VictorJuiz/thesis huggingface dataset:
Mechanisms in Ascl1-mediated reprogramming of fibroblasts into neurons [electronic resource]
Keywords: Bioengineering.

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.
Medicine Boy
Keywords: Native
Native American
Indigenous
Indian
American Indian
Crow
Historical Trauma
Survivors Guilt
Comparative Studies of Race and Ethnicity
Race
Thesis

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.
Mental files and shallow pretense [electronic resource]
Keywords: Philosophy.

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.
Metabolic regulation of muscle stem cell histone acetylation landscape during regeneration [electronic resource]
Keywords: Genetics.

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.
Metalinguistic awareness in the acquisition of German as a third language [electronic resource] : the role of L2 proficiency
Keywords: German Studies.

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.
Methods for high-resolution functional MRI [electronic resource]
Keywords: Bioengineering.

The resolution of an fMRI acquisition is determined not only by the spatial resolution of the images but also the functional resolution of the underlying contrast mechanism. The former is determined by the extent of k-space sampled, with higher resolutions typically requiring longer readouts, while the latter depends on the type of sequence used (among other factors), and places an upper limit on the functional resolution achievable by the rest of the acquisition. Obtaining higher spatial resolution and utilizing alternative contrast mechanisms pose challenges for functional MRI for various reasons. In this thesis, we present a few projects which address these challenges. In the first project, we performed spin-echo fMRI at a high field strength (7T) as an alternative to conventional gradient-echo fMRI to leverage its greater spatial and functional specificity, using an adiabatic refocusing pulse and phase-precompensated excitation pulse to address B1 inhomogeneity concerns. In the second project, we developed a method to perform simultaneous brain and spinal cord fMRI, using dynamic shimming and reduced field-of-view imaging to address B0 inhomogeneity concerns. In the third project, we extended a method that utilizes the Z2 higher-order gradient and a spatial-spectral RF pulse to excite a fully localized region, and used it to perform a high-resolution reduced FOV fMRI experiment.
Methods for inferring nucleosome positioning and transcription factor binding [electronic resource]
Keywords: Genetics.

Transcription factors bind DNA and regulate the expression of genes, thereby controlling cellular identity and differentiation. Where transcription factors bind is partially determined by DNA sequence, but is also influenced by chromatin architecture, with most transcription factors predominantly binding accessible, nucleosome-free DNA. Inferring when and where transcription factors bind is crucial for understanding how gene regulation is controlled during key cellular transitions. The Assay for Transpose Accessible Chromatin with high throughput sequencing (ATAC-seq) enables profiling of chromatin accessibility genome-wide and provides information about both nucleosome positioning and transcription factor binding within accessible regions of the genome. This work describes an algorithm for using ATAC-seq fragment size and position information to infer nucleosome positioning at high resolution within regulatory regions, as well as an extension of that algorithm for the inference of transcription factor binding. Recently, the ATAC-seq method was also adapted for application to single cells. While single-cell ATAC-seq can be used to probe heterogeneity in chromatin accessibility within populations, the resulting data is very sparse, presenting significant analytic challenges. This work also describes a method for using single cell or other sparse chromatin accessibility data to infer transcription factors associated with accessibility variation in single cells. The algorithms described in this work enable characterization of nucleosome positioning and transcription factor binding at high positional resolution using bulk, deeply sequenced data or characterization of transcription factor associated accessibility at single cell resolution using extremely sparse data. As studies continue to probe how cells differentiate or transition from one state to another, such interpretable analytic tools will be crucial for understanding how transcription factors and chromatin architecture mediate these complex processes.
Military Expenditure and Growth in Conflict: An Instrumental Approach
Keywords:  Department of Economics
Military Expenditure
Civil Conflict
Foreign Aid
Instrumental Variable
Stanford Department of Economics
Thesis

The study of the relationship between military expenditure and economic growth contains a large history of contradictory results. While the literature includes many different samples of countries of different income groups, threat levels, and government spending decisions, none incorporate the presence of civil conflict into the relationship. Using an over-identified instrumental variable of U.S. military foreign aid to developing countries from 1990-2014, this study investigates how civil conflict affects the relationship between military expenditure and economic growth in developing countries. While military expenditure alone yields insignificant results, the presence of civil conflict creates a negative relationship between military spending and GDP growth rate.
Millennial scale denudation rates of the Santa Lucia Mountains, CA: Implications for landscape evolution in steep, high relief, coastal mountain ranges
Keywords:  Department of Geological Sciences
Department of Geological Sciences
School of Earth Energy &amp; Environmental Sciences
denudation
cosmogenic radionuclides
tectonic geomorphology
Thesis

We use a suite of topographic metrics and cosmogenic 10Be-derived catchment-averaged denudation rates from 18 watersheds to evaluate patterns of millennial-scale erosion of the Santa Lucia Mountains, and test the explanatory power of the power-law incision rule for this landscape. Though the Santa Lucias possess up to ~1500 m of relief, catchment-averaged denudation rates are predominantly low, generally ranging between ~90 m/Myr - 350 m/Myr, with a single drainage yielding a rate >450 m/Myr. We test two forms of the power-law incision rule, one incorporating multiple, lithologically dependent erodibilities and one containing a single erodibility term. In both cases, power-law exponents are varied between 0 - 2. Despite an apparently noisy relationship between denudation rate and normalized channel steepness index, statistical analyses indicate the power-law incision rule provides an improved fit relative to a model that does not relate erosion rate to channel steepness. However, tests comparing both model forms indicate no significant improvement in model fit when using unique erodibility and channel steepness terms for each rock type. Estimates of erodibility coefficients are consistently low, ~10-6 - 10-5 m0.2/yr for all rock types mapped in the region. These low erosivities provide an explanation for lower-than-anticipated denudation rates. Where range asymmetry is most pronounced, watershed divides are identified as mobile by the χ landscape morphometric, yet we resolve no cross-divide change in erosion rate. Conversely, divides predicted by χ to be close to an equilibrium configuration have markedly different erosion rates in adjoining basins. These conflicting data sets, considered in conjunction with geomorphic indicators of river capture, may suggest that divide migration occurs in abrupt, punctuated episodes, rather than by gradual migration of divides.
Mimicking the Human Bone Marrow: Developing a 3D Co-Culture System to Maintain Hematopoietic Stemness
Keywords:  Department of Biology
Biology
Hematopoietic Stem Cell
Hematopoietic Niche
Bone Marrow
Co-Culture
Three-dimensional scaffolds
Thesis

Hematopoietic stem cells (HSCs) are used to treat many hematologic diseases and cancer. However, there is an overall shortage of HSCs available for patient therapy and current standard methods to multiply HSCs in vitro has limited success. Thus, a need to develop methods to maintain HSC stemness is critical. The bone marrow niche naturally maintains and allows self-renewal of HSCs in vivo, and we report the creation of a co-culture system that sufficiently mimics the bone marrow niche condition in vitro to increase preservation of HSC pluripotency ex vivo. First, we determined mesenchymal stem cells (MSCs) maintain the hematopoietic progenitor population with greater efficiency than osteoblasts, and identify MSCs as a candidate cell to test the co-culture efficacy of our culture system. Then, we utilized the novel gelatin-based microribbon material to develop a HSC and MSC co-culture matrix and test the system to establish assays to evaluate co-culture efficacy. Specifically, we use a fibrinogen-based microribbon as it satisfies our co-culture requirements. Overall, we have created a co-culture matrix that both mimics natural bone marrow conditions in 3D structure, cellular components, and growth factors, and can be used to expand HSCs in future research or clinical applications.
Mindfulness & engineering [electronic resource] : a pathway to divergent thinking and innovation
Keywords: Mechanical Engineering.

The current paradigm in engineering education promotes linear, convergent thinking focused on gaining technical knowledge. Although convergent thinking is important in engineering, divergent thinking is critical to considering the context in which engineering design problems are situated and to generating innovative ideas to address those problems. This is especially true in today's professional engineering workplace where, more and more often, we are tackling engineering problems from a broader perspective in larger, more interdisciplinary teams. Engineering work requires divergent thinking skills that are not emphasized in most engineering programs. To this end, there is a growing body of research showing that a fundamental human capacity, mindfulness, fosters divergent thinking, and that mindfulness can be cultivated through practice. Mindfulness is defined as intentionally paying attention with openness, curiosity and discernment. Although psychologists continue to explore the exact mechanisms by which mindfulness facilitates divergent thinking, there is convincing evidence that there is a causal link between a mindfulness and divergent thinking ability. In the present work, I develop a conceptual framework connecting mindfulness, divergent thinking, and innovation to explore three outcomes: does mindfulness predict (1) divergent thinking in an ideation task (2) divergent thinking in an engineering problem scoping task, and (3) one's confidence in his/her ability to be innovative. This dissertation covers the methods and findings designed to answer these questions and concludes with discussion of the results and recommendations for application of this research to engineering education and engineering practice.
Miniaturized biosensor for point-of-care total protein measurement [electronic resource]
Keywords: Electrical Engineering.

Point-of-care test is defined as medical diagnostic testing at the time and place of patient care. Compared to conventional medical lab exams, point-of-care tests are accessible at home and produce near real-time test results at much lower cost. We have demonstrated a point-of-care biosensor for measurement of total protein in human serum and urine, with applications to clinical testing of diabetes as well as kidney and liver diseases, among other medical conditions. The first part of the thesis covers the design principles of the sensor, which is a miniaturized optoelectronic device comprising of a VCSEL, a PIN photodetector and emission filter bonded on the same chip. The VCSEL (vertical cavity surface emitting laser) acts as the light source and its vertical and low divergence emission enables miniaturization at low cost. The integrated photodetector and emission filter further lower the footprint of the device. The sensor operates in the NIR (Near Infra-Red) region ideal for biomedical sensing. It induces and records a fluorescence signal from the biological sample, yielding photocurrent proportional to fluorescence intensity. The second part of the thesis covers the development of a simplified assay preparation using a bare fluorescent dye, Cy5.5 that exhibits increased fluorescence in the presence of protein, with signal change linearly proportional to protein concentration. We harnessed this 'protein-induced fluorescence' phenomenon to measure the concentration of total proteins present in biological fluid samples, such as human serum or urine. These samples were analyzed using our VCSEL sensor, which demonstrated a highly linear correlation between protein concentration and photocurrent (resulting from fluorescence emission) within a dynamic range much larger than the clinical standard. The VCSEL sensor demonstrated greater accuracy than large-scale fluorescence imaging systems like the spectrophotometer and the IVIS that are deemed "gold standards" commonly used in biomedical applications. Compared to other conventional methods for detecting proteins, our point-of-care device presents a greatly simplified, inexpensive, real time and sensitive sensing method requiring a very small sample volume (3 drops~150µl). With thorough analysis of the results across wide range of protein concentrations in human serum and urine, we concluded the efficacy of the proposed sensing method using the VCSEL biosensor and PIFE assay with promising future applications in multiplex detection platforms like smart toilets or personalized health-monitoring tools for patients with limited access to medical labs.