VictorJuiz/thesis huggingface dataset:
N-glycosylated Proteomic Detection of Serum Biomarkers for High-grade Serous Ovarian Carcinoma

High–grade serous ovarian carcinoma (HGSC) is the most common and lethal subtype of gynecological malignancy in women. The current standard of treatment is cytoreductive surgery and adjuvant chemotherapy. Despite the efficacy of initial standard treatment, most patients develop recurrent cancer, and 70% of patients die within the 5–years of initial diagnosis. Cancer antigen 125, or Mucin–16 (CA125) is the current FDA approved biomarker used in the clinic for monitoring response to treatment and cancer recurrence. Although increasing levels of CA125 precede clinical symptoms of cancer recurrence, often “second–look” surgeries reveal microscopic and macroscopic tumors that are beneath the detection limits of CA125. I describe a two–stage strategy for discovery of serum biomarkers for earlier detection of cancer recur- rence. In the first stage, I detected 3693 N–glycosylated sites from sera and tumors of patient–derived xenografts (PDX) mice made from recurrent tumors. Using label–free shotgun–proteomics, I showed that HGSC tumor–associated proteins (CA125, MSLN) can be quantified in PDX sera. Following species– assignment and bio–informatic prioritization; targeted–proteomics based screening in the second stage revealed the presence of 27 candidates in longitudinal sera from HGSC patients. The refined targeted– proteomics quantification of the 27 targets in a second independent cohort of longitudinal sera accurately quantified four N–glycosylated proteins with tumor burden profiles of CA125 and earlier rise of the sig- nal. Interestingly, the four proteins are associated with biological functions in the extracellular matrix, which have been linked to cancer progression. Together, the results demonstrate the discovery of novel markers for cancer recurrence using a rational serum–biomarker discovery strategy, where initial targets are discovered in PDX mouse models and subsequently verified in longitudinal patient sera.

Keywords: Biomarkers
N-glycosylation
Ovarian cancer
Proteomics
Advisor: Kislinger, Thomas
Greener Big Data: Optimizing Data Exchange and Power Procurement for Data Centers

Big data is revolutionizing modern day life at an environmental cost due to the “ungreen” practices associated with the operation of data centers, a workhorse for big data processing. Turning the big data enterprise into a greener enterprise requires two fundamental steps. The first step is curtailing resource consumption, and making data centers energy efficient. The second step is using greener energy sources to power data centers. Big data processing has challenged the ability of data centers to operate in a greener fashion. In particular, the rise of the cloud and distributed data-intensive (“big data”) applications puts pressure on data center networks due to the movement of massive volumes of data. Reducing the volume of communication is crucial for embracing greener data exchange by efficient utilization of the resources. This thesis proposes the use of a mixing technique, spate coding, as a means of dynamically-controlled reduction in volume of communication. We introduce real-world use-cases, and present a novel spate coding algorithm for the data center networks. We also analyze the computational complexity of minimizing the volume of communication in a distributed data center application, and provide theoretical limits. Moreover, we proceed to bridge the gap between theory and practice by performing a proof-of-concept implementation of the proposed system in a real-world data center. We use MapReduce, the most widely used Big Data processing framework, as our target. Experimental results employing industry standard benchmarks show the advantage of our proposed system compared to the current state-of-the-art. Another important step in promoting green practices for the big data enterprise is reshaping the energy mix required to operate data centers. In this context, we consider power procurement for data centers while incorporating the green initiatives and cyber-physical constraints imposed by evolving power systems. Moreover, we consider implications of our formulation to solution complexity. We use the concept of matroid theory to model the problem as a combinatorial problem and propose a distributed and optimal solution. We account for communications and computational complexity and provide solutions for practical scenarios. In the end, we propose a futuristic cross-plane green orchestrator.

Keywords: Big Data
Cloud Computing
Data Center
Hadoop
Network Coding
Spate Coding
Advisor: N/A, N/A
Organizational structure and child welfare decisions: The influence of role specialization and service integration

The objective of this dissertation was to contribute to the understanding of child welfare organizations by testing the hypothesis that the characteristics of organizations influence decisions made by child protection staff for vulnerable children. Two aspects of organizational structure were examined: 1) role specialization, or the division of tasks to accomplish the mandate of the organization; and 2) service integration, or whether child welfare organizations and other services such as childrenâ s mental health are integrated. Other organizational factors proposed by the theoretical and empirical literature as salient to understanding child welfare decisions were included in the analyses (e.g., the location of the organization, service availability, etc.). The dissertation tests a theoretical framework that integrated the Decision-Making Ecology Framework (Baumann, Dalgleish, Fluke, Kern, 2011) and Yoo, Brooks, and Pattiâ s (2007) conceptual framework of organizational constructs as predictors of service effectiveness. Three decisions along the child protective services Decision-Making Continuum (Fluke, Baumann, Dalgleish, Kern, 2014) were examined: service referrals, provision of ongoing services, and placement in out-of-home care. Secondary data analysis of the Ontario Incidence Study of Reported Child Abuse and Neglect 2013 (OIS-2013) was conducted. A subsample of 4,949 investigations from 16 agencies was included in the multi-level models. The results confirm the importance of clinical factors to child welfare decisions. Organizational factors also influence decisions; specifically, investigations conducted at agencies with a specialist structure were less likely to include a service referral. Although structure did not influence the ongoing service decision, urban agencies were less likely than rural agencies to keep a case open following an investigation. Structure had no effect on the decision to place a child in out-of-home care, and there was no variance at the organizational level. The utility of the theoretical framework was demonstrated and should be applied to future studies. This dissertation contributes to the limited empirical evidence regarding the association between organizational structure and decisions.

Keywords: child welfare
decisions
organizations
service integration
specialization
structure
Advisor: Mishna, Faye
Fluke, John D.
Characterization of Mice with Altered Dopamine Transporter and Vesicular Monoamine Transporter 2 Levels

Dopamine is a key neurotransmitter that regulates motor coordination and dysfunction of the dopamine system gives rise to Parkinsonâ s disease. Nigrostriatal dopamine neurons are vulnerable to various genetic and environmental insults, suggesting that these cells are inherently at-risk. A cell-specific risk factor for these neurons is the neurotransmitter, dopamine itself. If intracellular dopamine is not appropriately sequestered into vesicles, it can accumulate in the cytosol. Cytosolic dopamine is highly reactive and can trigger oxidative stress, leading to cellular toxicity. Cytosolic dopamine levels are modulated by the plasma membrane dopamine transporter (DAT) that takes up dopamine from the extracellular space, and the vesicular monoamine transporter 2 (VMAT2) that stores dopamine into vesicles. In this thesis, we altered DAT and VMAT2 levels to investigate the detrimental consequences of potentially amplifying cytosolic dopamine in transgenic mice. Project 1 focused on selective over-expression of DAT in dopaminergic cells of transgenic mice (DAT-tg). DAT-tg mice displayed phenotypes of dopaminergic damage: increased dopamine-specific oxidative stress, L-DOPA-reversible fine motor deficits and enhanced sensitivity to toxicant insult, suggesting that increasing DAT-mediated dopamine uptake is detrimental for dopamine cells. As an extension of Project 1, Project 2 focused on mice that simultaneously over-express DAT and under-express VMAT2 (DAT-tg/VMAT2-kd mice). These animals were hypothesized to demonstrate exacerbated dopaminergic toxicity due to buildup of cytosolic dopamine caused by increased uptake and decreased packaging. While DAT-tg/VMAT2-kd mice displayed detrimental phenotypes (poor survival, decreased body weight, reduced dopamine tissue content and release) and compensatory changes (increased dopamine receptors and metabolism), they did not show dopamine cell loss. This is due to unexpected loss of phenotypes in DAT-tg mice from a new colony that no longer displayed dopaminergic neurodegeneration. Thus, instead of Parkinsonian behavior, DAT-tg/VMAT2-kd mice showed novel phenotypes such as hyperactivity and improved fine-motor and cognitive skills compared to other genotypes. DAT-tg/VMAT2-kd mice were also highly sensitive to amphetamine-induced locomotion. Hence, in the absence of neurodegeneration, altered DAT and VMAT2 levels produced unique behavioral changes in DAT-tg/VMAT2-kd mice, shedding light on the complex function of the dopamine system. Collectively, these studies demonstrate how perturbations in dopamine compartmentalization can impact dopamine homeostasis and behavior.

Keywords: Dopamine
Dopamine transporter
Transgenic mice
Vesicular monoamine transporter 2
Advisor: Salahpour, Ali
Novel Nation: Victorian Realism and the Fiction(s) of England

The idea that the Victorian novel—in particular, the Victorian realist novel—became an integral and transformational part of both individual and national identity in England during the nineteenth century provides the broad framework of my dissertation project. In “Novel Nation: Victorian Realism and the Fiction(s) of England,” I examine the careers, works, and public reception of four of the most celebrated authors—then and now—from the second half of the nineteenth century: Elizabeth Gaskell, Anthony Trollope, George Eliot, and Thomas Hardy. These authors, I suggest, saw themselves and were themselves seen as writing within a newly emergent, specifically English literary tradition that placed the novel as a genre, and their novels in particular, at the centre of a living national literature that was actively shaping the contours and character of the nation in very real and lasting ways. More specifically, I argue the representational claims to (and in some cases, denials of) “the real” that these authors made—particularly in relation to place—along with the critical constructions by reviewers and readers of these authors as cultural authorities and national icons, worked to shape a powerful new vision of the English nation as a fundamentally literary entity. By taking into account how the immediate reception of an author’s works influenced their subsequent writings, as well as how their writings influenced their readers, I examine the reciprocal, even porous relationship that existed between the Victorian novel and its readers—a relationship that reveals the seepage between fiction and reality that is at the core of this dissertation project. Thus, while my project examines the specific and varied ways in which these authors and their works imagined, engaged with, and challenged ideas of English national identity and the English nation, it is equally interested in exploring how they and their novels became (willingly or not) symbols and repositories of Englishness—how, that is, they became England’s national culture—and, more broadly, how the English nation became rooted in, realized through, and reimagined by such fictions so that England itself became a “Novel Nation.”

Keywords: Critical Reception
England
Imagined Geographies
National Identity
Realism
Victorian Novel
Advisor: Jaffe, Audrey
The Modulation of Endothelial Progenitor Cell Function by the Liver X Receptors

Atherosclerosis is a chronic disease that predisposes patients to myocardial infarction and is characterized by deposition of lipid-laden plaques in the aorta. These plaques arise after macrophages uptake modified cholesterol-rich lipoproteins. Bone marrow (BM) transplant experiments highlight the important anti-atherogenic effects of liver x receptors (LXRs) in promoting macrophage cholesterol efflux. However, transplantation of whole BM contains other cells, aside from monocytes/macrophages, including endothelial progenitor cells (EPCs), which facilitate endothelial repair through the release of vasoreparative factors. We hypothesized EPCs may also be involved in the anti-atherogenic response of LXRs by reducing endothelial defects during atherosclerosis. We first investigated the effects of Western diet (WD) feeding on disrupting hematopoietic balance in LXR-knockout (Lxr-/-) mice. Despite increased plasma cholesterol in both WT and Lxr-/- mice after WD feeding, myeloid progenitor and mature populations were increased only in the WD-fed Lxr-/- mice, whereas EPC numbers were significantly decreased. We demonstrated that increased cholesterol content of culture-derived EPCs from WD-fed Lxr-/- mice correlated with increased expression of endothelial markers, Cd144 and Vegfr2, and altered the release of factors that increased in vitro adhesion of monocytes to endothelial cells. We next evaluated the therapeutic potential of LXR activation in EPCs during atherosclerosis. Pharmacologic activation of LXRs during differentiation decreased the expression of Cd144 and Vegfr2 in WT EPCs. Analysis of the secretome by mass spectrometry revealed qualitative changes which resulted in decreased in vitro monocyte-endothelial adhesion. Tail vein administration of conditioned media from agonist-treated EPCs to Ldlr-knockout mice resulted in decreased adhesion molecule expression (VCAM-1), leukocytes (CD45), and lesion area in the aortic sinus. Together, these data support important roles for LXRs in i) regulating the numbers and function of EPCs; ii) preserving the balance of EPCs relative to pro-atherogenic myeloid populations; and iii) producing a secretome from culture-derived EPCs that elicits anti-atherogenic effects.

Keywords: Atherosclerosis
Cholesterol
Endothelial progenitor cell
Hematopoietic stem cell
Liver x receptor
Advisor: Cummins, Carolyn L.
On the Matter of the Digital in Contemporary Media Art

This dissertation brings together aesthesis, media art and theory to explore how contemporary media artists are aestheticizing, conceptualizing and grappling with “digital materiality” through their artworks and practices of making. It stems from a series of process-oriented interviews conducted with thirty-three contemporary media artists from across North America and Europe. Responding to prominent themes that emerged through a triangulated analysis of the interviews, corresponding artworks and media theory, the dissertation offers grounded accounts of five coinciding strategies that artists are enacting in an effort to make sense of the materiality of the digital. Developed over five substantive chapters, these key areas of material analysis include: the materiality of glitch; the indexical materialism of digital surfaces; the treatment of digital materiality as a matter of “resolutions”; the transpositional concretization of “formal materialism” in Post-Internet Art; and the deployment of “synesthetic catachresis” as a means of grasping at modes of materialism that remain definitionally evasive. While each chapter maps out a different perspective on materiality, the driving intention of the dissertation is to advance an overarching aesthetic approach that moves beyond hardware/software distinctions to provide needed perspective on the material dynamism of contemporary digital processes.

Keywords: Arts-Based
Digital
Materiality
Media Art
Mediat Theory
Advisor: Dallas, Constantinos
The role of FAK and related signalling in adipocytes and the pathogenesis of obesity and diabetes

Obesity and diabetes, key elements of the metabolic syndrome, are fast expanding global epidemics. While obesity is the strongest risk factor for type 2 diabetes, most obese people do not develop diabetes, and many people with diabetes are not obese. This suggests a complex relationship between excess body weight, primarily adipose tissue, and diabetes, characterized by insulin resistance. Adipocyte cell death has been hypothesized to be an initiating factor in chronic, obesity-associated inflammation thought to lead to insulin resistance and diabetes, but the mechanisms regulating this process remain poorly understood. Thus, in this work, I sought to better understand the cell survival pathways regulating adipose tissue and its role in glucose and energy homeostasis. Focal adhesion kinase (FAK) plays a central role in integrin signaling which regulates growth and survival of tumors, but its role in growth in other contexts is less well known. In Chapter IV, I find that FAK is increased in adipose tissue of mice and humans with obesity and insulin resistance. Using adipose tissue-specific FAK knockout mice I report that FAK in adipose tissue is required to maintain insulin sensitivity, particularly in the setting of metabolic stress induced by high fat diet feeding or genetic models of obesity. In Chapter V, I demonstrate that disruption of FAK impairs adipocyte survival both in vitro in 3T3-L1 adipocytes and in vivo, contributing to inflammation and insulin resistance, which can be attenuated by pharmacologic or genetic inhibition of apoptosis. In Chapter VI, I further identify the specific role of apoptotic protein caspase 8 in adipose tissue regulation of glucose and energy homeostasis. I show that disruption of caspase 8 improves glucose tolerance and protects from weight gain in mouse models of obesity and insulin resistance. Our results identify novel roles for FAK in promoting adipocyte survival and insulin sensitivity with metabolic stress, whereas caspase 8 promotes cell death and inflammation contributing to insulin resistance with metabolic stress. Characterizing the interplay of specific signaling pathways helps us to better understand the complex interaction between obesity and diabetes. These findings improve our knowledge of the signaling pathways regulating adipose tissue and their role in obesity, diabetes and metabolic syndrome.

Keywords: adipose tissue
caspase
diabetes
focal adhesion kinase
obesity
Advisor: Woo, Minna
Comparing Patient Engagement and Patient Advocacy Activities and Measuring Preferred Roles in Medical Decision Making among Cystic Fibrosis Patients, Caregivers, Family Members and Patient Advocates

Background: Patient engagement has become a priority for healthcare organizations, yet remains inconsistently defined. Patient engagement has also become a priority for healthcare providers. Current discourse suggests that patients today desire more control over medical decision making than ever before, and that the proliferation of online health information is empowering patients to make autonomous medical decisions. Yet, prior research indicates that patients typically prefer to share decisions with their physician, raising questions about what patient engagement is and whether preferences have changed over time. Methods: This study addresses multiple research questions using three phases of data collection. Phase one asked: how are ‘patient engagement’ and ‘patient advocacy’ defined and perceived by individuals who are involved in engagement and advocacy activities? This question was addressed by conducting semi-structured key informant interviews (N=11). Phases two and three examined preferred roles in medical decision making among cystic fibrosis (CF) patients, caregivers, family members and patient advocates, and whether these roles were related to: trust in the physician, self-assessed health information literacy and demographics. Phase two involved conducting a quantitative cross-sectional survey (N=165), which included three scales: the Problem-Solving Decision-Making Scale (PSDM), the Trust in Physician Scale (TPS), and the electronic Health Information Literacy Scale (eHEALS). T-tests and logistic regressions were computed to determine the relationships between variables. Phase three involved interviewing a subgroup of survey participants to help to explain survey results (N=19). Thematic analysis was used to identify common themes. Results: Our findings suggest that patient engagement and advocacy have multiple meanings, that most survey participants preferred to share medical decisions with their physician (>80%), and that self-assessed health information literacy was associated with preferred roles; as eHealth literacy went down, so did desire for participation in making medical decisions. Follow-up interviews supported these results; participants mentioned how they assessed the credibility of online health information and how they preferred to direct questions to their physician. Conclusion: This research highlights the need for clear language regarding patient engagement activities. This study also suggests that eHealth literacy may influence decision making preferences, and that preference for autonomous decision making should not be assumed.

Keywords: cystic fibrosis
medical decision making
patient advocacy
patient engagement
Advisor: Deber, Raisa