and a zero-bias conductance that changes slope at 0.7 T. Our observations are interpreted as signatures of multiband superconductivity with different gaps on parts of the Fermi surface. Spatial conductance maps on the surface of 2H-NbSe&#8322; revealed a field-dependent stripe pattern that can be quantitatively identified as the lateral projection of a subsurface vortex lattice. The dominant periodicity of the stripes undergoes a discrete shift at 0.7 T, applied along [100], which is evidence for a novel reorientation transition of the inplane lattice. This observation is correlated with multiband characteristics seen in bulk measurements, implicating the multiband pairing of 2H-NbSe&#8322; in the transition. This technique demonstrates a general method for probing multiband superconductivity, as well as studying the subsurface vortex lattice and isolated vortices in real space. Measurements down to 300 mK on Fe1+yTe&lt;sub&gt;1&minus;x&lt;/sub&gt;Sex showed a gap structure and the presence of low-energy quasiparticles, which could result from excess Fe. Topography of Fe1+yTe&lt;sub&gt;1&minus;x&lt;/sub&gt;Sx and BaFe2&minus;xNixAs2 showed nanometer-sized clustering and different surface terminations, respectively. Thin film c-axis heterostructures of YBa2Cu3O7&minus;&delta; and La2/3Ca1/3MnO3 were grown using pulsed laser deposition. Spectra on the manganite layer at 4.2 K provide microscopic evidence for a short-ranged proximity effect, and are difficult to reconcile with scenarios involving spin-triplet pairing.

Keywords: Superconductivity
Scanning Tunneling Microscope
Microscopy
Thin Film
NbSe2
Vortices
Flux lattice
Vortex lattice
Iron-based superconductor
FeSe
Cryogenics
STM
Condensed matter physics
Multiband superconductivity
Phase transitions
Cuprate
Manganites
YBCO
Conductance imaging
Subsurface
Magnetic field
Doppler effect
Yttrium barium copper oxide
Lanthanum calcium manganese oxide
Advisor: Wei, John Y. T.