VictorJuiz/thesis huggingface dataset:
Towards personalized medicine in understudied populations [electronic resource] : coagulation and anti-coagulation in African Americans

Personalized genomic medicine uses a patient's genetic information to assess disease risk or to make decisions about drug dosing. However, genetic risk variants in one population do not always represent risk in another population. Research across a diverse set of populations identify important population-specific risk variants, and reveal new biology by associating new pathways to a phenotype. In this thesis, I undertook multiple studies that addressed personalized genomic medicine in the context of diverse populations. First, I developed a tool for assessing ClinVar designated pathogenic variants in genetic data. I studied the distribution of variation across different populations and found differences between populations in the number of Clinvar designated pathogenic variants. Most studies look at genetic variants in isolation -- that is, each variant is tested for an association with a phenotype. However, these methods make it difficult to detect signal from rare variants and variants of modest effect. I created a method of aggregating variants across a biologically relevant pathway to detect signal missed in single loci analysis. With this method, I showed that the aggregate variation across the warfarin metabolic pathway explains some of the missing heritability in that phenotype. Finally, I focus on the genetics of diagnosing and treating clotting disorders in African Americans, a population with great phenotypic variability and understudied genetic risk. In this domain, I (1) created a method of aggregating variants across a biologically relevant pathway to detect signal missed in single loci analysis, which showed that the aggregate variation across the warfarin metabolic pathway explains some of the missing heritability in that phenotype; (2) identified a missense mutation (Val510Met) in the anti-coagulant Protein S which is associated with abnormal clotting in the African American population using a family study and a case-control analysis of 205 individuals; (3) using an extreme phenotype design and exome sequencing, I identified a population-specific regulatory variant in folylpolyglutamate synthase (FPGS), which is associated with lower warfarin dose in the African American population. In order to broadly understand the genetic risk factors affecting disease and drug phenotypes, we need studies in diverse populations. Here, I identified new, population specific variation associated with two such phenotypes -- coagulation and anticoagulation -- in an African American population.

Keywords: Genetics.
Advisor: Altman Russ primary advisor. Thesis advisor
Bustamante Carlos (Carlos D.) advisor. Thesis advisor
Snyder Michael
Tracking resilience to infections by mapping disease space [electronic resource]

In ecology, resilience is the ability of a system to absorb a change and still maintain the same function, structure, and identity (Holling, 1973). I wanted to study resilience in response to infections, where I define resilience as the ability of a host to return to its original health. Here I explore resilience by monitoring the full course of an infection and plot the path that infected individuals take through "disease space." Disease space is a multi-dimensional universe with quantitative measurements of disease symptoms for axes. I refer to a host's trajectory through disease space as a "disease map." These maps allow us to observe the paths hosts take when they follow a successful outcome or when they shift towards permanent disability or death. Ultimately, I would like to learn how to control the shape of these trajectories to help improve health. The work in this thesis takes the first steps towards this goal by characterizing and quantifying the differences between resilient and non-resilient paths. To study host resilience, I followed the effects of an acute infection on host health. I monitored mice infected with the non-lethal malaria parasite, P.chaubaudi, and created disease maps with the physiological and transcriptional data collected overtime. I used nearest neighbor and topological data analysis to cluster the multi-dimensional data and disease maps using either temporal or non-temporal data. I compared and quantified the different routes taken by resilient and non-resilient mice by transforming the trajectories into polar coordinates, centering the data, and obtaining an angle and radius to describe each sample. This transformation let me measure deviations from the path by comparing radii between survivors and non-survivors. Using this approach, I determined that hosts with large radii were more likely to die. I applied these ideas to an existing data set of humans diagnosed with malaria and found that human malaria patients who are heterozygotes for the sickle cell trait also took a smaller loop in this disease space suggesting that they are resilient against malaria. This observation suggests that our disease maps could be used to identify resilient patients using cross sectional data. I applied a similar framework in studying the resilience of the vaginal microbiota. I present some preliminary work that suggests a new way of visualizing longitudinal microbiota data.

Advisor: Schneider David (David Samuel)
Boothroyd John C. advisor. Thesis advisor
Relman David A. advisor. Thesis advisor
Sonnenburg Justin
Trade politics and China's image in the United States [electronic resource] : congressional discourse on the People's Republic

China has played a role in American politics since the nineteenth century when politicians worried about a flood of immigrants coming across the Pacific, while today, their concerns center on topics such as trade policy, human rights, and national security. With China's growing international clout, understanding the logic behind politically motivated depictions of the PRC becomes increasingly important. This dissertation seeks to do that with a systematic analysis of the nature of American political rhetoric about China and how it has varied across time and space. Examining twenty-five years of Senate speeches, using natural language processing techniques and machine learning, demonstrates that trade politics play an important role in shaping rhetoric. First, while congressional conversations about China in the 1990s covered a variety of topics, since the early 2000s, they have focused primarily on trade, often with the goal of depicting China as an economic threat. Likewise, trade interests determine the sentiment of language used, as senators from states highly dependent on manufacturing are more negative, while senators from states that send a lot of exports to China are less so. Public opinion data confirm that there is a public constituency for negative rhetoric about the PRC.

Keywords: Political Science.
Advisor: Oi Jean C. (Jean Chun) primary advisor. Thesis advisor
Blaydes Lisa
Grimmer Justin advisor. Thesis advisor
Trajectory planning and control for an autonomous race vehicle [electronic resource]

Autonomous vehicle technologies offer potential to eliminate the number of traffic accidents that occur every year, not only saving numerous lives but mitigating the costly economic and social impact of automobile related accidents. The premise behind this dissertation is that autonomous cars of the near future can only achieve this ambitious goal by obtaining the capability to successfully maneuver in friction-limited situations. With automobile racing as an inspiration, this dissertation presents and experimentally validates three vital components for driving at the limits of tire friction. The first contribution is a feedback-feedforward steering algorithm that enables an autonomous vehicle to accurately follow a specified trajectory at the friction limits while preserving robust stability margins. The second contribution is a trajectory generation algorithm that leverages the computational speed of convex optimization to rapidly generate both a longitudinal speed profile and lateral curvature profile for the autonomous vehicle to follow. The final contribution is a set of iterative learning control and search algorithms that enable autonomous vehicles to drive more effectively by learning from previous driving maneuvers. These contributions enable an autonomous Audi TTS test vehicle to drive around a race circuit at a level of performance comparable to a professional human driver. The dissertation concludes with a discussion of how the algorithms presented can be translated into automotive safety systems in the near future.

Keywords: Mechanical Engineering.
Advisor: Gerdes J. Christian primary advisor. Thesis advisor
Kochenderfer Mykel J.
Okamura Allison advisor. Thesis advisor
Transcription factor-mediated lineage conversion into neuronal cells [electronic resource]

Induced pluripotent stem cells technology has introduced many possibilities for regenerative medicine as therapy can potentially be tailored to specific patients. More recently, direct reprogramming using transcription factors to convert somatic cells into neuronal cell types has further bent the paradigm that the adult cell fate is fixed. Previous studies have identified specific transcription factors that can directly generate neurons from fibroblasts. Here, we hypothesized that a different combination of transcription factors can generate specific neuronal subtypes. In particular we looked at midbrain dopamine neurons that are implicated in Parkinson's disease. We identified 5 transcription factors Ascl1, Nurr1 Lmx1a, En1, FoxA2 that can convert mouse fibroblasts into midbrain dopamine neurons. In murine and human embryonic stem cells, we identified 6 transcription factors Ascl1, Nurr1, Lmx1a, En1, FoxA2 and Pitx3, together with an exogenous supply of WNT1 protein that can generate dopamine neurons of the central nervous system fate. These dopamine neurons express midbrain-type markers, produce dopamine and exhibit electrophysiological properties akin to midbrain dopamine neurons. This study also suggests that a different combination of neuronal transcription factors might generate neurons of other subtypes, such as inhibitory or adrenergic neurons. Generation of subtype neurons could have important implications for drug studies, disease modeling and potential clinical applications.

Keywords: Microbiology and Immunology.
Advisor: Wernig Marius primary advisor. Thesis advisor
Blau Helen M. advisor. Thesis advisor
Carette Jan
Sarnow P. (Peter) advisor. Thesis advisor
Transcription factors regulate enhancer-promoter contact dynamics in differentiation and disease [electronic resource]

Since the development of chromosome conformation capture (3C) by Job Dekker et al. in 2002, interrogation of enhancer-promoter interactions has led to an increased understanding of the vital role that three-dimensional structure plays in gene regulation. However, the technical difficulty of 3C and related assays, as well as the sequencing depth required to make quantitative comparisons between contact frequencies in HiC, have limited investigations of enhancer-promoter dynamics in differentiation and disease. Knowledge of the contact landscape is critical to our understanding of both human disease and normal tissue function. For example, the correlation of common genetic variation with associated diseases through genome-wide association studies (GWAS) has revealed many disease-associated polymorphisms outside annotated exons or promoter regions. This implies that much disease-relevant regulation may occur from distal regions that rely on three-dimensional contacts to target their associated genes. In this work, we describe two applications of chromosome conformation capture technology that expand our understanding of differentiation and disease. In the first section, we seek to understand and disrupt regulation of a single gene involved in therapeutic resistance in melanoma. In the second and third sections, we identify novel regulators of epidermal differentiation, then create a map of histone modification and contact dynamics during this process to understand how regulators interact with and alter the chromatin environment to facilitate terminal differentiation.

Advisor: Khavari Paul A. primary advisor. Thesis advisor
Chang Howard Y. (Howard Yuan-Hao)
Greenleaf William James advisor. Thesis advisor
Wysocka Joanna
Translational Allele-Specific Expression (TASE) in Humans

Protein expression levels can determine disease genesis and progression. However, various processes occur between DNA and protein that can affect protein expression levels in the cell. Transcriptional allele-specific expression (ASE) is a process between DNA and RNA that yields differential expression of maternal and paternal alleles in the RNA. The mechanism behind this phenomenon has been a widely understood and applied to various cancer research initiatives. However, little work has been done to understand a similar process that happens between RNA and protein, translational allele-specific expression (TASE), where differential translational preference of alleles from mRNA contributes to differential expression of those alleles in proteins. Detecting TASE is more difficult because the same protein sequence could have come from various mRNAs and degradation makes it hard to quantify and sequence proteins accurately. Although few research papers have revealed the potential of TASE in yeast, none have shown this in humans. Here, we use a previously developed method to model and detect TASE in human samples. We develop a sensitive pipeline to quantify allelic expression in free mRNA and compare it to the quantity of those same alleles in mRNA that is actively being translated by ribosomes (‘ribosome-protected’ mRNA) of thirty human samples. We then use a bootstrapping method to detect the significant in the difference of allelic expression in these two groups of mRNA. We find that translational allele-specific expression occurs in almost all of the human samples, some alleles of which might be important for disease genesis.

Keywords:  Department of Biology
Biology
Molecular Genetics
RNA Sequencing
Ribosome Profiling
Allele-Specific Expression
Thesis
Advisor: Snyder Michael
Bergmann Dominique
Transmission and interpretive facilitation [electronic resource] : teaching Hebrew bible in Jewish elementary schools

This dissertation explores how elementary school Jewish studies teachers understand the goals of Jewish education and the pedagogies they adopt to achieve these goals. Jewish education theorists and Jewish institutions make two demands on their teachers: to transmit Jewish knowledge and to cultivate students' interpretive autonomy. Do teachers in real Jewish studies classrooms understand their teaching in these terms? This study observed whole class text discussions in six Jewish studies classrooms in Jewish day schools and conducted stimulated-recall interviews (SRIs) with the teachers after every observation. Analysis of classroom observations found that the pedagogy of transmission was most prevalent, but there were also teachers who adopted the pedagogy of interpretive facilitation. Analysis of the SRIs revealed that teachers in this study articulated deeply held educational goals that motivated their pedagogical choices. But, teachers did not primarily articulate their goals in the language of the dual demands, transmission and interpretive autonomy. Instead, teachers described their goals either as religious or literary. Only three teachers mentioned the dual demands. Of these three teachers, two saw the goals of transmission and interpretive autonomy as mutually exclusive and one saw them as complementary. This study concludes with a comparative analysis of these three teachers and argues that much more theoretical attention needs to be paid to explaining why cultivating students' interpretive autonomy is fundamentally a religious responsibility.

Keywords: Education.
Advisor: Kelman Ari
Aukerman Maren (Maren Songmy)
Goldenberg Claude
Traversing the roads to Osorezan [electronic resource] : priests, pilgrims, and spirit mediums at a pilgrimage site in contemporary Japan

The Sōtō Zen temple Osorezan Bodaiji in the northernmost part of Aomori prefecture is renowned as a place where the spirits of the dead cross into the other world and blind spirit mediums called itako perform séances. However, from the early modern period Osorezan has undergone multiple shifts in identity. The temple began its history as a local site of hot spring cures and recreation, was gradually identified with Jizō and this-worldly blessings, and then offered opportunities for pilgrims to participate in memorial services. The itako began coming to Osorezan in the contemporary period, and today only two remain and perform séances at the temple festivals. This dissertation positions the pilgrimage site Osorezan Bodaiji "in situ" within the economic, historical, and religious networks of Shimokita peninsula and investigates the roles these factors have played in its development into a major pilgrimage site. I argue that the main story of Osorezan is not the itako, or even the dead, but a wide variety of human actors that shaped the landscape and practice at the mountain. Although Osorezan is a major tourist destinations and operates on the margins of organized Buddhism, it nevertheless shares many similarities with traditional pilgrimage sites. The managing priests from Entsūji pursued political alliances, published and propagated an engi, origin tale, performed sect-sanctioned prayer services, and responded to social tragedy such as earthquakes with temple installations. Even today, pilgrims from the local area come to practice seasonal worship, make offerings to Bodhisattvas and Buddhas on the site, and participate in standard rituals for the ancestors. Osorezan faces challenges such as decline in local confraternity practice that may threaten the future of the mountain as a place of belief.

Keywords: Religious Studies.
Advisor: Bielefeldt Carl primary advisor. Thesis advisor
Harrison Paul
Kieschnick John
Wigen Kären
Tropical coordinates on the space of persistence barcodes [electronic resource]

In the last two decades applied topologists have developed numerous methods for `measuring' and building combinatorial representations of the shape of the data. The most famous example of the former is persistent homology. This adaptation of classical homology assigns a barcode, i.e. a collection of intervals with endpoints on the real line, to a finite metric space. Unfortunately, barcodes are not well-adapted for use by practitioners in machine learning tasks. In this dissertation, I identify classes of max-plus polynomials and tropical rational functions that can be used as coordinates on the space of barcodes. All of these are stable with respect to standard distance functions (bottleneck distance, Wasserstein distances) used on the barcode space. I demonstrate how these coordinates can be used by combining persistent homology with SVM to classify numbers from the MNIST dataset. In order to identify functions on the barcode space, I find generators for the semirings of tropical polynomials, max-plus polynomials and tropical rational functions invariant under the action of the symmetric group. The fundamental theorem of ordinary symmetric polynomials has an equivalent in the tropical and max-plus semirings. There are interesting differences if we consider the tropical polynomial semiring with nr variables that come in n blocks of r variables each and are permuted by the symmetric group. As opposed to the ordinary polynomial case, the semiring of r-symmetric tropical polynomials is not finitely generated, but the semiring of r-symmetric tropical rational functions is.

Keywords: Mathematics.
Advisor: Carlsson G. (Gunnar)
Brumfiel Gregory W. advisor. Thesis advisor
Kerckhoff Steve advisor. Thesis advisor
Tropical instability waves and mixing in the equatorial Pacific Ocean [electronic resource]

The unique dynamics of the equatorial oceans play an important role in the El Nino - Southern Oscillation (ENSO) and the ocean's meridional overturning circulation (MOC), both of which are critical processes that drive global climate variability on a range of time-scales. This dissertation makes a number of contributions to our understanding of equatorial ocean dynamics, lateral and vertical mixing at the equator, the behavior of equatorial waves and deep equatorial mixing, with implications for both ENSO and the MOC. The main contributions are: 1) Tropical instability waves (TIWs), the main drivers of lateral eddy mixing in the eastern equatorial Pacific, share a number of dynamical features with submesoscale flows in the mid-latitudes. In particular, their formation depends on the detailed frontal dynamics and sharp vertical gradients around their fringes, with implications for TIW energetics and the accurate representation of TIWs in low-resolution ocean models. 2) TIWs drive modulations in vertical mixing by altering the vertical shear of the Equatorial Undercurrent (EUC) through horizontal vortex stretching. This modulation can drive net sea surface cooling over the eastern Pacific cold tongue that may partially offset the warming driven by TIW lateral mixing. The magnitude of the net cooling depends on the mixing scheme used to parameterize vertical mixing, with implications for the role of TIWs in the mixed-layer heat budget in different ocean models. 3) Downwelling (upwelling) equatorial Kelvin waves can drive large decreases (increases) in the amplitude of the TIW field in the eastern equatorial Pacific and thus TIW-driven lateral and vertical mixing. The Kelvin waves alter the strength and structure of the background flow from which the TIWs gain energy, resulting in complex changes to the TIW energy budget. One major sink of TIW energy, the downward radiation of waves, is strongly altered with implications for deep and abyssal equatorial ocean circulation. 4) Mixing in the abyssal equatorial Pacific can exhibit a seafloor-intensified vertical structure even over smooth topography. The generation and breaking of lee waves over smooth topography at low latitudes is one possible mechanism that could contribute to this mixing. However, downward-propagating equatorial waves generated at the surface by TIWs or wind events could also supply energy for seafloor-intensified mixing through two possible mechanisms, wave trapping due to the horizontal component of Earth's rotation and inertial instability initiated by wave-driven displacement of fluid away from the equator. These results suggest that more attention should be devoted to measuring and understanding mixing over smooth topography in the abyssal equatorial oceans because of its potential role in the global overturning circulation.

Keywords: Environmental Earth System Science.
Advisor: Thomas Leif N. primary advisor. Thesis advisor
Diffenbaugh Noah S. advisor. Thesis advisor
Fringer Oliver B. (Oliver Bartlett) advisor. Thesis advisor
Tumor-induced suppression of host immunity [electronic resource]

Interactions between the immune system and cancer cells have long been appreciated to play a role in regulating tumor progression. Accumulating evidence have pointed to the phenomenon of cancer immunosurveillance, where the host immune system is able to inhibit or eradicate malignant tumor cells. Conversely, research has also revealed multiple mechanisms by which tumor cells can suppress and overcome host immunity. In this thesis, I examine mechanisms by which tumor-initiating cells in head and neck cancer can regulate their immunogenicity and selectively evade the host immune response. I also examine how natural killer (NK) cells become functionally exhausted during tumor progression, and identify markers of exhaustion that can be targeted by antibody blockade.

Advisor: Sunwoo John B.
Engleman Edgar G. advisor. Thesis advisor
Krams Sheri Michele advisor. Thesis advisor
Majeti Ravindra