VictorJuiz/thesis huggingface dataset:
Novel Machine Learning Models for Identification, Characterization and Prioritization of Phenotype-Genotype Associations

This thesis is centered on the broad problem of inferring, characterizing and prioritizing molecular and functional phenotype effects of genetic variants. I first investigate the problems caused by phenotype heterogeneity in association studies of complex traits. Many complex diseases, such as autism, diabetes and cancer, are very heterogeneous in terms of the realized phenotypes, i.e. individuals diagnosed with the same disease might experience substantially different symptoms. I introduce the JBASE: Joint Bayesian Analysis of Subphenotyping and Epistasis model, which simultaneously accounts for non-additive interactions and phenotype heterogeneity while searching for associations. Next, inspired by the hypothesis that some phenotypes can be better explained by additive (small) effects of a large number of variants, I investigate the applicability of sparse supervised learning models for association studies of complex traits. In particular, I investigate integrative machine learning models that can leverage additional biological knowledge about phenotypes and genetic variants while searching for genetically informed associations. Towards this goal I present AAALasso: Accounting for Antagonistic Associations in Lasso, a novel sparse additive multi-task learning model that takes network structured information between markers and phenotypes into account. While identifying variants associated with a phenotype is important, being able to validate them by establishing causal biomolecular links is equally important. As such, in the last part of this thesis, I focus on the problem of predicting stability effects of non-synonymous coding mutations as a tool for the prioritization of variants discovered in association mapping studies. I introduce ELASPIC: Ensemble Learning Approach for Stability Prediction of Interface and Core mutations, a supervised ensemble learning approach to accurately predict effects of non-synonymous single nucleotide polymorphisms (SNPs) on protein stability and, for the first time, on protein-protein binding affinity. Overall, this thesis proposes three new complementary machine learning models for inferring, characterizing and prioritizing the phenotype effects of genetic variants. The first two approaches propose novel tools for finding underlying variants of a given phenotype, whereas the third approach focuses on predicting the molecular effects of the discovered variants.

Keywords: Genome variation
Genome Wise Association Studies
Genomics
GWAS
Machine Learning
Phenotype variation
Advisor: Kim, Philip M
Brudno, Michael
Essays on Organizational Strategy and Social Networks

This dissertation proposes that the success of organizational strategic change is influenced by the reconfiguration of the interpersonal interactions among individual members, and that the reconfiguration is influenced by individual preferences for the strategic change. It is the contention of the three chapters that self-interested actors may possess different understandings of, and preferences for, the strategic choices of leaders. The main argument of this dissertation asserts that individual preference for the implementation of organizational strategy differentially motivates the search behavior of individuals as they self-organize and interact with others in the organization. The outcome of this search is a network of interactions that affects the success of the strategic change through performance adjustments by both leaders and individuals. A dynamic agent-based network simulation and a supporting empirical study are used in support of this argument to investigate the relationship between an organization’s strategy choice, the emergent internal interpersonal network, and the success of organizational strategic change.

Keywords: computational models
informal networks
organizational identity
organizational strategy
social networks
strategic change
Advisor: McEvily, Bill
A Concord of Alchemy with Theology: Isaac Newton's Hermeneutics of the Symbolic Texts of "Chymistry" and Biblical Prophecy

That early modern natural philosophers such as Isaac Newton were deeply preoccupied by religious concerns, which were entwined with their study of nature, has become—at last—a fairly uncontroversial commonplace. In the area of the relationship between Newton’s natural philosophy, alchemy, and theology, Dobbs’ Janus Faces of Genius has had an enduring impact. However, the new historiography of alchemy and insights gained from the application of book history to the history of science—particularly the bookishness of alchemy—require Newton’s alchemy and theology to be revisited. Accordingly, this dissertation makes two main arguments: 1) Specific connections between Newton’s alchemy, or, to use the more inclusive term, “chymistry”, and his theology can be found by considering Newton’s methods of interpreting symbolic texts—as opposed to searching for specific unity of subject matter. Analysis of Newton’s textual research methods reveals his cross-comparative organization of textual sources and his particular descriptive-translational approach to symbolic texts: figurative alchemical texts and the prophetic texts of the Bible. 2) General connections between Newton’s chymistry and theology can be seen as his overall trend to incorporate statements of God into his natural philosophy was specifically manifested in physico-theological and divine metaphysical arguments that he built from chymical phenomena in his optical writing, particularly the Queries to the Opticks. The dissertation develops these arguments through analysis of Newton’s reading practices, evidenced by his particular method of dog-earing the books he owned and his organizational lists of hermeneutical rules and figurative vocabulary. Additionally, it analyses Newton’s integration of chymical sources and experimentation into his published optical work and its accompanying natural-philosophical discourse of God. While the necessary connectedness of Newton’s thought, the “unified mind” thesis articulated by Dobbs, may no longer be a viable way of conceiving Newton’s various intellectual (and practical) pursuits, this does not mean that they were unrelated. On the contrary, a uniquely textual connection can be seen within Newton’s work with the symbolic texts of alchemy and prophecy: his descriptive-translational approach. Moreover, Newton’s well-documented integration of matter theory and concepts of God are revealed to have an essential foundation in alchemical experimentation and theory.

Keywords: Alchemy
Bible
Book History
Chemistry
Hermeneutics
Isaac Newton
Advisor: Fehige, Yiftach
Experiencing the State: The Making of Falangaw Amis Community in Taiwan

Seeing the state as an idea and as apparatus which intervenes in people’s lives, this thesis addresses how the Falangaw Amis people of Taiwan have experienced these two dimensions of the state since 1896. This thesis presents how the Amis reflexively use these experiences to fulfill their project of community construction when being in a situation of fragmentation and marginality. After introducing Falangaw Amis people’s original and transformed concepts regarding historicity, the body/person/self, and different sorts of social relatedness, this thesis demonstrates how they have experienced the state in their ordinary daily life and on some extraordinary occasions such as stage performances, baseball games, and political festivals. Specifically, in response to the state idea and apparatus, Falangaw Amis people present a modern version of genesis that contains symbols of the state; a new concept of the body that relates to the statist hierarical value system; and use faki (MB) to connect and maintain different sorts of social relatedness when facing state regulations. This thesis emphasizes that to understand the interaction between the margin and the center from a bottom-up perspective, we need to examine Taiwan’s peculiar statehood and Falangaw Amis people’s being conditioned by it. However, even in such a disadvantaged situation, Falangaw Amis people still gain some knowledge of the state in their practices and experiences, and materialize the knowledge to fulfill the task of community construction. Moreover, not only does the result of their community construction illustrate how the Falangaw Amis claim the indigenous citizenship after negotiating with the power of state idea and apparatus, it also reveals how they give positive feedback to the schismatic colonial state system and the country’s hardship in order to survive in global politics. In a word, when it comes to indigenous-state relation, the researcher should go beyond the rigid model of regulation from above and resistance from below. Instead, by taking the Falangaw Amis as an example, this thesis shows how complicated power relations sometimes counteract each other and sometimes connects things together in multi-dimensional ways and the surprising results of the connections and counteractions.

Advisor: Luong, Hy van
Li, Tania Murray
Multi-tasking in Adults with Traumatic Brain Injury: Examining the Impact of Concurrent Motor and Cognitive tasks

After moderate-severe traumatic brain injury (TBI), community reintegration is a well-documented challenge. A focus of this dissertation is the role of balance in community integration: Balance impairments, shown to correlate with poorer community integration, are a common and enduring consequence of TBI; moreover, even in patients who appear to be well-recovered in balance control, residual impairment can be revealed when examined with multi-tasking paradigms. Multi-tasking is a particularly important capacity for community integration because so many activities that enable people to successfully engage in the community require concurrent performance of motor and cognitive tasks. To date, limited research has examined static postural control and cognitive performance after moderate-severe TBI, and no studies have examined postural control in the context of facial emotion perception (FEP). However, this combination is particularly relevant to community integration because many inter-personal activities (e.g., having coffee with a friend, speaking with an employer) require both. Therefore the overall aims of this dissertation were to examine the relationship between multi-tasking and community integration, and better characterize multi-tasking impairment after TBI, employing postural control measures designed to simulate real-world functioning plus a conventionally used cognitive test (the Stroop), and a newly developed measure of FEP designed to provide a more ecologically valid assessment of this capacity in TBI. We first demonstrated that balance correlated with early, but not later community integration, and balance functioning that necessitated multi-tasking in the earlier stages of recovery correlated with community integration in the later stages. We developed an FEP task using an indirect test format to permit implicit processing that employed dynamic faces and provided environmental context; we demonstrated preliminarily that it was feasible for brain-injured adults. Finally, in comparing adults with TBI to controls, we found that when combining postural control and Stroop tasks, only postural control was affected in TBI. These findings extended to the indirect FEP task. Taken together, the findings suggest that early identification of multi-tasking impairment and targeted intervention might improve long-term community integration. Further research is required to better understand the mechanisms that underlie multi-tasking impairment after TBI in order to design such targeted interventions.

Advisor: Green, Robin E.A.
McFadyen, Bradford J.
UV-advanced Oxidation Treatment of Micropollutants in Secondary Wastewaters

Ultraviolet light+hydrogen peroxide (UV/H2O2) advanced oxidation is known to effectively oxidise micropollutants in wastewater. Its relatively high cost and energy requirements in comparison to other treatment options, however, have limited its implementation. This research evaluated the use of coagulation as a modification to the pre-tertiary component of the wastewater treatment process. The objective was to reduce the background scavenging capacity of the wastewater as a means of improving the oxidation efficiency of UV/H2O2 while reducing the cost and energy requirements. Effluent organic matter (EfOM) was identified as the primary wastewater component responsible for scavenging of the hydroxyl radicals required for oxidation in UV/H2O2 treatment. The organic constituents of EfOM that are the driving force for its reactivity with the hydroxyl radical were identified as the high molecular weight components (biopolymers) and tryptophan-protein like components. Since EfOM concentration and composition can vary from one water matrix to another, a comparison of secondary wastewaters from membrane bioreactor (MBR) and activated sludge (AS) treatment systems showed that the average scavenging capacity of the AS systems exceeded the average of the MBRs such that MBRs may be more amenable to UV/H2O2 treatment. Coagulation of the wastewater using ferric chloride, aluminium sulphate, and polyaluminium chloride primarily removed the high molecular weight components and significantly reduced the EfOM scavenging capacity. This improvement in wastewater quality also resulted in an improvement in the degradation rates of micropollutant compounds, reduced the energy requirements required to achieve 1-log removal of the compounds, and significantly reduced the costs associated with the UV/H2O2 system. No one coagulant outperformed any of the others; however the study demonstrated that coagulation is a feasible modification for a wastewater treatment plant upstream of an UV-AOP system. It was also found that the cost benefit to UV/H2O2 exceeded the chemical costs of coagulation. Nevertheless, facilities considering UV-AOP systems should weigh the benefits of increasing the H2O2 concentration or using coagulation as the cost savings are relatively similar at high H2O2 concentrations.

Keywords: advanced oxidation processes (AOP)
coagulation
effluent organic matter (EfOM)
micropollutant removal
scavenging capacity
UV/hydrogen peroxide (H2O2)
Advisor: Hofmann, Ronald
"The Passions of A Discontented Minde": The Earl of Essex and Elizabethan Literature and Culture

Where recent criticism has focused disproportionately on drama as social influence, this dissertation investigates early modern thinking about theatre and the powers of spectacle by exploring the motivations and strategies of Robert Devereux, the third Earl of Essex. Although chiefly the subject of political and historical studies of the late Elizabethan period, I argue that he is an exemplary figure in his capacity to illuminate through his writing and that of his contemporaries the emotional and political implications of the major cultural and literary transitions of the late sixteenth century. My argument, articulated through analyses of medicine, psychology, and religion as well as of literature, begins with the proposition that Essex, like those drawn to him, understood the self, politics, and the theatre as transcendent and collective, where the divisions between and among component individuals were, at most, porous. I suggest that he and his contemporaries were well aware of the odds at which he stood with the prevailing modality of individuation; not only do Essex’s own writings express this malaise, but so, too, do those of his immediate and wider circles, most notably Donne, Greville, Bacon, and Shakespeare. Finally, I turn to the theatre itself, placing the theatrical experience of the Essex circle in the context of the same evolving phenomenology, arguing that in this light the political motives of the bespoke performance of Richard II on the eve of Essex’s rebellion are less revealing than the conspirators’ apparent belief in its potential to rouse its audience to action. In so doing, I both contextualize and limit the utility of “self-fashioning” as a hermeneutic.

Keywords: Devereux
Robert
Early Modern Literature
Essex
Earl of
Renaissance England
Subjectivity
History of
Advisor: Harvey, Elizabeth
The T Cell Co-stimulatory Molecule GITR in the Control and Treatment of a Persistent Viral Infection

During persistent viral infections such as human immunodeficiency virus (HIV) in human or lymphocytic choriomeningitis virus (LCMV) in mice, the immune response must achieve a balance between immune control and pathology. CD4 T cell help and co-stimulatory factors remain under-investigated in this context. This thesis explores the role of the Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein (GITR) and its efficacy as a target for therapy in chronic infection. Mice that lack the T cell co-stimulatory molecule GITR have impaired LCMV-specific CD8 T cell responses and control of chronic LCMV infection. The effects of GITR were lost when mice were depleted of CD4 T cells. GITR directly supports the accumulation of IL-2+ T helper type 1 (Th1) cells, thereby indirectly facilitating early LCMV-specific CD8 T cell responses, late B cell responses, and viral control. In vivo GITR-induced signals were detected at day 3 post-infection, and defects in CD4 T cell accumulation in GITR-deficient T cells were apparent starting at day 5 post-infection. GITR-Ligand (GITRL) is maximally induced on antigen presenting cells at day 2 post-infection, but is downregulated to below baseline levels by day 8 post-infection, and remains so at the chronic stage of infection (day 21 post-infection). GITR expression was highest on regulatory T cells (Tregs) but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 post-infection and was maintained at low levels at day 21 post-infection. As GITRL was limiting at this late time point, we investigated the potential of therapeutic stimulation of GITR using an anti-GITR agonist monoclonal antibody. Anti-GITR treatment at day 21 post-infection increased the frequency and number of LCMV-specific CD8 T cells and improved viral control. These effects of anti-GITR were CD8 T cell-intrinsic. Taken together, this thesis demonstrates that GITR plays an important early role on CD4 T cells to support CD8 T and B cell responses to persistent LCMV infection, but at later time points, anti-GITR therapy acts directly on the CD8 T cells to improve viral control. These studies may inform the development of novel immune therapies for human persistent viral infections as well as malignancies.

Keywords: B cells
Co-stimulation
GITR
LCMV
T cells
TNFR
Advisor: Watts, Tania H
Exploring FGL2 Immunomodulatory Activity in Models of Transplantation and Colitis using the FGL2 Overexpressing Mouse

CD4+Foxp3+ regulatory T cells (Treg) are critical in the maintenance of immune homeostasis and in controlling immune responses to pathogens. Fibrinogen-like protein 2 (FGL2) is an immunosuppressive effector of Treg and negatively regulates T cell, B cell and DC responses. To gain further insight into FGL2’s immunoregulatory function, we generated an fgl2Tg mouse that overexpresses FGL2 ubiquitously. FGL2 expression was increased >6-fold in the plasma of fgl2Tg. Fgl2Tg did not have altered growth and development but they were protected against the development of glomerulonephritis seen in fgl2-/- mice. We showed that FGL2 overexpression regulates the function of Treg and T cells. Fgl2Tg Treg had increased suppressive activity in a standard suppression assay. Fgl2Tg T cells were hypo-responsive to stimulation with alloantigen, anti-CD3 and anti-CD28 antibodies, and ConA. In a mouse model of fully mismatched cardiac transplantation, 50% of fgl2Tg recipients showed indefinite graft survival in the absence of immunosuppression. Fully accepted BALB/c cardiac grafts from fgl2Tg recipients lacked evidence of rejection such as vasculitis and cardiomyocyte necrosis. Accepted BALB/c grafts showed increased numbers of Foxp3+ T cells compared to BALB/c grafts from C57BL/6 recipients. Furthermore, the proportion of Foxp3+ to CD3+ T cells was significantly increased in accepted grafts. In a murine model of T cell dependent colitis, the co-transfer of fgl2Tg Treg with C57BL/6 Teff into rag1-/- mice showed enhanced protection from colitis compared to C57BL/6 Treg co-transfer as seen by improved colonic tissue architecture and decreased cellular infiltrate. The cellular infiltrates of fgl2Tg Treg-treated mice had increased proportions of Treg in the mesenteric lymph nodes and the colon. In two in vivo models, FGL2 overexpression skewed the balance of Treg to Teff to a protective, Treg-regulated immune response. In the studies presented in this thesis, FGL2 overexpression was shown to alter the function of Treg and Teff establishing an important role for FGL2 in immune regulation. These studies provide the basis for studies to use FGL2 as a therapeutic to induce transplant tolerance and/or in the treatment of inflammatory bowel disease in the clinic.

Keywords: Colitis
Regulatory T cells
T cell Immunology
Transplantation
Advisor: Levy, Gary A
Antiretroviral Therapy in Walvis Bay, Namibia

Highly Active Antiretroviral therapy (HAART) is a successful means of treating infection with the Human Immunodeficiency Virus (HIV). Namibia was among the first countries in sub-Saharan Africa to achieve universal access to HAART for HIV-positive citizens through the public sector. In this thesis, I explore treatment outcomes in Walvis Bay, a busy port city at Namibia’s coast. I find that gender is the most important factor shaping HAART, with women reporting for testing and treatment in greater numbers than men, sooner in the course of their illness, and enjoying lower mortality after treatment initiation. There are no compelling biological explanations for this distribution; I postulate a series of socio-cultural and political-ecological factors driving outcomes in Walvis Bay. In particular, changing gender roles and different points of entry into care are important at the individual level. I describe a ‘toxic masculinity’ that, however fragile, actively interferes with testing, treatment, and health-seeking behavior. Female identity, conversely, emerges as altogether more stable and more suited to the clinical and social demands of HAART. More broadly, actions are shaped by large-scale processes of urbanization and globalization, and especially the effects these have on labour, subsistence, and culture change. I conclude by suggesting modifications to the rollout program that may help to distribute the benefits of HAART more equitably through the treatment population. This research has important implications for other countries in sub-Saharan Africa as they gradually move toward universal access to HAART. More generally, it may presage future challenges of globalization and infectious disease.

Keywords: Antiretroviral Therapy
Gender
HIV/AIDS
Masculinity
Namibia
Political Ecology
Advisor: Lee, Richard B
Sellen, Daniel W