VictorJuiz/thesis huggingface dataset:
Mathematical and statistical approaches to elucidate recent human evolutionary history [electronic resource]

Reconstructing human evolutionary history is of central importance to many fields, from medical genetics and biological anthropology to archaeology and environmental studies. Human population histories, such as where and when people move, and how populations grow or adapt to their environments, affect human genetic and phenotypic variation, and disease risk. The past decade has reinforced the importance of recent human population history for the distributions of variation; over the past fifteen thousand years, populations around the world have undergone dramatic demographic changes related to environmental and cultural adaptation. This thesis develops multiple new methods to leverage genetic and archaeological evidence to reconstruct past human demography during the past ~15,000. Chapters 2-4 derive a set of mechanistic models describing the impact of sex-biased admixture on distributions of genetic ancestry in an admixed population. Chapters 3 and 4 infer the sex-specific admixture history of major human migrations during the last ten thousand years. Finally, Chapter 5 leverages models from ecological statistics and demographic archaeology to test the relationship between human population growth, local environments, and agricultural development. Together, these chapters interrogate the impact of environmental and cultural change on human demography during the last fifteen thousand years using new mathematical and statistical methods.

Keywords: Biology.
Advisor: Rosenberg Noah
Bustamante Carlos (Carlos D.) advisor. Thesis advisor
Feldman Marcus W. advisor. Thesis advisor
Mathematical proficiency, game aesthetics, and cultural models in digital game-based learning [electronic resource]

This dissertation examines the digital game-based learning experiences of historically underserved students in their elementary mathematics classes. Using the Digital Math Game-Based Experience Framework, I describe their experience in terms of the mathematical proficiency gains, cultural models of high functioning digital math game players, and preferences in game aesthetics. In a pilot study, I found that students' mathematical proficiency increased compared to students who did not play. The follow-up study revealed that among historically underserved students who play a cognitively challenging digital math game, girls showed higher gains in mathematical proficiency, eliminating differences that existed before game play. Unlike widely held cultural models of gamers in media and gaming research, the students held images of high-functioning digital math game players with a wide range of physical characteristics. Students also responded positively to the game aesthetics. Implications for educators and game designers are discussed.

Keywords: Education.
Advisor: Boaler Jo
Langer-Osuna Jennifer primary advisor. Thesis advisor
Devlin Keith J.
Schwartz Dan
Measuring sample quality with Stein's method [electronic resource]

As the size of datasets has grown, classical methods like Markov chain Monte Carlo have become increasingly burdensome from a computational perspective. Practitioners have been turning to biased Markov chain Monte Carlo procedures that are able to trade off asymptotic exactness for computational speed. Unfortunately, previously used diagnostics to aid with these methods are insufficient for assessing the asymptotic bias incurred. We will first introduce a new computable quality measure based on Stein's method that quantifies the maximum discrepancy between sample and target expectations over a large class of test functions. Our first main theoretical contribution will be showing that our measure converges to zero only if a sample converges to its target distribution. Empirically we will show this discrepancy avoids the problems faced by previous diagnostics, e.g., effective sample size. Our next step will be to generalize these ideas to cover a larger class of target distributions. By studying Ito diffusions with fast-mixing rates, we will be able to extend the purview of acceptable target distributions from distributions with strongly log-concave densities with bounded third and fourth derivatives to a much larger class that includes multimodal and heavy-tailed distributions. Finally, in the last chapter, we will study a variation of our previous methods that is computationally feasible to obtain for much larger samples. This variation will combine our ideas with those from reproducing kernel Hilbert spaces to define a closed-form expression for our measure. While other authors have also recommended this faster variation, we show that most common choices for the kernel function are insufficient for controlling convergence in the multivariate setting. A special class of kernel functions that do indeed control convergence will be proposed and shown to dominate the other traditional kernel functions empirically.

Keywords: Statistics.
Advisor: Candès Emmanuel J. (Emmanuel Jean) primary advisor. Thesis advisor
Mackey Lester
Holmes Susan
Mechanical behavior of deep interseismic slip from geodetic inversions and physics-based models [electronic resource]

While substantial progress has been made in understanding how and where interseismic strain accumulates on faults, enabling the identification of fault segments that are more likely to host earthquakes, the mechanical behavior of the deep locked-to-creeping transition remains unclear. Estimates of slip deficit in such transitional regions are particularly complicated. Since earthquakes result from the sudden release of elastic strain along a fault interface, reasonable estimates for slip deficit, and consequent strain accumulation, are critical for earthquake hazard assessment. In this thesis, I combine physics-based models of the locked-to-creeping transition region with geodetic inversions of surface deformation rates to evaluate the slip and stress behavior of the deep edge of the locked region. Most of my work focuses on the Cascadia subduction zone, a region known to host Mw 9 megathrust events which presents one of the greatest earthquake hazards in the US. In northern Cascadia, interpretations of interseismic slip deficit on the megathrust are complicated by an unresolved "gap" between the down-dip limit of the locked region, inferred from kinematic inversions of deformation rates, and the top of the ETS (Episodic Tremor and Slip) zone. I first present evidence that negative shear stress rates in this transitional region are required to fit the surface velocities, producing unexpected large interseismic slip rates. I then develop a new method that allows slip to penetrate up dip into the locked region. Up dip propagation of deep interseismic slip indeed provides a physical explanation for the steep slip rate profile and the negative shear stress rates inferred in northern Cascadia without requiring temporal changes of the fault strength. I finally extend this model to strike-slip faults, by applying this new tool to the Carrizo Plain section of the San Andreas fault in California. This final model constitutes a first step at explaining the discrepancy between geodetically-derived locking depths and microseismicity along the San Andreas fault.

Keywords: Geophysics.
Advisor: Segall Paul
Beroza Gregory C. (Gregory Christian) advisor. Thesis advisor
Dunham Eric advisor. Thesis advisor
Mechanism of dietary cholesterol uptake by niemann-pick C1-like 1 protein [electronic resource]

Cholesterol is an essential biomolecule playing a number of key physiological roles; disruption of its homeostasis can result in developmental errors, illness or premature death. NPC1L1 plays an important role in cholesterol regulation by mediating its dietary uptake and biliary re-uptake. However, the mechanism of its action and how the drug, Ezetimibe, inhibits NPC1L1 are poorly understood. In this project, we have shown that the existing model that suggested NPC1L1-mediated cholesterol uptake requires endocytosis, and that Ezetimibe works by blocking endocytosis is incorrect. Endocytosis is not involved in NPC1L1-mediated cholesterol uptake or function. We have proposed an alternative, though still incomplete mechanism, based on the similarity between the lysosomal protein NPC1 and NPC1L1. Our data suggest that the N-terminal domain and domain 2 of NPC1L1 require an interaction for both cholesterol uptake and Ezetimibe binding. In addition, we have demonstrated that a functional sterol sensing domain is required for NPC1L1 protein function. Finally, we have shown that microsomal triglyceride transfer protein is involved in regulating the biosynthesis of NPC1L1.

Keywords: Biochemistry.
Advisor: Pfeffer Suzanne primary advisor. Thesis advisor
Harbury Pehr advisor. Thesis advisor
Rohatgi Rajat
Mechanisms in Ascl1-mediated reprogramming of fibroblasts into neurons [electronic resource]

Lineage reprogramming of somatic cells, i.e. the conversion of one cell type into another, unrelated cell type, has innovated the fields of stem cell research and translational medicine. The goal of my thesis is to understand the molecular mechanisms of induced lineage reprogramming to improve efficiencies and thereby enable its translation for clinical applications. Previous studies have shown that during reprogramming of fibroblasts into induced pluripotent stem cells (iPSCs) using transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM), OSK act cooperatively as pioneering factors to first bind fibroblast enchancers to shut down the donor program before moving to activate the pluripotency circuit. It was also shown that iPSC reprogramming involves an initial stochastic phase to activate a subpopulation of cells that eventually enter a late hierarchical phase that activates the endogenous pluripotent circuitry. In contrast, studies in direct reprogramming of fibroblasts into induced neuronal (iN) cells and muscles by Ascl1 and Myod1 respectively have shown that Ascl1 and Myod1 bind immediately to their endogenous binding sites and activate their respective target programs. This leads us to hypothesize that the mechanism of direct reprogramming differs from iPSC reprogramming. Using single cell and bulk RNA sequencing (RNA-seq), Assay of Transposase Accessibly Chromatin with sequencing (ATAC-seq) and Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) to observe Ascl1 binding and changes in gene expression and chromatin accessibility during iN cell reprogramming, we found that in contrast to iPSCs, there is an initial homogenous response to Ascl1 within 2 days of transgene induction. There is a corresponding increase in accessibility of chromatin regions bound by Ascl1 within 12 hours, which leads to the up-regulation of a series of Ascl1 target genes that act in concert to facilitate a major cell fate transition between 2 -- 5 days. Finally, a maturation phase between occurs after 5 days whereby the cells begin to activate neuronal and synapse maturation genes to become fully functional neurons. Surprisingly, we also found a small fraction of cells that got redirected to an alternate myogenic program, and showed that it can be attributed to unexpected similarities in Ascl1 and Myod1 DNA-binding affinities. Finally, we found that the myogenic program can by suppressed by pro-neuronal Myt1l to both increase Ascl1-mediated iN cell reprogramming efficiency and also redirect Myod1-expressing cells towards a neurogenic fate. These observations underscore the different molecular mechanisms between iN cell and iPSC reprogramming, reveal specific properties of transcription factors able to induce reprogramming, and also show the underlying the importance of endogenous co-factors in regulating cell fate during development.

Keywords: Bioengineering.
Advisor: Wernig Marius primary advisor. Thesis advisor
Altman Russ advisor. Thesis advisor
Chang Howard
Quake Stephen Ronald advisor. Thesis advisor
Mechanisms of neuronal computation in the visual system [electronic resource]

Neuronal circuits perform stepwise transformations of sensory input to extract critical information about the environment. This information then ultimately guides behavior, making these computations essential for the organism's survival. Specifically, what are the computations that neuronal circuits perform? What are the circuit and molecular mechanisms that implement them? The work presented in this dissertation addresses these questions in the early visual system of the fruit fly Drosophila melanogaster. By combining two-photon imaging of neuronal voltage and calcium signals with genetic manipulations, I have dissected the mechanisms underlying several core transformations in visual processing. In Chapter 1, I review elementary motion detection in Drosophila, the critical computation by which visual motion is first computed and is therefore a paradigmatic computation for neural processing more broadly. This chapter also serves as an introduction to the Drosophila visual system, as I discuss the anatomy and physiology of a number of neurons, including those that I studied. Following the introduction, my dissertation contains three chapters documenting the primary research projects that I have worked on during my doctoral training. Dynamic changes in membrane potential and intracellular calcium concentrations in axons and dendrites implement neuronal computations. However, as it has been challenging to measure membrane potential in neurites in vivo, how these signals are transformed as information flows through neurons and across synapses remains incompletely understood. Genetically encoded voltage indicators are promising tools for functional characterization of membrane potential changes with subcellular resolution. Chapter 2 describes the development and validation of the novel voltage indicator ASAP2 in vitro as well as in vivo in the Drosophila visual system. Chapter 3 expands upon this work and uses two-photon imaging of both voltage and calcium to reveal neuronal computations in the Drosophila visual system, including the origin of ON and OFF selectivity. I next asked about the circuit and molecular mechanisms that implement these computations. This required manipulation of gene function with cell type specificity, but the techniques for doing so in Drosophila often reduced gene activity incompletely. Chapter 4 describes the development of an improved tool for conditional gene disruption and the demonstration of its utility for investigating how individual genes contribute to neuronal function in vivo. My dissertation additionally includes two appendices. Appendix A reviews genetically encoded voltage indicators, focusing on the properties that determine indicator performance and the biological questions that these tools are primed to address. Appendix B is an eLife Insight piece commenting on Seeds et al., 2014.

Advisor: Clandinin Thomas R. (Thomas Robert)
Baccus Stephen A. advisor. Thesis advisor
Goodman Miriam Beth advisor. Thesis advisor
Luo Liqun
Medicine Boy

A 50-page pilot television script, Medicine Boy seeks to provide an authentic snapshot of the physical and existential struggles that come with being a Native in the 21st century. The story follows the lives of an upper-middle class Native family as the death of a relative forces them to leave the comfort of their Los Angeles home and return to their ancestral homelands on the Crow Reservation. The move escalates tensions between the Ben and Roberta, as they struggle to reconcile their radically different views of their Native identity. The story also follows their 7-year-old son, Manny, as he embarks on a series of wondrously crazy adventures with his troublemaking cousin. Within the reach of the plot lies an abundance of opportunity to both reflect on multitude of recognizable themes, including that of cultural-romanticism, self-hatred, survivor’s guilt, and historical trauma. In addition, the artist statement seeks to add context by briefly summarizing two centuries of Native misrepresentation in popular culture and entertainment.

Keywords: Native
Native American
Indigenous
Indian
American Indian
Crow
Historical Trauma
Survivors Guilt
Comparative Studies of Race and Ethnicity
Race
Thesis
Mental files and shallow pretense [electronic resource]

A group of philosophers hold that the truth-condition of a belief ascription utterance contains the modes of presentation associated with the singular terms occurring in the complement clause of the uttered sentence. This view is supported by the claim that those modes of presentation are truth-conditionally relevant because the truth-value of a belief ascription utterance is affected by its function of meta-representation, i.e., the representation of how the belief agent presents the object of thought referred to by the used singular terms. However, ordinary people have the intuition that these singular terms are simply about the things to which they refer. It seems that their linguistic understanding is so simple that they do not consciously represent modes of presentation. I argue that we can reconcile the simplicity of linguistic understanding with the meta-representational truth-condition by accepting Crimmin's (1998) theory of shallow pretense. Furthermore, I argue that, by accepting a mental file framework, we can understand modes of presentation as mental files in which pieces of information are stored. In Chapter 1, as a preliminary discussion, I address Evans' (1981, 1982) idea of dynamic Fregean thought. After revealing some problems facing Evans' view, I propose an alternative account that explains the dynamics of modes of presentation in terms of the notion of mental files. In chapter 2, I elaborate the notion of mental files pertaining to the project of providing a general theory of linguistic understanding of the utterances in which singular terms are used. On this notion, mental files are repositories of the pieces of information that have extensional contents, and their roles of mode of presentation are individuated by the information contained in them. In chapter 3, I provide an account of how the standard uses of mental files are extended to the non-standard cases of mental file use, in which we understand singular terms without referents or those which occur in the complement clause of a belief report sentence. Also, I provide a model of linguistic understanding, which I call 'the file-mirroring model', according to which the grasp of the linguistic understanding for successful communication is forming a thought as a mental file structure that contains the contextually salient information that controls one's thoughts. In chapter 4, based on what has been argued in the previous chapters, I argue that Crimmins' theory of shallow pretense supplemented with my mental file account can be effectively defended from the existing criticisms. Shallow pretense is explained in terms of the exploitation of the seeming content of the relevant information. Just as we directly entertain what it appears in experiencing a perceptual illusion even when we know that there is an illusion, we directly entertain the phenomenology of what is shallowly pretended without any imaginative play and any conscious representation of the pretense itself.

Keywords: Philosophy.
Advisor: Crimmins Mark primary advisor. Thesis advisor
Hills David A. (David Allen)
Lawlor Krista advisor. Thesis advisor
Metabolic regulation of muscle stem cell histone acetylation landscape during regeneration [electronic resource]

Muscle is a highly glycolytic tissue, yet the impact of glucose metabolism on muscle stem cell function remains unresolved. Here we identify glucose metabolism as an essential driver of histone acetylation during muscle stem cell (MuSC) fate transitions in myogenesis. We use mass cytometry (CyTOF) and flow cytometry to characterize histone acetylation state at the single cell level following injury. We demonstrate an increase in histone acetylation upon MuSC activation, followed by a global reduction that is required for commitment to differentiation. This epigenetic switch is driven by reduced metabolic flux through pyruvate dehydrogenase (PDH), which generates acetyl-CoA, the substrate for histone acetylation. Activation of PDH in myoblast progenitors increases histone acetylation and impedes myogenic differentiation. In vivo, knockout of PDH inhibitory kinases, PDK2 and PDK4, leads to increased histone acetylation and accumulation of undifferentiated MuSCs following injury, resulting in impaired muscle regeneration. Conversely, high fat diet induces skeletal muscle Pdk2 and Pdk4 overexpression leading to aberrant PDH phosphorylation, dysregulated histone acetylation in MuSCs, and reduced MuSC expansion after injury. These studies identify PDH as a previously unrecognized metabolic mediator of histone acetylation landscape crucial to myogenic differentiation and muscle regeneration.

Keywords: Genetics.
Advisor: Blau Helen M. primary advisor. Thesis advisor
Fuller Margaret
Montgomery Stephen
Sage Julien advisor. Thesis advisor
Metalinguistic awareness in the acquisition of German as a third language [electronic resource] : the role of L2 proficiency

As part of the Dynamic Model of Multilingualism (DMM), Herdina & Jessner (2002) cite multilinguals' increased metalinguistic awareness as one of the key factors that distinguish third language acquisition from second language acquisition. Many TLA studies have sought to show that this increased metalinguistic awareness and the beneficial effects that it has on L3 language learning is related to the number of languages known by an individual. The current study, however, questions whether multiple language-learning experiences alone are enough to influence metalinguistic awareness and L3 learning ability and investigates the role of L2 proficiency. Similar to Cummins' (1976) threshold hypothesis with regard to the relationship between degree of bilingualism and metalinguistic awareness, the current study seeks to determine whether some threshold level of proficiency must be achieved in at least one of an individual's second languages before the benefits of increased metalinguistic awareness as they relate to L3 learning can be observed. In order to investigate the relationship between language proficiency, metalinguistic awareness, and subsequent language learning ability; the current study examines the performance of university students at low versus high L2 proficiency on tests of German language attainment after approximately 45 minutes of interactive, communicative online instruction in German as a third language.

Keywords: German Studies.
Advisor: Bernhardt Elizabeth B. (Elizabeth Buchter)
Berman Russell A.
Hakuta Kenji advisor. Thesis advisor