VictorJuiz/thesis huggingface dataset:
Dynamic Tensile, Flexural and Fracture Tests of Anisotropic Barre Granite

Granitic rocks usually exhibit strongly anisotropy due to pre-existing microcracks induced by long-term geological loadings. The understanding of anisotropy in mechanical properties of rocks is critical to a variety of rock engineering applications. In this thesis, the anisotropy of tension-related failure parameters involving tensile strength, flexural strength and Mode-I fracture toughness/fracture energy of Barre granite is investigated under a wide range of loading rates. Three sets of dynamic experimental methodologies have been developed using the modified split Hopkinson pressure bar system; Brazilian test to determine the tensile strength; semi-circular bend method to determine the flexural strength; and notched semi-circular bend method to determine the Mode-I fracture toughness and fracture energy. For all three tests, a simple quasi-static data analysis is employed to deduce the mechanical properties; the methodology is assessed critically against the isotropic Laurentian granite. It is shown that if dynamic force balance is achieved in SHPB, it is reasonable to use quasi-static formulas. The dynamic force balance is obtained by the pulse shaper technique. To study the anisotropy of these properties, rock blocks are cored and labeled using the three principal directions of Barre granite to form six sample groups. For samples in the same orientation group, the measured strengths/toughness shows clear loading rate dependence. More importantly, a loading rate dependence of the strengths/toughness anisotropy of Barre granite has been first observed: the anisotropy diminishes with the increase of loading rate. The reason for the strengths/toughness anisotropy can be understood with reference to the preferentially oriented microcracks sets; and the rate dependence of this anisotropy is qualitatively explained with the microcracks interaction. Two models abstracted from microscopic photographs are constructed to interpret the rate dependence of the fracture toughness anisotropy in terms of the crack/microcracks interaction. The experimentally observed rate dependence of the anisotropy is successfully reproduced.

Keywords: Experiment
Dynamic
Rock
SHPB
Anisotropy
Tensile Strength
Fracture Toughness
Advisor: Xia, Kaiwen
Exploiting Linguistic Knowledge to Infer Properties of Neologisms

Neologisms, or newly-coined words, pose problems for natural language processing (NLP) systems. Due to the recency of their coinage, neologisms are typically not listed in computational lexicons---dictionary-like resources that many NLP applications depend on. Therefore when a neologism is encountered in a text being processed, the performance of an NLP system will likely suffer due to the missing word-level information. Identifying and documenting the usage of neologisms is also a challenge in lexicography, the making of dictionaries. The traditional approach to these tasks has been to manually read a lot of text. However, due to the vast quantities of text being produced nowadays, particularly in electronic media such as blogs, it is no longer possible to manually analyze it all in search of neologisms. Methods for automatically identifying and inferring syntactic and semantic properties of neologisms would therefore address problems encountered in both natural language processing and lexicography. Because neologisms are typically infrequent due to their recent addition to the language, approaches to automatically learning word-level information relying on statistical distributional information are in many cases inappropriate. Moreover, neologisms occur in many domains and genres, and therefore approaches relying on domain-specific resources are also inappropriate. The hypothesis of this thesis is that knowledge about etymology---including word formation processes and types of semantic change---can be exploited for the acquisition of aspects of the syntax and semantics of neologisms. Evidence supporting this hypothesis is found in three case studies: lexical blends (e.g., "webisode" a blend of "web" and "episode"), text messaging forms (e.g., "any1" for "anyone"), and ameliorations and pejorations (e.g., the use of "sick" to mean `excellent', an amelioration). Moreover, this thesis presents the first computational work on lexical blends and ameliorations and pejorations, and the first unsupervised approach to text message normalization.

Keywords: Computer science
Computational linguistics
Natural language processing
Lexical acquisition
Neologisms
Advisor: Stevenson, Suzanne
Characterizing the Role of Regulator of G-protein Signalling 4 as a Mediator of Sinoatrial Node and Atrial Cardiomyocyte Function

Heart rate is modulated by the opposing activities of sympathetic and parasympathetic inputs to pacemaker cardiomyocytes in the sinoatrial (SA) node. Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M2 muscarinic receptors and activation of Gαi/o signalling. Although, regulators of G-protein signalling (RGS) proteins are potent inhibitors of Gαi/o signalling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SA node are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SA node compared to right atrium. Conscious freely moving RGS4-null mice showed a greater extent of bradycardia in response to parasympathetic agonists compared to wild-type animals. Moreover, anaesthetized rgs4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from rgs4-null mice also showed enhanced negative chronotropic responses to carbachol, while isolated SA node myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, rgs4-null SA node cells showed decreased levels of G-protein-coupled inward rectifying potassium (GIRK) channel desensitization, and altered modulation of acetylcholine-sensitive potassium current (IKACh) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signalling and IKACh activity. Following these results, we predicted that loss of RGS4 expression and function will result in increased levels of parasympathetic effector activity leading to increased susceptibility to atrial fibrillation. Susceptibility to atrial fibrillation (AF) depends strongly on parasympathetic activity. Since RGS4 inhibits parasympathetic / M2-dependent Gαi/o signalling in the SA node, we explored whether changes in RGS4 levels altered the susceptibility of atrial fibrillation. We found that, RGS4 levels were decreased in atria of tachypaced dogs prior to their development of chronic AF. Moreover, in vivo ECG recordings of anaesthetized mice showed greater susceptibility to AF while optical mapping of isolated atrial preparations using a voltage-sensitive dye revealed greatly increased susceptibility to rotor formation when RGS4 was ablated. Consistent with altered parasympathetic signalling in the myocardium of rgs4-null mice, IKACh evoked by carbachol application were greater in isolated atrial myocytes from rgs4-null mice. These IKACh changes were, as expected, associated with marked action potential duration shortening in response to parasympathetic activation, but not to slower conduction velocities. Together, our findings establish that RGS4 protects atrial tissues from excess parasympathetic signalling that predispose to atrial fibrillation.

Keywords: RGS4
atrial fibrillation
parasympathetic
Advisor: Heximer, Scott P.
Functional Dissection of Lupus Susceptibility Loci on the New Zealand Black Mouse Chromosome 1

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong and complex genetic basis. To dissect the function of the lupus susceptibility loci on New Zealand black (NZB) mouse chromosome 1, the lab had previously generated congenic mice with an introgressed homozygous NZB chromosome 1 intervals extending from ~35 or ~82 to 106 cM on the C57BL/6 background. Although both mouse strains made IgG anti-nuclear antibodies (ANAs), ANA titres and cellular activation were significantly higher in mice with the longer interval. These studies suggest the presence of two susceptibility genes. In this thesis I have sought to further characterize the cellular abnormalities and underlying genetic polymorphisms that produce them in these mice. Using mixed hematopoietic chimeric mice, with a mixture of tagged-B6 and congenic bone marrow I demonstrate that there are intrinsic B and T cell functional defects in chromosome 1 congenic mice. I further show that an intrinsic B cell defect is required for efficient recruitment of B cells into the spontaneous germinal centres and differentiation of autoantibody producing cells in these mice. To more precisely localize the susceptibility loci, I produced and characterized a number of additional subcongenic mouse strains. This revealed surprising genetic complexity with the presence of at least four lupus susceptibility loci and a suppressor locus on chromosome 1, several of which appeared to impact on T cell function. Finally, I generated bicongenic mice carrying both NZB chromosome 1 and 13 intervals, hypothesizing that since these were two of the major intervals associated with autoimmune disease in NZB mice they would fully recapitulate the autoimmune phenotypes. Although this hypothesis was incorrect, several novel phenotypes developed including marked expansion of the plasmacytoid and myeloid dendritic cell compartments and increased BAFF and IgA autoantibody production. Although this expansion was associated with TLR hyper-responsiveness, disease severity remained mild, possibly due to the lack of IFN- production, which appeared to be inhibited in these mice. Thus, lupus arises from immune defects affecting several cellular populations, which are the product of multiple genetic polymorphisms that interact in a complex fashion to produce the autoimmune phenotype.

Keywords: Systemic Lupus Erythematosus
Mouse Model
Advisor: Wither, Joan
Predicting Treatment Response and the Role of the ISG15/USP18 Ubiquitin-like Signaling Pathway in Hepatitis C Viral Infection

Hepatitis C Virus (HCV) infects 170 million people worldwide. The current treatment regimen, which is combination therapy with pegylated interferon (PegIFN) and Ribavirin (Rib), cures only 50% of the patients infected with the most prevalent HCV genotype. Therefore, there is a pressing need to understand the molecular mechanism of interferon resistance and to develop a prognostic tool to predict who will respond to treatment before initiation of therapy. It has been firmly established that the virus-host interaction plays an important role in determining treatment outcomes. My thesis investigated the host factors that are involved in interferon resistance with an aim to provide insights into the molecular mechanism of IFN resistance. cDNA microarray analysis identified 18 differentially expressed hepatic genes from pretreatment liver tissues of responders (Rs) and non-responders (NRs). Based on the differential expression levels of these 18 genes, a prognostic tool was developed to predict who will respond to therapy, with a positive predicting value (PPV) of 96%. Most of these 18 genes are interferon stimulated genes (ISGs) and they are more highly expressed in NR livers, indicating that preactivation of interferon signaling in the pre-treatment liver tissues contributes to NR. 3 out of the 18 genes are involved in an ubiquitin-like ISG15/USP18 signaling pathway that plays an important role in interferon response. Over-expression of USP18 and ISG15 in the pretreatment liver tissues of NR promotes HCV production and blunts interferon anti-HCV activity. There exists a distinct cell-type specific ISG activation in the pretreatment liver tissues of Rs and NRs. Up-regulation of the two ISGs that I tested (ISG15 and MxA) was found mainly in hepatocytes in NRs while ISG activation was preferentially observed in macrophages in Rs. Taking all these data together, pre-activation of interferon signaling and cell-type specific gene activation in the pretreatment liver tissues of patients infected with HCV are associated with treatment non-response. HCV exploits the host interferon system to favour its persistence by enhanced replication /secretion stimulated by a few ISGs (ISG15, USP18) in response to IFN. The developed prognostic tool can be used to stratify patients for treatment and the novel insights of the molecular mechanism of IFN resistance in HCV patients offer potential drug targets for future development.

Keywords: Hepatitis C Virus
ISG15/USP18
gene expression profiling
treatment response prediction
Advisor: Edwards, Aled M.
Hypoxia Suppresses DNA Repair: Implications for Cancer Progression and Treatment

Acute and chronic hypoxia exists within the microenvironment of solid tumours and drives therapy resistance, genetic instability and metastasis. Despite its importance in solid tumour progression, very little is known regarding the functional consequences of hypoxia-mediated changes in the expression of DNA repair proteins. I studied the relationship between hypoxia and DNA repair using a prolonged chronic hypoxic gas treatment model in a variety of human tumour cell lines to mimic the dynamic state of proliferation and DNA repair in cells distant from the tumour blood vasculature. I observed decreased expression of homologous recombination (HR) and base excision repair (BER) proteins due to a novel mechanism involving decreased protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O2 as measured by the DR-GFP reporter system and functional BER was impaired as assessed with a functional glycosylase assay. This decrease in protein expression and function resulted in increased sensitivity to the DNA damaging agents MMC, cisplatin, H2O2 and MMS. Additionally, chronically hypoxic cells were relatively radiosensitive (OER = 1.37) when compared to acutely hypoxic or anoxic cells (OER = 1.96 - 2.61). As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, I evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. I observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or depletion of PARP1. PARP-inhibited hypoxic cells accumulated γH2AX foci consistent with an accumulation of collapsed replication forks. Additionally, tumour xenografts exposed to PARP1 inhibition showed increased γH2AX and cleaved caspase-3 expression in hypoxic subregions with suppressed RAD51 protein expression and decreased ex vivo clonogenic survival. I conclude that persistent down-regulation of DNA repair components by the microenvironment could result in faulty DNA repair with significant implications for therapeutic response and genetic instability in human cancers. Specifically, hypoxic cells may be sensitized to PARP inhibitors and other agents targeting repair pathways down-regulated by hypoxia as a consequence of microenvironment-mediated “contextual synthetic lethality”.

Keywords: Hypoxia
DNA Repair
Advisor: Bristow, Robert
A Structural and Evolutionary Analysis of the Bacteriophage Head-tail Connector

Macromolecular complexes are important in almost all cellular processes. The bacteriophage head-tail connector complex offers a model with which to study the mechanisms that control their formation and the interactions that govern their assembly. The head-tail connector joins DNA-filled heads with mature tails. This thesis describes the structures, functions, and evolution of two connector proteins, HK97 gp6 and Lambda gpFII. Middle-ring connector proteins act as head-stabilizing proteins after the packaging of DNA in the heads. I found that gp6 is the middle-ring connector protein of bacteriophage HK97. I determined that gp6 is part of a large family of middle-ring connector proteins that share common sequence and structure elements. I also show that the mechanism for the addition of gp6 to the connector is mediated by limiting gp6 expression by strictly controlling translation initiation. I also describe a three-dimensional model for the assembly of the head-tail joining protein of bacteriophage Lambda, gpFII. This model correctly predicts regions of the protein predicted to interact with the Lambda head and tail. It also provides evidence for the description of a new family of proteins that evolved from a tail tube protein. This family includes members from both contractile and non-contractile phage tails and the bacterial type VI secretion system.

Advisor: Davidson, Alan R.
Genetic Determinants of Serum Ascorbic Acid Concentrations

Background: The adequacy of serum ascorbic acid (vitamin C) concentrations in young Canadian adults is unknown. Individuals have varied serum ascorbic acid response to dietary vitamin C, possibly due to genetic variation. Objective: To investigate the prevalence of serum ascorbic acid deficiency in young Canadians and to determine whether common genotypes modify the association between dietary vitamin C and serum ascorbic acid. Methods: Subjects were 1277 men and women aged 20-29 years from the Toronto Nutrigenomics and Health study. Vitamin C intakes were estimated by a 196-item FFQ. Fasting blood was collected to measure serum ascorbic acid by HPLC and to genotype for common polymorphisms in genes that code for glutathione S-transferase (GST) (GSTM1, GSTT1 and GSTP1), haptoglobin (Hp), and vitamin C transporters (SLC23A1 and SLC23A2). Results: 53% of subjects had adequate, 33% had suboptimal and 14% had deficient serum ascorbic acid. Subjects with deficiency had higher mean C-reactive protein, waist circumference, BMI and blood pressure than subjects with adequate serum ascorbic acid. The odds ratio (95% confidence interval) for serum ascorbic acid deficiency was 3.43 (2.14, 5.50) for subjects who did not meet the vitamin C recommendation compared to those who did. The corresponding odds ratios were 2.17 (1.10, 4.28) and 12.28 (4.26, 33.42) for individuals with the GSTT1 functional and null genotypes respectively (interaction p=0.01), and 2.29 (0.96, 5.45) and 4.03 (2.01, 8.09) for the GSTM1 functional and null genotypes (interaction p=0.04). These odds ratios were 4.77 (2.36, 9.65) for the Hp2-2 genotype, but 1.69 (0.80, 3.63) for carriers of the Hp1 allele (interaction p=0.02). Serum ascorbic acid concentrations (mean +/- SE) differed among SLC23A1 rs4257763 genotypes (GG: 24.4 +/- 1.3, GA: 26.8 +/- 1.1, AA: 29.7 +/- 1.4, p=0.002). Conclusions: Serum ascorbic acid deficiency is prevalent and associated with markers of chronic disease. Individuals with GST null or Hp2-2 genotypes had an increased risk of deficiency if they did not meet the recommendation for vitamin C, suggesting that GSTs and haptoglobin may spare ascorbic acid when dietary vitamin C is insufficient, thus protecting against serum ascorbic acid deficiency.

Keywords: Ascorbic acid
Nutrigenomics
Vitamin C
Chronic disease
Genotypes
Diet-gene interaction
GSTT1 polymorphism
GSTM1 polymorphism
Hp polymorphism
Vitamin C transporters 1 and 2
Advisor: El-Sohemy, Ahmed
Synthesis of Aromatic Heterocycles and Carbocycles Through Tandem Palladium-catalyzed Cross-couplings of gem-dihaloolefins

Our group has developed a strategy for the synthesis of benzofused carbocycles and heterocycles through tandem palladium-catalyzed reactions of gem-dibromoolefins. In these syntheses, one bromide undergoes a Pd-catalyzed cyclization reaction, and the other participates in an orthogonal inter- or intramolecular Pd-catalyzed reaction to functionalize or annulate that ring, respectively. Chapter 1 describes the pairing of an intramolecular C–N bond forming reaction (the Buchwald-Hartwig coupling) with an intramolecular direct arylation for the synthesis of fused indole derivatives. A range of previously unknown heterocycles were synthesized through this method. Chapter 2 describes the synthesis of benzothiophenes through the combination of a Pd-catalyzed C–S coupling with an orthogonal Suzuki, Heck, or Sonogashira reaction. This represents the first example of the incorporation of Pd-catalyzed C–S coupling into a tandem reaction. In Chapter 3, a tandem intramolecular Heck / intermolecular Suzuki reaction is described for the synthesis of methyleneindenes. Studies on this reaction have provided advanced understanding of the mechanism, including how variation of the ligand controls the regioselectivity of the reaction.

Keywords: Cross-Coupling
Palladium
Advisor: Lautens, Mark
Structural Color and Odors: Towards a Photonic Crystal Nose Platform

The present thesis describes a novel photonic crystal platform dubbed the photonic nose, a color-based analogue of the human olfactory system. The platform is founded on a one dimensional photonic crystal architecture known as Bragg stacks, which are fabricated using bottom-up self-assembly approaches. Structural and compositional aspects of this novel class of photonic crystals are established that provide them with functionality and utility. Silicon dioxide, titanium dioxide, tin oxide, clays and zeolites are among the materials incorporated into one-dimensional photonic structures. Retention of materials functionality is demonstrated by vapor and liquid sensing experiments. This class of Bragg stacks displays well defined optical properties that have been thoroughly investigated by use of spectroscopic ellipsometry, as we demonstrate in a chapter dedicated to the technique. Utilizing conventional building blocks comprised of nanostructured silicon and titanium dioxide we discuss various aspects of technique pertaining single layered as well as multilayered films. In terms of practical applications these kinds of Bragg stacks show significant potential in areas such as display and sensors that exploit their vibrant and tunable colors. These colors are an important attribute of photonic crystals with bandgaps in the visible range and in this thesis work we present new approaches for characterizing photonic crystal color using well established methods from the field of color imagery. With this knowhow we have been able to assemble a pixilated array of chemically functionalized Bragg stacks in which each pixel responds differently to vapor phase analytes. The combinatorial response of the entire array enables a unique diagnostic fingerprint of a given analyte vapor as determined from color imagery and multivariate statistical methods of analysis. It was possible to discriminate between ethanol, butanol, hexanol, hexane, octane and decane. We also demonstrate the power of the photonic nose platform by distinguishing different bacteria from a photonic nose color analysis of the complex mixture of vapors in the bacteria culture headspace. Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa could be discriminated based on this technique.

Keywords: Photonic Crystals
Electronic Noses
Advisor: Ozin, Geoffrey Alan