VictorJuiz/thesis huggingface dataset:
Investigations into the Significance of the Evolutionary Descent of Prion Genes from Ancestral Zip Transporter

The conformational conversion of the cellular prion protein (PrPC) to PrP scrapie (PrPSc) is a hallmark of prion diseases [1]. The cellular role of PrP and the mechanism of PrPSc neurotoxicity remain largely elusive. Therefore, the identification of new prion-like proteins can assist in revealing the function of PrP. A recent study identified a sub-branch of ZIP (Zrt-, Irt-like protein) metal transporters, including ZIP5, ZIP6 and ZIP10, to be evolutionarily related to PrP. This thesis attempts to understand the functional relevance of this relationship between PrP and ZIP transporters with regard to PrP pathobiology. Preliminary observations indicated that PrP, ZIP6 and ZIP10 underwent endoproteolysis in scrapie-infected mouse brains. PrP and ZIP10 processing mimicked the proteolysis which occurs in cell culture during zinc-deficient conditions, suggesting that scrapie infection may be associated with zinc deficiency. More work is needed to uncover whether ZIPs can contribute to the propagation of prion diseases.

Keywords: Prion
ZIP
ZIP5
ZIP6
ZIP10
LIV1
PrP
Endoproteolysis
Advisor: Schmitt-Ulms, Gerold
Effects of Aberrant HGF/MET Signalling on Cerebellar Development and Medulloblastoma Pathogenesis

Medulloblastoma is the most common malignant paediatric brain tumour. Similar to other tumours, medulloblastoma pathogenesis involves abnormal regulation of several developmental growth pathways. As my thesis project, I studied the effects of aberrant HGF/MET signalling on medulloblastoma formation in two ways. In my first objective, I investigated the role that mutations play in activated HGF/MET signalling in medulloblastoma by searching for mutations in HGF/MET pathway genes, SPINT1, SPINT2, and MET, within primary medulloblastoma specimens. This screen identified several single nucleotide polymorphisms (SNPs) and two novel variations, one in each SPINT1 and SPINT2 genes. In my second objective, I generated a transgenic mouse model with cerebellar-specific aberrant MET signalling. These mice developed extensive cerebellar abnormalities but formed no tumours. These results indicate that mutations in the HGF/MET pathway components alone are not sufficient to initiate medulloblastoma formation and must coincide with additional genetic insults to promote tumour formation, maintenance, and progression.

Keywords: medulloblastoma
brain tumour
HGF/MET signalling
transgenic mouse
Advisor: Rutka, James T.
Immunoglobulin G: A Potential Immuno-modulatory Therapy for Traumatic Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition that causes its victims to experience functional deficits. Inflammation plays a complex role in the progression of SCI. While some inflammatory cells attenuate further damage to the spinal cord tissue, other inflammatory mediators exacerbate the damage. Attenuating the detrimental aspects of inflammation after SCI is an attractive neuroprotective strategy that could potentially lead to significant functional improvement. In this regard, intravenous immunoglobulin G (IgG), which has many proposed immuno-modulatory mechanisms, is a potential treatment candidate. In this study, we investigated the neuroprotective properties of IgG by examining its effects after SCI at the molecular, cellular, and neurobehavioral levels. We observed that IgG treatment after SCI is associated with significant reduction in pro-inflammatory mediators and significant improvement in neurobehavioral recovery compared to the control. The results of the study suggest that IgG could potentially be used as an immuno-modulatory therapy for SCI.

Keywords: Spinal Cord Injury
Inflammation
Immunoglobulin G
Therapy
Advisor: Fehlings, Michael G.
Quantitative Classification of Pediatric Swallowing through Accelerometry

Abstract Background: Dysphagia or swallowing disorder negatively impacts a child's health and development. The gold standard of dysphagia detection is videofluoroscopy which exposes the child to ionizing radiation, and requires specialized clinical expertise and expensive institutionally-based equipment, precluding day-to-day and repeated assessment of fluctuating swallowing function. Swallowing accelerometry is the non-invasive measurement of cervical vibrations during swallowing and may provide a portable and cost-effective bedside alternative. In particular, dual-axis swallowing accelerometry has demonstrated screening potential in older persons with neurogenic dysphagia, but the technique has not been evaluated in the pediatric population. Methods: In this study, dual-axis accelerometric signals were collected simultaneous to videofluoroscopic records from 29 pediatric participants (age 6.8 ± 4.8 years; 20 males) previously diagnosed with neurogenic dysphagia. Participants swallowed 3-5 sips of barium-coated boluses of different consistencies (normally, from thick puree to thin liquid) by spoon or bottle. Videofluoroscopic records were reviewed retrospectively by a clinical expert to extract swallow timings and ratings. The dual-axis acceleration signals corresponding to each identified swallow were pre-processed, segmented and trimmed prior to feature extraction from time, frequency, time-frequency and information theoretic domains. Feature space dimensionality was reduced via principal components. Results: Using 8-fold cross-validation, 16-17 dimensions and a support vector machine classifier with an RBF kernel, an adjusted accuracy of 89.6% ± 0.9 was achieved for the discrimination between swallows with and with out airway entry. Conclusions: Our results suggest that dual-axis accelerometry has merit in the non-invasive detection of unsafe swallows in children and deserves further consideration as a pediatric medical device.

Keywords: dual-axis acceleometry
swallowing
dysphagia
classification
Advisor: Chau, Tom
Berall, Glenn
CD31(-) HipOps - A Highly Osteogenic Cell Population From Mouse Bone Marrow

Multipotent mesenchymal stem cells (MSCs), found in many adult tissues, may be useful for regenerative medicine applications. Their identification and purification have been difficult due to their low frequency and lack of unambiguous markers. Using a magnetic micro-beads negative selection technique to remove contaminating hematopoietic cells from mouse bone marrow stromal cells (BMSCs), our lab recently isolated a highly purified osteoprogenitor (HipOp) population that was also enriched for other mesenchymal precursors, including MSCs (Itoh and Aubin, 2009). To further enhance enrichment, we positively selected BMSCs and HipOps for CD73, a putative MSC marker, which resulted in no significant additional enrichment for osteoprogenitors when the population was tested in vitro. However, we also found that HipOps were enriched in vascular endothelial cells, and that removing these cells by further negative selection with CD31/PECAM resulted in a CD31(-) HipOp population with higher osteogenic capacity than HipOps in vitro and in vivo.

Keywords: mesenchymal stem cell
osteoprogenitor
osteoblast
MACS
magnetic bead cell sorting
cell sorting
osteogenesis
CD31
platelet endothelial cell adhesion molecule
PECAM
cell culture
negative selection
cell marker
bone marrow stromal cell
BMSC
HipOp
highly purified osteoprogenitor population
bone marrow
vascular endothelial cell
limiting dilution analysis
accessory population
CD73
Advisor: Aubin, Jane E.
High Glucose-induced ROS Production is Mediated by c-Src in Mesangial Cells

The pathogenesis of diabetic nephropathy (DN) remains incompletely understood. In previous studies, we observed the activation of Tyr kinase Src by high glucose (HG) and showed that Src is required for MAPK activation and synthesis of collagen IV in cultured rat mesangial cells (MCs). Reactive oxygen species (ROS) are also important mediators of DN, and our present study aimed to investigate the role of Src in HG-induced ROS generation. In MCs, we found that HG led to ROS accumulation that was blocked by Src inhibitors or Src-specific siRNA. Downstream of Src, Vav2 was phosphorylated/activated leading to Rac1-dependent NADPH oxidase activation. Long-term HG exposure resulted in Src-dependent Nox4 protein induction. Nox2-specific siRNA abrogated ROS production only in short-term HG, while Nox4-specific siRNA blocked ROS production only in long-term HG. Taken together, our data indicate Src to be important in mediating ROS generation from both Nox2- and Nox4-containing NADPH oxidases.

Keywords: Diabetic nephropathy
Src
Reactive oxygen species
Advisor: Fantus, I. George
The Effects of Lactobacillus rhamnosus GR-1 on Cytokines/Chekmokines and Prostaglandins in Human Amnion Cells

The incidence of preterm labor has risen over recent decades and preventative antibiotic treatment is ineffective. Associated with a 40% increased risk of preterm birth, bacterial vaginosis is characterized by a decrease in lactobacilli and increase in pathogenic bacteria in the vaginal flora. Ascent of bacterial products to the intrauterine environment stimulates cytokine and prostaglandin secretion from invading immune cells and gestational tissues. Probiotic lactobacilli modulate the immune responses in mouse macrophages and human placental trophoblast cells. The focus of this thesis was to determine the influence of Lactobacillus rhamnosus GR-1 (GR-1) on cytokines and prostaglandins which are part of the activated pathway in infection and/or inflammation mediated preterm labour. GR-1 increased amnion chemokine and reduced pro-inflammatory cytokine release. GR-1 elevated prostaglandin E2 release that was paralleled by an increase in mPGES2 expression. It is possible that t that GR-1 may enhance the host defense barriers of the amnion to pathogenic bacteria.

Keywords: pregnancy
preterm birth
cytokines
prostaglandins
probiotics
amnion
Advisor: Challis, John R. G.
Bocking, Alan
A Comparative Study of the Impact of Sustained and Intermittent Docetaxel Chemotherapy in Brain in a Mouse Model

Title: “A comparative study of the impact of sustained and intermittent docetaxel chemotherapy in brain in a mouse model” Ji Zhang Master of Science Graduate Department of Pharmaceutical Sciences, University of Toronto November, 2011 Abstract A subset of patients suffers cognitive impairment during or long after chemotherapy. This may result from chemotherapeutic agents crossing the blood brain barrier (BBB). This thesis examined the effects of docetaxel (DTX) on brain toxicity, and the effects of different dosing schedules on brain DTX concentrations and neurotoxicity. Examination of DTX treated mice (total dose of 32mg/kg) revealed appreciable amounts of DTX crossed the BBB after either intermittent (four weekly doses) or sustained (one injection of DTX-PoLigel) administration despite differences in peak drug concentrations and overall exposure profiles. Measurements of autophagy and astrocytes activation not only provided evidence of DTX caused neurotoxicity in the central nervous system, but also revealed a link between dosing schedule and neurotoxicity. Furthermore, the discovery suggested connections between DTX brain exposure, diverse biological events (such as BBB permeability and reactive oxygen species activity), and the microenvironment at synapse-neuron junctions, which should be further explored.

Keywords: Docetaxel
Chemotherapy
Cognitive impairment
Neurotoxicity
Autophagy
Astrocyte
Apoptosis
Neuronal Calcium Sensor-1
Advisor: Piquette-Miller, Micheline
The Role of Chloride Channels in Remote Ischemic Preconditioning of Ventricular Cardiomyocytes

Sarcolemmal chloride channels and associated cell volume regulatory pathways have been shown to be important in local ischemic preconditioning (IPC) induced protection against myocardial ischemia/reperfusion injury. Similarities between intracellular pathways in remote (rIPC) and classic IPC suggest that these mechanisms may also play an important role in rIPC. rIPC protected cultured rabbit ventricular cardiomyocytes against necrosis caused by 75 minutes simulated ischemia followed by 60 minutes simulated reperfusion. The protective effect was abolished by chloride channel blockade using 50 μM indanyloxyacetic acid 94 (IAA-94). rIPC also reduced peak cardiomyocyte swelling during exposure to 200 mOsm hypo-osmotic buffer. The reduction in peak swelling was also abolished by IAA-94. These results suggest that the protective effect of rIPC is achieved, at least in part, by enhancing cell volume regulation and that this effect is dependent on the availability of chloride channels in a similar fashion to local IPC.

Keywords: remote preconditioning
cardiomyocytes
chloride channels
volume regulation
IAA-94
Advisor: Wilson, Gregory J.
The Coevolutionary Genetics of Medicago truncatula and its Associated Rhizobia

Contrary to the predictions of numerous theoretical models, variation in partner quality continues to persist in mutualisms, including in the symbiosis between legumes and rhizobia. One potential explanation for the maintenance of this genetic diversity is genotype × genotype interactions, however it is unknown which genetic regions might underlie these interactions. To investigate this question, I performed a quantitative trait loci mapping experiment with two different rhizobium strains to locate potential regions of the genome influencing genotype × genotype interactions between the legume Medicago truncatula and its symbiont Sinorhizobium meliloti. I found no evidence for genotype × genotype or QTL × rhizobium interactions, however some of the QTLs colocalized with genes involved in the symbiosis signaling pathway, suggesting variation in these genes could potentially affect plant performance and fitness traits. These findings have important implications for the evolutionary interactions between legumes and rhizobia, and the genetic architecture of Medicago truncatula.

Keywords: mutualism
legume
rhizobia
QTL mapping
Nod factor signaling
coevolution
genotype by genotype
Medicago truncatula
Sinorhizobium meliloti
G x G
Advisor: Stinchcombe, John
A PFC Power Supply with Minimized Energy Storage Components and a New Control Ttechnique for Cascaded SMPS

This Master of Applied Science thesis proposes a new design of low power, power factor corrected (PFC), power supplies. By lifting the hold up time restriction for devices that have a battery built in, the energy storage elements of the converter can be reduced, permitting a small and inexpensive power converter to be built. In addition, a new control technique for controlling cascaded converters is presented, named duty mode control (DMC). Its advantages are shown through simulations. The system was proven using a prototype developed in the laboratory designed for a universal ac input voltage (85 - 265VRMS at 50 - 60Hz) and a 40W output at 12V. It consisted of two interleaved phases sensed and digitally controlled on the isolated side of the converter. The prototype was able to achieve a power factor of greater than 0.98 for all operating conditions, and input harmonic current distortion well below any set of standards.

Keywords: power factor corrected
PFC
smps
switch mode power supply
energy storage
minimized energy storage components
cascaded converter
cascade
duty mode control
dmc
new control technique
harmonic current
portable electronic equipment
Advisor: Lehn, Peter W.
Prodic, Aleksandar
A Novel Approach for Identifying Synthetic Dosage Lethal Interactions in Pooled Yeast Cultures

Systematic genomic studies in the budding yeast S. cerevisiae have greatly increased our capacity to conduct functional profiling of the eukaryotic genome. I describe a new method that makes use of yeast “Barcoder” strains to uniquely tag strains in a yeast overexpression collection (FLEX) and to systematically examine the effects of gene overexpression on cell fitness. This novel system is compatible with the so-called Synthetic Genetic Array (SGA) method, which automates yeast genetics and allows introduction of marked query alleles of interest into arrayed collections of yeast mutants. I identified SDL interactions for two key regulatory kinases, Dun1 and Mck1, using my system. I also used my array and approach to identify SDL interactions for Dun1 that are only manifest in the presence of DNA damage. These studies demonstrate the utility of the pooled SGA-SDL method for systematic discovery of condition-specific genetic interactions in conserved biological pathways.

Keywords: yeast
genomics
kinases
genetics
barcode
overexpression
Advisor: Andrews, Brenda
Dissecting the Role of the Jumonji Family Member Jhd2p, a Histone Lysine Demethylase

In Saccharomyces cerevisiae, Set1p-mediated deposition of trimethylation on lysine 4 of histone H3 is a histone modification often associated with active transcription. Recently, it was discovered that members of the Jumonji family of proteins have the enzymatic ability to remove methylation on histone lysine residues. Here, I describe the function of the yeast Jumonji protein Jhd2p, the only yeast Jumonji with known demethylase activity towards histone H3 lysine 4 methylation. I find that during the development program of yeast sporulation, Jhd2p is responsible for demethylating lysine 4 on a global scale. Further, ChIP analysis examining lysine 4 methylation levels reveals that genes whose expression is dependent on JHD2 during sporulation are subject to what appears to be Jhd2p-mediated demethylation. Additionally, synthetic dosage lethality screens performed to identify genetic interactors of Jhd2p revealed that Jhd2p is a likely component of mitochondrial retrograde signaling, working alongside the transcription factors Rtg1p/Rtg3p.

Keywords: histone
epigenetics
demethylation
Jumonji
yeast
sporulation
retrograde
mitochondria
lysine 4
transcription
Advisor: Meneghini, Marc
Association of Tissue Promoter Methylation Levels of APC, RASSF1A, CYP26A1, and TBX15 with Prostate Cancer Progression

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses. I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005). My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.

Keywords: DNA Methylation
Prostate Cancer
Epigenetic Mechanism
Progression
Biochemical Recurrence
Advisor: Bapat, Bharati
The Contributions of Positive Illusions to Cultural Differences in Well-being: The Positivity Model

“Positive illusions” refer to the tendencies to perceive the self and others positively. The current study proposes that cultural norms regarding positive illusions contribute to cultural differences in well-being. All pairs of participants completed self-reports and informant reports, and served both as perceivers and targets (N = 906 undergraduate students). A novel validated measure of positive illusions and multi-method assessment of well-being were used to examine cultural differences between Asians and Westerners in well-being. Positive illusions were assessed by means of the halo-alpha-beta model of correlations among ratings of participant’s own and an acquaintance’s personality on the Big Five dimensions (Anusic, Schimmack, Pinkus, & Lockwood, 2009). The results suggest that rating biases influence cross-cultural comparisons of well-being and that European and Asian Canadians have similar levels of well-being.

Keywords: culture
well-being
positive illusions
self-enhancement
bias
multi-method
Advisor: Schimmack, Ulrich
Design and Analysis of Morphing Wing for Unmanned Aerial Vehicles

This study is concerned with the design and development of a novel wing for UAVs that morphs seamlessly without the use of complex hydraulics, servo motors and controllers. The selected novel design is characterized by a high degree of flight adaptability and improved performance with a limited added weight. These characteristics were attained through the use of shape memory actuators in an antagonistic fashion. Unlike compliant actuators, the antagonistic setup requires the thermal energy to deform the wing but not to maintain its deformed shape. Structural analysis based upon safety factors specified by FAR23 standards and aerodynamic analysis using FLUENT were conducted on the novel design to validate its suitability as a viable wing for UAVs. In addition, thermal conditioning of the shape memory actuators was conducted using a specially designed programmable controller. This thesis does not concern itself with the design of a skin that accommodates the shape changes.

Keywords: Morphing Wing
UAV
Shape Adaptation
Smart Materials
Shape Memory Alloy
Conceptual Design
RPV
Biomimetics
Advisor: Meguid, Shaker A.
Towards 'S4' Molybdenum with Two Labile Sites: New Ligands for Molybdenum Bisdithiolenes

Molybdenum disulfide (MoS2) catalysts are used for hydrodesulfurization processes, needed for the removal of sulfur from oil feedstocks. The commonly accepted active site of MoS2 is believed to have a S4 pyramidal geometry with molybdenum (IV) at the apex. This work is interested in small molecules as models. Recent work has shown that one ligand can be removed from a molybdenum trisdithiolene by reacting the metal complex with an olefin creates a labile chelate cap. The resulting structure resembles the active site of interest. The present contribution will show approaches to molybdenum bisdithiolenes with one or two labile solvent molecules. The use of acetonitrile, adiponitrile, isobutyronitrile, and oxalate has been investigated. A complex containing two different labile moieties (tetrahydrothiophene, acetonitrile) was crystallographically characterized. Other nitrile molybdenum complexes were monitored using NMR spectroscopy. Two complexes have been characterized with an oxalato ligand; a single unit, and a dimer.

Keywords: molybdenum
bisdithiolene
hydrodesulfurization
Advisor: Fekl, Ulrich
The Effects of Marangoni Convection on the Rate of Condensation of Pure Water

A series of steady-state water condensation experiments were conducted to determine the effects of Marangoni convection on the condensation flux. The interface was flat so that the results of the interfacial temperature discontinuities could be compared to past condensation experiments conducted under similar experimental conditions using a spherical interface. Two experimental methods were used. Method 1 was to vary the temperature in the cooling pipes (Tcp ) with the position of the interface relative to the cooling pipes fixed. Method 2 was to vary the position of the interface while Tcp was held constant. The interfacial temperature discontinuities in this study were approximately 2.3-9 times smaller in magnitude, than those measured using a spherical liquid-vapour interface. The experimental results showed that the condensation flux increased as thermocapillary convection increased (increase in interfacial temperature gradients and speed). This increase resulted in a 1.37-12.5 times enhancement in the condensation flux of pure water.

Keywords: Marangoni Convection
Condensation
Advisor: Ward, Charles A.