VictorJuiz/thesis huggingface dataset:
Mesenchyme Induces Embryonic and Induced Pluripotent Stem Cells to a Distal Lung Epithelial Cell Phenotype

Derivation of lung epithelial cells from stem cells remains a challenging task, due in part to a lack of understanding of the molecular mediators driving commitment of endoderm to an early lung lineage. Reciprocal signalling between the lung mesenchyme and epithelium is crucial for proper differentiation and branching morphogenesis to occur. We hypothesized that the combination of signalling pathways comprising early epithelial-mesenchymal interactions and the 3-D spatial environment are required for induction of embryonic and induced pluripotent stem cells (ESC and iPSC, respectively) into a lung cell phenotype with the hallmarks of the distal niche. Aggregating early lung mesenchyme with endoderm-induced ESC and iPSC resulted in differentiation to an NKX2.1 and pro-SFTPC positive lineage. The differentiating cells organized into tubular structures and became polarized epithelial cells. Ultrastructure analysis revealed precursors of lamellar bodies, and Sftpb mRNA expression was detected. Quantification of the differentiation using an Nkx2.1-reporter ESC line revealed that 80% were committed to an early lung lineage, a vast improvement over what has previously been published. The FGF growth factor family comprises well-known mediators of growth and differentiation during the development of many organs, including the lung. We found that FGF2 signalling through the FGFR2iiic receptor isoform was mediating the commitment of the stem cells to an early lung epithelial phenotype, as defined by NKX2.1/proSFTPC expression. FGF7 signalling through the FGFR2iiib receptor was found to be important for the maturation and morphogenesis of the NKX2.1/proSFTPC positive lineage, but did not play a role in the initial commitment. The addition of FGF2 to endoderm-induced ESC or iPSC in the absence of mesenchyme was able to commit the cells to an NKX2.1-positive lineage, but no proSFTPC was detected. Furthermore,the cells did not become polarized and no longer organized into tubular structures. These findings suggest that while FGF2 is important for initial commitment, additional mesenchyme components including matrix proteins, supporting cell lineages and other growth factors are crucial for an efficient differentiation to an early lung epithelial cell lineage.

Keywords: Lung Development
embryonic stem cells
Induced Pluripotent Stem cells
Advisor: Post, Martin
Bioinformatics Approaches to Biomarker and Drug Discovery in Aging and Disease

Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed the landscape of aging and disease biology. They have revealed novel molecular markers of aging, disease state, and drug response. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and the underlying biology of aging and disease is heterogeneous and complex. Methods from integrative computational biology can help diminish these challenges by creating new analytical methods and software tools that leverage the large and diverse quantity of publicly available HTP data. In this thesis I report on four projects that develop and apply strategies from integrative computational biology to identify improved biomarkers and therapeutics for aging and disease. In Chapter 2, I proposed a new network analysis method to identify gene expression biomarkers of aging, and applied it to study the pathway-level effects of aging and infer the functions of poorly-characterized longevity genes. In Chapter 4, I adapted gene-level HTP chemogenomic data to study drug response at the systems level; I connected drugs to pathways, phenotypes and networks, and built the NetwoRx web portal to make these data publicly available. And in Chapters 3 and 5, I developed a novel meta-analysis pipeline to identify new drugs that mimic the beneficial gene expression changes seen with calorie restriction (Chapter 3), or that reverse the pathological gene changes associated with lung cancer (Chapter 5). The projects described in this thesis will help provide a systems-level understanding of the causes and consequences of aging and disease, as well as new tools for diagnosis (biomarkers) and treatment (therapeutics).

Keywords: bioinformatics
aging
biomarkers
genomics
Advisor: Jurisica, Igor
Bases for Invariant Spaces and Geometric Representation Theory

Let G be a simple algebraic group. Labelled trivalent graphs called webs can be used to produce invariants in tensor products of minuscule representations. For each web, a configuration space of points in the affine Grassmannian is constructed. This configuration space gives a natural way of calculating the invariant vectors coming from webs. In the case of G = SL_3, non-elliptic webs yield a basis for the invariant spaces. The non-elliptic condition, which is equivalent to the condition that the dual diskoid of the web is CAT(0), is explained by the fact that affine buildings are CAT(0). In the case of G = SL_n, a sufficient condition for a set of webs to yield a basis is given. Using this condition and a generalization of a technique by Westbury, a basis is constructed for SL_n. Due to the geometric Satake correspondence there exists another natural basis of invariants, the Satake basis. This basis arises from the underlying geometry of the affine Grassmannian. There is an upper unitriangular change of basis from the basis constructed above to the Satake basis. An example is constructed showing that the Satake, web and dual canonical basis of the invariant space are all different. The natural action of rotation on tensor factors sends invariant space to invariant space. Since the rotation of web is still a web, the set of vectors coming from webs is fixed by this action. The Satake basis is also fixed, and an explicit geometric and combinatorial description of this action is developed.

Keywords: Mathematics
Invariants
Representations
Geometry
Advisor: Kamnitzer, Joel
Harnessing Mitochondria-penetrating Peptides for the Organellar Delivery of Small Molecule Drugs

Mitochondria play essential roles in numerous cellular processes, including oxidative phosphorylation and apoptotic initiation. As a result, organellar dysfunction has been implicated in several pathologies such as cancer, diabetes and neurodegenerative diseases. The opportunity to deliver compounds to probe or treat these conditions would be highly beneficial but accessing this organelle is challenging. Prior work investigated the physicochemical properties required for mitochondrial targeting and yielded mitochondria-penetrating peptides (MPPs). MPPs possess hydrophobic and cationic character and exhibit efficient cellular uptake and mitochondrial localization. In this proof-of-principle study, MPPs were harnessed to re-route an anti-leukemia agent, chlorambucil (Cbl), from the nucleus to mitochondria. This DNA alkylating agent was selected for its rapid kinetics and facile conjugation to an MPP. In addition, because mitochondria possess their own genome, the target of this drug would also be present in the organelle. Conjugation of an MPP to Cbl (mt-Cbl) confirmed that the drug was re-routed to the mitochondria and an increase in potency was observed in several cell lines and patient samples. This gain in activity was due to the increased accessibility of the mitochondrial genome, its lack of introns and its limited repair capacity. However, despite this enhanced toxicity, a therapeutic window continued to be maintained due to the elevated mitochondrial membrane potential in cancer cells. The re-routing of Cbl also resulted in evasion of several drug resistance mechanisms. Damage directly within the organelle was sufficient to initiate apoptosis even in cell lines with disabled apoptotic triggering. In addition, mitochondrial sequestration protected mt-Cbl from drug inactivation mechanisms. Lastly, mt-Cbl inhibited Pgp efflux by unexpectedly interacting with the pumps and inhibiting activity for a short period of time. The anti-cancer activity of mt-Cbl was also assessed in vivo in xenograft models of leukemia. The conjugate was stable in mouse plasma and displayed an improved pharmacokinetic profile. In addition, mt-Cbl successfully delayed tumor growth in two xenograft models and continued to alkylate mitochondrial DNA in vivo. These studies demonstrate that MPPs can be harnessed to re-route drugs to this organelle. Mitochondrial re-targeting could be a novel method of re-purposing FDA-approved drugs to enhance activity and evade resistance.

Keywords: mitochondria
chlorambucil
targeting
Advisor: Kelley, Shana O.
Molecular and Cellular Mechanisms of the Angiogenic Effect of Poly(methacrylic acid-co-methyl methacrylate) Beads

Poly(methacrylic acid -co- methyl methacrylate) beads were previously shown to have a therapeutic effect on wound closure through the promotion of angiogenesis. However, it was unclear how this polymer elicited its beneficial properties. The goal of this thesis was to characterize the host response to MAA beads by identifying molecules of interest involved in MAA-mediated angiogenesis (in comparison to poly(methyl methacrylate) beads, PMMA). Using a model of diabetic wound healing and a macrophage-like cell line (dTHP-1), eight molecules of interest were identified in the host response to MAA beads. Gene and/or protein expression analysis showed that MAA beads increased the expression of Shh, IL-1β, IL-6, TNF-α and Spry2, but decreased the expression of CXCL10 and CXCL12, compared to PMMA and no beads. MAA beads also appeared to modulate the expression of OPN. In vivo, the global gene expression of OPN was increased in wounds treated with MAA beads, compared to PMMA and no beads. In contrast, dTHP-1 decreased OPN gene expression compared to PMMA and no beads, but expressed the same amount of secreted OPN, suggesting that the cells decreased the expression of the intracellular isoform of OPN. Interestingly, MAA beads had no effect on the expression of pro-angiogenic growth factors VEGF, bFGF and PDGF-B in vivo or in vitro, suggesting that MAA beads do not induce angiogenesis by simply increasing the expression of pro-angiogenic factors, but use more subtle mechanisms. It was hypothesized that these mechanisms may involve modulation of toll-like receptor signaling in macrophages interacting with the protein layer adsorbed on to MAA beads, in a manner distinct from PMMA beads and no beads. Taken together, the results suggest that MAA beads promote angiogenesis through increased expression of Shh, decreased expression of CXCL10 and modulation of the expression of OPN, but not through increased expression of typical pro-angiogenic growth factors. The resulting vessel-rich “alternative foreign body reaction” has exciting clinical implications as the polymer itself was found to exert a therapeutic effect in the absence of bioactive components or transplanted cells. Understanding the mechanism could lead to new applications for this material and others designed on similar principles.

Keywords: Biomaterial
Wound healing
Host response
Angiogenesis
Advisor: Sefton, Michael
Including Women: The Establishment and Integration of Canadian Women’s History into Toronto Ontario Classrooms 1968-1993

Social movement activism throughout the 1960s and 1970s provided space for feminist concerns in a variety of arenas. Women's movement activism and women's scholarship in history challenged the ways in which women’s experiences had been marginalized or omitted in school history programs and curricula. Women's organizations developed and broadened networks, created and published resources, and lobbied governments and institutions. Their widespread activism spilled into a range of educational circles and influenced history teachers in altering curricula to include women in course materials. Advocating for women, on a curricular or professional development level, however, was complicated because of entrenched neo-liberal systems in place within education institutions. Although the Ontario Ministry of Education and the Toronto Board of Education demonstrated clear support for a wide range of gender equity-based initiatives, they committed to implementing a 'piecemeal' approach to curricular change. The fundamental work to include women in history curricula relied heavily on grassroots networks that allowed for women’s experiences to leak into classrooms, and were responsible for bringing women’s voices into the history curricula. This study explores the initiatives of the Toronto Board of Education from 1968-1993, with particular analysis of women’s committees, teacher/librarians in resource centers, Affirmative Action representatives, individual teachers and administrators. Within the broader public sphere, the contributions of concerned parents, activists, small independent publishers, educational reformers, political leaders and women’s history organizations lent their voices to ideas about how the inclusion of women in history curricula should take shape in Toronto schools. Ministry gender equity policies and history course guidelines provided incremental and therefore politically safe responses to educational change. The Toronto Board's "add-on" approach to including women in course examinations avoided instituting major "top-down'" curricular change, which kept the integration of women’s history within classrooms on the periphery of most course work. The substantive grassroots activism and the commitment of women’s organizations and individual teachers, however, allowed women’s history to flourish within individual classrooms in Toronto and demonstrates the ways in which "bottom-up" initiatives can be a powerful force in curricular change.

Keywords: History
Education
Curriculum
Women's Studies
Advisor: Sandwell, Ruth W.
Controlled, Encouraged or Adrift? Sources of Variation in Adolescent Substance Use

The frequent consumption of alcohol and cannabis by youth poses both concern and ambivalence to society about the nature of the problem and how to respond. In the last few decades, social science research has devoted considerable attention to substance use among youth, making it an important issue to consider; however, controversy abounds when considering where consumption patterns of youth fall on a continuum from normal to deviant. Central to these debates is the social acceptability of the substances being used, their legal status, the frequency with which they are consumed, and the particular groups most often engaged in their use. Youth who consume alcohol are viewed with less trepidation than those who consume cannabis. Moreover, those who use either substance recreationally or experimentally are deemed to be more typical than those who have escalated their use to more regular or frequent episodes. Finally, drug-using youth who are embedded in conventional society are viewed more positively than those who occupy the margins of society, such as those who are delinquent or homeless. To fully understand the debate about the deviancy versus the normalcy of adolescent substance use, more inclusive approaches that take into account structural, individual and situational explanations are needed; however, existing studies fail to consider all of these influences. Instead, there is debate about the dominance of each of these explanations. This dissertation examines and tests these competing representations and explanations of adolescent substance use by drawing on multiple sociological theories of deviance including control theories, differential association theory, routine activity approaches, and drift theory. Using a combined sample of high school students and street youth, the findings suggest that adolescent substance use is far too complex to be explained by only one theory. Instead, explanations for the variations in substance use must take into account both individual backgrounds and more immediate situational influences. Most importantly, individual beliefs about substances are an important and often ignored aspect of individual substance use patterns.

Keywords: adolescence
alcohol
cannabis
social bonds
social influences
leisure activities
Advisor: Erickson, Patricia
Tanner, Julian
Breaking the Weak Governance Curse: Global Regulation and Governance Reform in Resource-rich Developing Countries

There is growing consensus that unless resource-rich developing countries improve their domestic governance systems, rising exploitation of mineral, oil and gas resources may result in long-term adverse developmental outcomes associated with the “resource curse”. Despite the consensus, reforms do not abound. This dissertation investigates the obstacles to such reforms, and the mechanisms and strategies that can possibly overcome these obstacles. I argue that two trapping mechanisms are binding these countries to a “weak governance curse”. One mechanism is the phenomenon of path dependence, which makes a dysfunctional governance path initiated at a past historical juncture resistant to change over time. The other mechanism is rent-seeking behaviour associated with high resource rents, which creates perverse incentives for political and economic actors to resist reforms. The Law and Development literature has recently produced a rich body of knowledge on governance reform in developing countries, yet it has largely neglected the potential role of innovative global regulatory mechanisms, beyond development assistance, in this process. I argue that this evolving literature ought to draw from global regulation studies to investigate the interaction between unconventional global regulatory mechanisms and domestic governance reform. In this thesis I analyze whether extraterritorial home country regulations, such as anti-bribery, anti-money laundering and securities disclosure regulations, and transnational public-private partnerships, such as the Extractive Industries Transparency Initiative, may offer institutional opportunities for external and internal actors to facilitate policy reforms in resource-rich and governance-poor countries. My conclusion is twofold. First, there is reason for cautious optimism regarding the potential for unconventional global regulatory mechanisms to provoke positive feedback effects in domestic governance reform. These mechanisms can open innovative institutional pathways of influence to outsiders and insiders promoting governance reform. Second, instead of searching for a regulatory silver bullet, the most promising way to promote reforms in resilient dysfunctional governance systems is to make use of the wide range of conventional and unconventional mechanisms available. A constellation of regulatory instruments opens up the possibility for outside and inside reformers to benefit from a different policy mix of available mechanisms, depending on the specific circumstances of a given country at a particular time.

Keywords: law
development studies
international relations
global regulation
law and development
path dependence
resource curse
least developed countries
natural resources
governance
institutions
economic development
global governance
developing countries
rule of law
rent-seeking
Advisor: Trebilcock, Michael
Prado, Mariana Mota
Tending to the “Flower of Capitalism:” Consuming, Producing and Censoring Advertising in South Korea of the '00s

My dissertation examines discourses and practices that surrounded consumption and production of advertising in South Korea in the first decade of the 21st century. In its approach, my study breaks away from works that assume that advertising performs the same role universally and that local advertising industries should follow the uniform path of development, in terms of both creative content and industry structures. Treating advertising as an integral part of social reality, I embed my analysis in Korea's idiosyncratic social, cultural, political, and economic contexts to interrogate non-marketing functions of advertising. My dissertation investigates multiple projects that advertising mediates in contemporary South Korea, from challenging social norms and renegotiating cultural meanings, to contesting capitalist control over mass media and articulating fantasies of humanist capitalism. I explore how advertising consumers (including advertising censors) and advertising producers channel, shape, enable or block the flows of advertising messages and revenues. My conclusion is that, in South Korea, the marketing instrumentality of advertising is subordinated to the ethos of public interest, and both advertising consumers and producers strive for advertising that promotes humanist values and realizes democratic ideals, even if it jeopardizes the commercial interests of advertisers. Theoretically, this study builds on critical theory and anthropology of media while drawing on Korean Studies scholarship to grasp interconnections between the practices of advertising production and consumption, on the one hand, and, on the other, the modern entanglements of capitalism and democracy. Methodologically, I combine a discourse analysis of advertising-related public texts—popular advertising campaigns, responses to them in mass media and the blogosphere as well as the exhibits of the Advertising Museum in Seoul—with ethnographic fieldwork at two sites, an advertising agency and a quasi-government advertising review board, both in Seoul.

Keywords: South Korea
advertising
anthropology of media
publics
Advisor: Schmid, Andre
Search for Universal Extra Dimensions in the Two Photon and Missing Transverse Energy Final State with the ATLAS Detector

A search for diphoton events with large missing transverse energy is conducted using 3.1 pb^{-1} of integrated luminosity of proton-proton collisions at center of mass energy \sqrt{s}=7 TeV. The data were collected with the ATLAS detector at the CERN Large Hadron Collider during the period from March 30, 2010 until August 30, 2010. No excess of such events is observed above the Standard Model background prediction. This result is interpreted in the context of a gravity mediated One Universal Extra Dimension model with \Lambda R=20, N=6 and M_{D}=5 TeV, where \Lambda is the cutoff scale, N is the number of large extra dimensions and M_{D} is the Planck scale in the higher dimensional theory. The compactification radius of the Universal Extra Dimension, R, is excluded for values of 1/R < 728 GeV at 95\% CL, providing the most stringent limit on this model at the time of publication.

Keywords: LHC
Extra Dimensions
ATLAS
Diphoton
Missing Transverse Energy
Advisor: Orr, Robert S.