VictorJuiz/thesis huggingface dataset:
The Application of Ontologies to Reasoning with Process Modeling Formalisms

Reasoning about processes in applications such as manufacturing, web services, enterprise modeling, and planning requires the representation of composite processes with complicated flows of control. Previous research in process representation has used formalisms such as Event Systems, Petri nets, and the Unified Modeling Language activity diagrams. The computational hardness of temporal projection problems in Event Systems has been extensively examined in the literature, whereas Petri nets and UML activity diagrams are applied to describe more elaborate processes. This thesis takes a systematic look into the temporal reasoning problems in Event Systems and assigns accurate semantics to both Petri nets and, for the first time, to UML activity diagrams. We give an analysis of computational complexity in temporal projection problems by exploring the boundary between their tractable and intractable subproblems. Our results provide new insights into the prominent role the properties of partial ordering play, however we also show that partial ordering is not the sole source of the intractability as has been claimed in an earlier work by Nebel and B{\"a}ckstr{\"o}m. Two influential modeling languages, Petri nets and UML activity diagrams, are axiomatized as two Basic Action Theories of Situation Calculus. They are called, respectively, SCOPE (Situation Calculus Ontology of PEtri nets) and SCAD (Situation Calculus theory of Activity Diagrams). We provide a Prolog implementation of SCOPE and prove the correctness of this program for regressable queries. We use SCAD to axiomatize the structural and dynamic properties of UML activity diagrams and also provide the first set of computational results with regard to the reachability problems in activity diagrams. The correctness of each of these two axiomatizations is also demonstrated by proving that the theory is satisfiable, and the intended interpretation corresponds to a model of the theory.

Keywords: Process Ontologies
Process Modeling Formalisms
Advisor: Gruninger, Michael John
Characterizing the Evolutionary Dynamics of Protein Phosphorylation Sites for Functional Phospho-proteomics

Protein phosphorylation is a prevalent reversible post-translational modification that influences protein functions. The advent of phospho-proteomic technologies now enables proteome-wide quantitative detection of residues phosphorylated under different physiological conditions. The functional consequences of the majority of these phosphorylation events are unknown. This calls for endeavors to characterize their molecular functions and cellular effects. This can be facilitated by systematic approaches to categorize phosphorylation events, interpret their importance and infer their functions. I carried out comparative, evolutionary and integrative analyses on in vivo phosphorylation events to address these challenges. First, I performed cross-species comparative phospho-proteomic analysis to identify evolutionarily conserved phosphorylation events in human. A sequence alignment approach was used to identify phosphorylation events conserved at similar sequence positions across orthologous proteins and a network alignment approach was applied to identify potential evolutionarily conserved kinase-substrate interactions. Conserved human phosphoproteins identified are found enriched for proteins encoded by known cancer- and disease-associated genes. Next, I developed a new approach to analyze the sequence conservation of known phosphorylated residues on human, mouse and yeast proteins that factored in the background mutational rates of protein and phosphorylatable residue. Furthermore, sites were analyzed according to (i) characterized functions, (ii) prevalence, (iii) stoichiometry, their occurrence in (iv) structurally disordered/ordered protein regions, in (v) proteins of various abundance and in (vi) proteins with different protein interaction propensity to identify the factors influencing sequence conservation of phosphorylated residues. Importantly, my analysis suggests that false positives and randomly phosphorylated residues are present in existing phosphorylation datasets and they are more common on high abundance proteins. Lastly, I characterized the theoretical maximum phosphorylation capacity in terms of phosphorylatable residues and discovered that genomic tyrosine frequency correlates negatively and significantly with tyrosine kinase frequency and cell type in metazoan. This observation suggests that fidelity of phosphotyrosine signaling occurred partially through global tyrosine depletion.

Keywords: Signal transduction
Evolution
Phosphoproteomics
Advisor: Bader, Gary D.
Pawson, Tony
Pedagogical Orientations towards the Integration of Language and Content: English Language Learners’ Opportunities to Learn in Mathematics Classrooms

Achieving equitable opportunities to learn has been recognized as an important issue in multilingual content classrooms. However, partially because mathematics is conceptualized as a language-free subject, there is limited research examining linguistic minority students’ opportunities to learn in mathematics classrooms. The purpose of this research is to identify linguistic minority students’ opportunities to learn in mathematics classrooms in a Canadian multilingual urban elementary school, where English was the main instructional language. Drawing on cultural historical activity theory, this study focuses on two aspects of learning: externalization, which emphasizes learners’ creation of new cultural artifacts and new contexts to apply the given artifacts, and internalization, which emphasizes learners’ acquisition of preexisting cultural artifacts. In this ethnographic study, I examined the activity systems of participatory action research (PAR) with the activity system of regular mathematics lessons. Within these activity systems, I focused on newly-arrived English language learners’ (ELLs) participation. Specifically, I examined the range of opportunities to learn afforded to students in the two activity systems and identified how focal ELLs accessed these opportunities to learn. In the activity system of PAR, which emphasized externalization, students conducted research and presented their conclusions in order to implement changes in their school environment. All students, however, did not participate equally. Specifically, the focal ELLs were not able to access these opportunities to learn as a result of group dynamics, marginalized social identities, and other students’ perceptions of their linguistic ability. In the activity system of regular mathematics lessons, which emphasized internalization, the teacher organized lessons in ways that allowed focal ELLs to receive extra support and resources to reach the curriculum expectations. These mathematics lessons allowed focal ELLs to increase their participation through mathematical reasoning, problem solving, and explanations with a variety of resources including visual representations. A critical examination of the interactions revealed that focal ELLs’ opportunities to learn were expanded or limited depending upon classroom configurations. Furthermore, this research suggests that students’ social identities serve as both a medium and a product of learning. These results have valuable implications for developing inclusive classroom practices and curriculum in multilingual content classrooms.

Keywords: English as a second language
English language learners
content-based language teaching
mathematics education
multicultural education
activity theory
sociocultural theory
opportunity to learn
elementary
equity
second language education
learning
content-language integration
pedagogy
multilingual classroom
linguistically diverse students
Advisor: Esmonde, Indigo
Development of Frequency and Phase Modulated Thermal-wave Methodologies for Materials Non-destructive Evaluation and Thermophotonic Imaging of Turbid Media

In frequency-domain photothermal radiometry (FD-PTR) a low-power intensity-modulated optical excitation generates thermal-wave field inside the sample and the subsequent infrared radiation from the sample is analyzed to detect material’s inhomogeneities. The non-contact nature of FD-PTR makes it very suitable for non-destructive evaluation of broad range of materials. Moreover, the methodology is based on intrinsic contrast of light absorption which can be used as a diagnostic tool for inspection of malignancy in biological tissues. Nevertheless, the bottom line is that the physics of heat diffusion allows for a highly damped and dispersive propagation of thermal-waves. As a result, the current FD-PTR modalities suffer from limited inspection depth and poor axial/depth resolution. The main objective of this thesis is to show that using alternative types of modulation schemes (such as linear frequency modulation and binary phase coding) and radar matched filter signal processing, one can obtain localized responses from inherently diffuse thermal wave fields. In this thesis, the photothermal responses of turbid, transparent, and opaque media to linear frequency modulated and binary phase coded excitations are analytically derived. Theoretical simulations suggest that matched-filtering in diffusion-wave field acts as constructive interferometry, localizing the energy of the long-duty excitation under a narrow peak and allowing one to construct depth resolved images. The developed technique is the diffusion equivalent of optical coherence tomography and is named thermal coherence tomography. It was found that the narrow-band binary phase coded matched filtering yields optimal depth resolution, while the broad-band linear frequency modulation can be used to quantify material properties through the multi-parameter fitting of the experimental data to the developed theory. Thermophotonic detection of early dental caries is discussed in detail as a potential diagnostic application of the proposed methodologies. The performance of the diagnostic system is verified through a controlled demineralization protocol as well as in teeth with natural caries.

Keywords: thermal-wave
thermophotonic imaging
matched filtering
thermal coherence tomography
thermal-wave radar
photothermal radiometry
Advisor: Mandelis, Andreas
Assessment of Endothelial Function and Approaches to Prevent Ischemia and Reperfusion-induced Endothelial Dysfunction in Humans

The endothelium is an integral mediator of vascular homeostasis and a dysfunctional endothelium is now recognized as an early marker of atherosclerosis. Importantly, the non-invasive measurement of endothelial function by flow-mediated dilation (FMD) predicts future cardiovascular events. However, the appropriate method of its assessment and the mechanisms that govern FMD are still poorly understood. We investigated alternative parameters and methods of FMD measurement in healthy volunteers and cardiovascular disease patients. We found time to peak FMD to be highly variable both within and between individuals. Accordingly, continuous arterial diameter measurement post-cuff release was more sensitive in discriminating between health and disease compared to the measurement of diameter at 60’’ post-cuff release. Reperfusion to an ischemic tissue can paradoxically contribute to endothelial dysfunction development and further tissue damage, in a phenomenon known as ischemia and reperfusion (IR) injury. Previous exposure to sublethal ischemia (ischemic preconditioning (IPC)) can reduce sensitivity to IR injury and pharmacologic agents have since been shown to mimic this response. Using the FMD technique, we investigated various preconditioning strategies to prevent IR-induced endothelial dysfunction in the forearm vasculature of healthy volunteers. The sodium-hydrogen exchanger inhibitor amiloride and the angiotensin-converting enzyme inhibitor captopril were found not to provide endothelial protection from IR. In contrast, potent protection from IR-induced endothelial dysfunction was observed during the high-estrogen, late follicular phase of the menstrual cycle in pre-menopausal women. Finally, daily episodes of IPC were found to provide endothelial protection equipotent to an acute episode of IPC. The findings from the FMD methodological study highlight the importance of continuous arterial diameter measurement post-cuff deflation, and provide mechanistic insight that may contribute to measurement standardization and normalization. The results of the preconditioning studies improve our understanding of potential approaches to mitigate the detrimental effects of IR on the endothelium in humans.

Keywords: endothelial function
flow-mediated dilation
ischemia
reperfusion
Advisor: Parker, John
Poly(LA-co-TMCC)-graft-PEG Self-assembled Polymeric Nanoparticles for Targeted Drug Delivery

Polymeric nanoparticles have gained increased popularity for drug delivery as they not only overcome the problem of limited aqueous solubility of many hydrophobic drug molecules, but also have the potential to improve the pharmacologic properties of anticancer drugs by increasing their in vivo half-life. A series of biodegradable poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate), P(LA-co-TMCC), was first synthesized by Sn(Oct)2 catalyzed bulk polymerization. In order to obtain the polymer product with a better-defined composition, the polymer synthesis was improved by using organo-catalytic ring-opening copolymerization. The copolymer molar mass and composition were controlled by varying the monomer to initiator ratio and the monomer feed ratio. By grafting amine-terminated polyethylene glycol (PEG-NH2) to the carboxylate groups on the copolymer backbone, amphiphilic copolymers were formed and self-assembled to form nanoparticles with narrow size distribution. The nanoparticle size was observed to be influenced by the polymer composition and the self-assembly conditions. To gain greater insight into the stability of these nanoparticles in blood, they were tested in both fetal bovine serum and individual serum protein solutions. By encapsulating Förster resonance energy transfer (FRET) pairs and following their release by fluorescence, these micelles demonstrated strong thermodynamic and kinetic stability in the presence of serum. By incorporating functional groups (azide or furan) on the PEG chains, either cell adhesive peptides (i.e. alkyne-functionalized GRGDS) or targeting antibodies (i.e. maleimide-modified trastuzumab) were coupled to the surface of the nanoparticles through Huisgen 1,3-dipolar cycloaddition reaction or Diels-Alder chemistry, respectively. The GRGDS modified nanoparticles showed specific binding affinity to rabbit corneal epithelial cells that express αvβ1 integrin receptors.

Keywords: Polymeric nanoparticle
Drug delivery
Advisor: Shoichet, Molly
New Porphyrin Architectures for Biomedical Applications

From the green chlorophyll in plants and algae that we depend upon to transform sunlight into useful energy, to the red heme that carries oxygen to the cells in our bodies, porphyrins are the colors of life. It is not surprising then, that porphyrins have been actively interrogated as tools for diverse applications to improve biotechnology and medicine. With the goal of improving cancer therapy and diagnosis in mind, this thesis examines new modular porphyrin architectures. These constructs have interesting properties that extend beyond their originally intended use as phototherapeutic agents. In Chapter 1, a comprehensive background on porphyrin-based activatable photosensitizers is presented. In Chapter 2, porphyrin singlet oxygen and fluorescence quenching is examined in a model system with respect to Förster theory. Chapter 3 examines a new DNA responsive molecular beacon that was quenched using multiple quenching moieties and its application for nanoparticle aggregation. Chapter 4 describes extremely self-quenched nanovesicles formed from porphyrin-lipid conjugates that displayed a number of desirable properties for nanomedicine applications. Chapter 5 presents a brief discussion and some potential future directions of the research. It is my hope that the data presented in this thesis set the stage for new porphyrin-based approaches to make a translational impact in the battle against cancer and other diseases.

Keywords: Porphyrins
Photomedicine
Advisor: Zheng, Gang
Assessment of Endothelial Function in Humans and the Endothelial-protective Effects of 3-hydroxy-3-methylglutaryl coenzyme A Reductase Inhibitors

The endothelium plays an essential role in the regulation of vascular homeostasis and a state of endothelial dysfunction, which develops in the presence of cardiovascular risk factors, may contribute to the development and progression of cardiovascular disease. As such, the measurement of endothelial function, beyond being an experimental tool, may serve as an important tool to complement current risk assessment algorithms in the identification of high-risk patients. Flow-mediated dilation (FMD) is a non-invasive measure of peripheral conduit artery endothelial function that holds great promise. Presently, FMD suffers from methodological heterogeneity and a poor understanding of the various biological components involved in eliciting the dilatory response to a given shear stimulus. We compared both traditional and alternative methods of arterial diameter characterization with regards to their repeatability, nitric oxide-dependency, and their sensitivity in distinguishing between normal and dysfunctional endothelial responses. Our findings emphasize the importance of continuous arterial diameter measurement and suggest that the time to peak FMD is not a useful adjunctive measure of the FMD response. Given that endothelial dysfunction may be of clinical importance, strategies to correct it or prevent it from occurring may be of benefit. The 3-hydroxy-3-methylglutaryl coenzyme A inhibitors are agents that have demonstrated marked cholesterol-independent, endothelial-protective effects. We investigated the ability of rosuvastatin and atorvastatin to protect against endothelial dysfunction associated with ischemia and reperfusion (IR) injury, and chronic nitrate therapy. Using the FMD technique, we demonstrated, for the first time in humans, that acute rosuvastatin administration protects against IR-induced conduit artery endothelial dysfunction. Additionally, we demonstrated that this effect likely occurred by a cyclooxygenase-2-dependent mechanism, which may provide mechanistic insight into the observed cardio-toxicity with cyclooxygenase-2 inhibitors. In contrast, we observed that this endothelial-protective effect was lost upon sustained rosuvastatin administration, which may have important implications regarding the generation of sustained cardioprotective phenotypes. Finally, we demonstrated that atorvastatin co-administration prevented the development of tolerance and endothelial dysfunction associated with continuous transdermal nitroglycerin therapy in humans, likely through an antioxidant mechanism. Future studies are needed in disease patients to determine whether the concept of nitrate tolerance needs reconsideration in the presence of vascular-protective agents.

Keywords: Endothelial Function
3-hydroxy-3-methylglutaryl coenzyme A Reductase Inhibitors
Flow-mediated dilation
Statin
Advisor: Parker, John
Investigarion of Activated Phosphaidylinositol 3’ Kinase Signaling in Stem Cell Self-renewal and Tumorigenesis

The phosphatidylinositol 3' kinase (PI3K) pathway is involved in many cellular processes including cell proliferation, survival, and glucose transport, and is implicated in various disease states such as cancer and diabetes. Though there have been numerous studies dissecting the role of PI3K signaling in different cell types and disease models, the mechanism by which PI3K signaling regulates embryonic stem (ES) cell fate remains unclear. It is believed that in addition to proliferation and tumorigenicity, PI3K activity might also be important for self-renewal of ES cells. Paling et al. (2004) reported that the inhibition of PI3K led to a reduction in the ability of leukemia inhibitory factor (LIF) to maintain self-renewal causing cells to differentiate. Studies in our lab have revealed that ES cells completely lacking GSK-3 remain undifferentiated compared to wildtype ES cells. GSK-3 is negatively regulated by PI3K suggesting that PI3K may play a vital role in maintaining pluripotency in ES cells through GSK-3. By using a modified Flp recombinase system, we expressed activated alleles of PDK-1 and PKB to create stable, isogenic ES cell lines to further study the role of the PI3K signaling pathway in stem cell fate determination. In vitro characterization of the transgenic cell lines revealed a strong tendency towards maintenance of pluripotency, and this phenotype was found to be independent of canonical Wnt signal transduction. To assess growth and differentiation capacity in vivo, the ES cell lines were grown as subcutaneous teratomas. The constitutively active PDK-1 and PKB ES cell lines were able to form all three germ layers when grown in this manner – in contrast to ES cells engineered to lack GSK-3. The resulting PI3K pathway activated cells exhibited a higher growth rate which resulted in large teratomas. In summary, PI3K signaling is sufficient to maintain self-renewal and survival of stem cells. Since this pathway is frequently mutationally activated in cancers, its effect on suppressing differentiation may contribute to its oncogenicity.

Keywords: PI3K pathway
PDK1
myr-PDK1
PKB
PKB-DD
GSK-3
p70S6K
β-catenin
Axin-2
Wnt pathway
embyronic stem cells
pluripotency
self-renewal
Oct-4
cell fate
differentiation
embryoid bodies
teratoma formation
tumorigenesis
Akti-1/2
mTOR
rapamycin
endothelial cells
vascularization
proliferation
apoptosis
Flp-In system
isogenic cell lines
signal transduction
myristoylation
phosphomimetic
Advisor: Woodgett, James