VictorJuiz/thesis huggingface dataset:
Probabilistic Models for the Analysis of Gene Expression Profiles

Gene expression profiles are some of the most abundant sources of data about the cellular state of a collection of cells in an organism. Comparison of the expression profiles of multiple samples allows biologists to find associations between observations at the molecular level and the phenotype of the samples. A key challenge is to distinguish variation in expression due to biological factors of interest from variation due to confounding factors that can arise for unrelated technical or biological reasons. This thesis presents models that can explicitly adjust the comparison of expression profiles to account for specific types of confounding factors. One such confounding factor arises when comparing tissue-specific expression profiles across multiple organisms to identify differences in expression that are indicative of changes in gene function. When the organisms are separated by long evolutionary distances, tissue functions may be re-distributed and introduce expression changes unrelated to changes in gene function. We developed Brownian Factor Phylogenetic Analysis, a model that can account for such re-distribution of function, and demonstrate that removing this confounding factor improves tasks such as predicting gene function. Another confounding factor arises because current protocols for expression profiling require RNA extracts from multiple cells. Often biological samples are heterogeneous mixtures of multiple cell types, so the measured expression profile is an average of the RNA levels of the constituent cells. When the biological sample contains both cells of interest and nuisance cells, the confounding expression from the nuisance cells can mask the expression of the cells of interest. We developed ISOLATE and ISOpure, two models for addressing the heterogeneity of tumor samples. We demonstrated that modeling tumor heterogeneity leads to an improvement in two tasks: identifying the site of origin of metastatic tumors, and predicting the risk of death of lung cancer patients.

Keywords: probabilistic models
gene expression profiling
cancer
prognosis prediction
expression evolution
tumor heterogeneity
expression deconvolution
tumor purification
topic models
Advisor: Morris, Quaid
Late Transition Metal Complexes Bearing Functionalized N-Heterocyclic Carbenes and the Catalytic Hydrogenation of Polar Double Bonds

Late transition metal complexes of silver(I), rhodium(I), ruthenium(II), palladium(II) and platinum(II) containing a nitrile-functionalized N-heterocyclic carbene ligand (C-CN) were prepared. The nitrile group on the C–CN ligand was shown to undergo hydrolysis under basic conditions, leading to a silver(I) carbene complex with a primary-amido functional group, and a trimetallic complex of palladium(II) with a partially hydrolyzed C–N–N–C donor ligand. The reduction of a nitrile-functionalized imidazolium salt in the presence of nickel(II) chloride under mild conditions yielded an axially chiral square-planar nickel(II) complex containing a unique primary-amino functionalized N-heterocyclic carbene ligand (C-NH2). A transmetalation reaction moved this chelating C–NH2 ligand from nickel(II) to ruthenium(II), osmium(II), and iridium(III), yielding important catalysts for the hydrogenation of polar double bonds. The ruthenium(II) complex, [Ru(p-cymene)(C–NH2)Cl]PF6 catalyzed the transfer and H2-hydrogenation of ketones. The bifunctional hydride complex, [Ru(p-cymene)(C–NH2)H]PF6, which contains a Ru–H/N–H couple showed no activity under catalytic conditions unless when activated by a base. The outer-sphere mechanism involving bifunctional catalysis of ketone reduction is disfavored according to experimental and theoretical studies and an inner-sphere mechanism is proposed involving the decoordination of the amine donor from the C–NH2 ligand. The ruthenium(II) complex [RuCp*(C–NH2)py]PF6 showed higher activity than the iridium(III) complex [IrCp*(C–NH2)Cl]PF6 in the hydrogenation of ketones. This ruthenium(II) complex also catalyzes the hydrogenation of an aromatic ester, a ketimine, and the hydrogenolysis of styrene oxide. We proposed an alcohol-assisted outer sphere bifunctional mechanism for both systems based on experimental findings and theoretical calculations. The cationic iridium(III) hydride complex, [IrCp*(C–NH2)H]PF6 , was prepared and this failed to react with a ketone in the absence of base. The crucial role of the alkoxide base was demonstrated in the activation of this hydride complex in catalysis. Calculations support the proposal that the base deprotonates the amine group of this hydride complex and triggers the migration of the hydride to the η5-Cp* ring producing a neutral iridium(I) amido complex. This system contains an active Ir–H/N–H couple required for the outer sphere hydrogenation of ketones in the bifunctional mechanism.

Keywords: catalysis
N-heterocyclic carbene
homogeneous hydrogenation
ketones
late transition metals
polar double bonds
metal hydrides
bifunctional catalysis
outer-sphere mechanism
inner-sphere mechanism
amine ligands
hydrolysis of nitriles
Advisor: Morris, Robert H.
Modification of Carbonaceous Materials with Sulfur and Its Impact on Mercury Capture and Sorbent Regenertion

Physical activation of oil-sands fluid coke, a dense carbonaceous material, using sulfur dioxide (SO2) was investigated as a means of utilizing a plentiful and inexpensive waste for elemental mercury (Hg) removal. A new model was developed to elucidate physical activation of dense carbonaceous materials. Experiments and model simulations revealed that, during activation with SO2, a sulfur-rich porous layer is formed around the periphery of the coke particles; this porous layer reaches a maximum thickness as a result of diffusion limitations; the maximum porous layer thickness is controlled by activation conditions and determines the maximum achievable specific surface area (SSA). Pre-oxidation in air prior to activation, acid washing after activation and smaller coke particle size all result in higher SSA. The highest SSA achieved was 530 m2/g, the highest yet found for oil-sands fluid coke with physical activation. If present, oxygen out-competed SO2 for carbon during activation. SO2 activation and porous layer formation did not occur until oxygen was depleted. Sulfur added to coke through SO2 activation is mainly in reduced forms which are more thermally stable than elemental sulfur in commercial sulfur-impregnated activated carbons (SIACs). TGA and elemental analyses revealed that only 17% of sulfur was removed at 800°C from SO2-activated coke under inert conditions, compared with 100% from a commercial SIAC. The role of sulfuric acid (H2SO4) in vapor Hg capture by activated carbon (AC) was studied due to conflicting findings in the recent literature. In the absence of other oxidizing species, it was found that Hg could be oxidized by oxygen which enhanced vapor Hg adsorption by AC and Hg absorption in H2SO4 solution at room and elevated temperatures. At 200°C, AC treated with 20% H2SO4 reached a Hg loading of more than 500 mg/g, which is among the highest Hg capacities yet reported. When oxygen was not present, S6+ in H2SO4 was found to act as an oxidizer of Hg, thus enabling Hg uptake by H2SO4-treated AC at 200°C. Treating the AC with SO2 at 700°C improved the initial rate of Hg uptake, with and without subsequent H2SO4 treatment.

Keywords: activated carbon
mercury
sulfur dioxide
petroleum coke
gas-solid reaction model
specific surface area
sulfuric acid
carbon-sulfur reactions
gas-phase adsorption
mercury control
porosity
coal combustion
Advisor: Jia, Charles Q.
From Ruthenium to Iron for the Catalytic Reduction of Ketones: Catalysis and Mechanistic Insights

A range of air- and moisture-stable phosphonium salts was prepared. Compounds were isolated in high yield and fully characterized. The properties of these compounds and the nature of their formation were explored. The phosphonium salts react with base to give phosphino-aldehydes which are important building blocks in the synthesis of PNNP ligands. The condensation reaction between phosphino-aldehydes and a diamine usually employed for the preparation of PNNP ligands was not applicable to the phosphino-aldehydes derived from these phosphonium salts as a result of the high reactivity of the nucleophilic phosphorus causing uncontrollable side-reaction. In order to resolve this problem, a template reaction with iron(II) Lewis acid was used to suppress the reactivity of the phosphorus via coordination. The reaction was successful and gave rise to bis-tridentate complexes with PNN ligands ([Fe(Ph2PCH2CH=N---NH2)2][BPh4]2, where N---NH2 depends on diamine used) as the kinetic product and to desired tetradentate complexes with PNNP ligands (trans-[Fe(Ph2PCH2CH=N---N=CHCH2PPh2)(CH3CN)2][BPh4]2, where N---N depends on diamine used) as a thermodynamic product of the reaction. The reaction appeared to be very general; complexes iii with various diamines incorporated in the ligand backbone were prepared in high yield and fully characterized. Mono-carbonylation reaction of the complexes containing tetradentate PNNP ligands resulted in the formation of the precatalysts with a general formula (trans-[Fe(Ph2PCH2CH=N---N=CHCH2PPh2)(CO)(Br)][BPh4]. These precatalysts give active (TOF up to 28000 h-1) and enantioselective (up to 95 % ee) catalytic systems for the ATH of ketones when activated with base in a solution of 2-propanol as the reducing agent. On the basis of a kinetic study and other evidence, we propose a mechanism of activation and operation of the catalytic system involving the precatalyst trans-[Fe(CO)(Br)(Ph2CH2CH=N-((S,S)-C(Ph)H-C(Ph)H)-N=CHCH2PPh2)][BPh4] and acetophenone as a model substrate. We determined that the activation of the precatalyst to the active species involves the stereoselective reduction of one imine group of the ligand, since when the active species are quenched with acid, the complex trans-[Fe(CO)(Cl)(Ph2CH2CH-(H)N-((S,S)-C(Ph)H-C(Ph)H)-N=CHCH2PPh2)][BPh4] containing amine and imine functionalities in the backbone is produced.

Keywords: Catalysis
Reduction
Advisor: Morris, Robert H.
In Each Other&rsquo;s Arms: France and the St. Lawrence Mission Villages in War and Peace, 1630-1730

Beginning in the late 1630s, a diversity of Algonquian and Iroquoian peoples established under the auspices of Jesuit and, later, Sulpician missionaries a string of village communities in the St. Lawrence Valley. A diversity of peoples, whom the French lumped under the rubrics of “Algonquins”, “Montagnais”, “Hurons”, “Iroquois”, “Abenakis” and “Loups”, migrated to these villages in the hope of bettering their lives in trying times. This dissertation retraces the formation and the early development of these communities, exploring the entangled influence of armed conflict, diplomacy, kinship, and leadership on migration, community-building, and identity formation. The historiography of the St. Lawrence Valley – the French colonial heartland in North America – has tended to relegate these Aboriginal communities to the margins. Moreover, those scholars who have considered the formation of mission villages have tended to emphasize missionary initiative. Here, these villages are reimagined as a joint creation, the result of intersecting French and Aboriginal desires, needs, and priorities. The significance of these villages as sites of refuge becomes readily apparent, the trajectories of individual communities corresponding with the escalation of conflict or with its tense aftermath. What also becomes clear is that the course of war and peace through the region cannot be accounted solely by the relations of the French and Iroquois, or of the French and British crowns. Paying close attentions to the nuanced personal and collective identities of the residents of the mission villages and their neighbours allows us to gain a better understanding of the geopolitics of the northeastern woodlands during the seventeenth and early eighteenth centuries.

Keywords: New France
Missions
Aboriginals
Native Americans
Ethnohistory
War
Advisor: Greer, Allan
Medical Image Processing Techniques for the Objective Quantification of Pathology in Magnetic Resonance Images of the Brain

This thesis is focused on automatic detection of white matter lesions (WML) in Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) of the brain. There is growing interest within the medical community regarding WML, since the total WML volume per patient (lesion load) was shown to be related to future stroke as well as carotid disease. Manual segmentation of WML is time consuming, labourious, observer-dependent and error prone. Automatic WML segmentation algorithms can be used instead since they give way to lesion load computation in a quantitative, efficient, reproducible and reliable manner. FLAIR MRI are affected by at least two types of degradations, including additive noise and the partial volume averaging (PVA) artifact, which affect the accuracy of automated algorithms. Model-based methods that rely on Gaussian distributions have been extensively used to handle these two distortions, but are not applicable to FLAIR with WML. The distribution of noise in multicoil FLAIR MRI is non-Gaussian and the presence of WML modifies tissue distributions in a manner that is difficult to model. To this end, the current thesis presents a novel way to model PVA artifacts in the presence of noise. The method is a generalized and adaptive approach, that was applied to a variety of MRI weightings (with and without pathology) for robust PVA quantification and tissue segmentation. No a priori assumptions are needed regarding class distributions and no training samples or initialization parameters are required. Segmentation experiments were completed using simulated and real FLAIR MRI. Simulated images were generated with noise and PVA distortions using realistic brain and pathology models. Real images were obtained from Sunnybrook Health Sciences Centre and WML ground truth was generated through a manual segmentation experiment. The average DSC was found to be 0.99 and 0.83 for simulated and real images, respectively. A lesion load study was performed that examined interhemispheric WML volume for each patient. To show the generalized nature of the approach, the proposed technique was also employed on pathology-free T1 and T2 MRI. Validation studies show the proposed framework is classifying PVA robustly and tissue classes are segmented with good results.

Keywords: Medical image processing
Magnetic Resonance Images
White matter lesion
Fluid Attenuation Inversion Recovery
Advisor: Venetsanopoulos, Anastasios N.
Evaluating Human Endogenous Retrovirus and LINE-1 Retrotransposable Element Antigens as Novel Targets for T cell Based HIV-1 Vaccine Strategies

The global HIV-1 pandemic is new only in the sense that it is the latest iteration in a conflict between humans and retroviruses that has spanned millions of years. Bearing witness to this, our genomes are littered with the DNA remnants of ancient retroviruses. These ‘human endogenous retroviruses’ (HERVs) are generally thought to be inert. In this thesis, I explore the hypothesis that HIV-1 has had to make a compromise in order to avoid extermination by a class of cellular defence factors that our cells evolved long ago in order to defend against ancient retroviruses. In disabling these defence factors to allow for its own replication, I posit, that HIV-1 enables the expression of the ancient retroviruses, as well as LINE-1 retroelements, in our genome. I propose to use this against the virus by targeted immune responses against HERV/LINE-1 antigens as a way of killing HIV-1-infected cells.

Keywords: HIV vaccines
Retrotransposable elements
Advisor: Ostrowski, Mario
The Effect of the Colon Cancer Check Program on Colorectal Cancer Screening in Ontario

Background: This thesis is composed of three studies testing the effect of the Colon Cancer Check (CCC) program, the organized screening program for colorectal cancer in Ontario, on screening participation. In the first paper, we described the trends of participation to Fecal Occult Blood Test (FOBT) and endoscopy, and the trend of ‘up-to-date’ consistent with guidelines, overall and stratified by demographic characteristics between 2005 and 2011. In the second paper, we tested the effect of physician’s recommendation on FOBT participation and disparities in participation. In the third paper, we measured the effect of the CCC program on FOBT participation using an interrupted time series. Methods: We identified six annual cohorts of individuals eligible for CRC screening in Ontario between 2005 and 2011 by linking the Registered Persons Database to Ontario Health Insurance Plan and 2006 Census from Statistics Canada. We used descriptive statistics to describe the trends of participation. The effect of physician’s recommendation on screening participation was tested using multiple logistic regression analysis. The effect of the CCC program on FOBT participation was tested using segmented regression analysis. Results: An increasing trend in FOBT participation and ‘up-to-date’ status was observed across all demographic characteristics. The disparity gaps persisted over time by gender, income, recent registrant and age. The rural/urban gap was removed. Physician’s recommendation tripled the likelihood of FOBT participation (prevalence rate ratio=3.23, CI= 3.22-3.24) and mitigated disparities. The CCC led to a temporary increase in level (8.2‰ person-month) in FOBT participation followed by a decline in trend and then a plateau. The increase in level was significant across all population sub-groups. Conclusions: We found that CRC screening has increased in Ontario across all subgroups of the population but remained suboptimal. Disparities in screening participation were identified. Proposed strategies to improve performance include interventions to increase the rate of physician’s recommendation at the practice level, tailored interventions to motivate under-users and public media campaigns.

Keywords: Health care evaluation
Colorectal cancer screening
Interrupted time series
Advisor: Bierman, Arlene
Record Linkage for Web Data

Record linkage refers to the task of finding and linking records (in a single database or in a set of data sources) that refer to the same entity. Automating the record linkage process is a challenging problem, and has been the topic of extensive research for many years. However, the changing nature of the linkage process and the growing size of data sources create new challenges for this task. This thesis studies the record linkage problem for Web data sources. Our hypothesis is that a generic and extensible set of linkage algorithms combined within an easy-to-use framework that integrates and allows tailoring and combining of these algorithms can be used to effectively link large collections of Web data from different domains. To this end, we first present a framework for record linkage over relational data, motivated by the fact that many Web data sources are powered by relational database engines. This framework is based on declarative specification of the linkage requirements by the user and allows linking records in many real-world scenarios. We present algorithms for translation of these requirements to queries that can run over a relational data source, potentially using a semantic knowledge base to enhance the accuracy of link discovery. Effective specification of requirements for linking records across multiple data sources requires understanding the schema of each source, identifying attributes that can be used for linkage, and their corresponding attributes in other sources. Schema or attribute matching is often done with the goal of aligning schemas, so attributes are matched if they play semantically related roles in their schemas. In contrast, we seek to find attributes that can be used to link records between data sources, which we refer to as linkage points. In this thesis, we define the notion of linkage points and present the first linkage point discovery algorithms. We then address the novel problem of how to publish Web data in a way that facilitates record linkage. We hypothesize that careful use of existing, curated Web sources (their data and structure) can guide the creation of conceptual models for semi-structured Web data that in turn facilitate record linkage with these curated sources. Our solution is an end-to-end framework for data transformation and publication, which includes novel algorithms for identification of entity types and their relationships out of semi-structured Web data. A highlight of this thesis is showcasing the application of the proposed algorithms and frameworks in real applications and publishing the results as high-quality data sources on the Web.

Keywords: Data Management
Databases
Record Linkage
Entity Resolution
Link Discovery
Data Integration
Data Quality
Advisor: Miller, Renee J.
Defining the Mechanisms By Which Transplanted Neural Precursor Cells Mediate Functional Recovery Following Spinal Cord Injury

Spinal cord injury (SCI) is uniquely devastating. Cellular transplantation strategies for SCI are showing promise. Little, however, is known about how transplanted neural precursor cells (NPCs) enhance functional recovery or the mechanisms by which they interact with the host spinal cord. Better understanding of these critical issues may lead to improved strategies to enhance recovery after SCI. Given this background, I hypothesized that NPCs mediate functional recovery by a number of mechanisms including trophin production, neuroprotection, modulation of the host inflammatory response or glial scarring, and/or remyelination. I thus endeavored to characterize trophin production by NPCs in vitro and in vivo in rats with clip compression SCI of the thoracic spinal cord, to determine if preservation of host cells and tissue contribute to functional recovery and to determine how NPC transplantation influences the host inflammatory response and glial scarring. Here I present unique and novel insights into NPC-host interactions following SCI. We show that NPCs are poised to provide trophic support to the injured spinal cord. We also show that the combination of NPCs, pharmacotherapy and trophin infusion is associated with sparing of grey and white matter, enhanced numbers of oligodendrocytes but not axons as well as an increased inflammatory response. To assess the potential impact of myelination as a mechanism underlying NPC-mediated functional recovery after SCI, experiments were undertaken using NPCs derived from shiverer mutant mice unable to produce central myelin. These experiments showed that while NPCs from wild-type mice generate myelin and mediate functional recovery after SCI; transplanted shiverer NPCs impede neurobehavioural recovery. In summary, my work provides unique insights into the functional effects of NPC transplantation after SCI. Of importance, this thesis provides novel evidence that remyelination is a key mechanism of action by which NPCs mediate recovery after SCI. Hence, this work has important implications for patients with SCI.

Keywords: spinal cord injury
neural precursor cell
transplantation
neural repair
Advisor: Fehlings, Michael G.