VictorJuiz/thesis huggingface dataset:
From stem cells to cancer [electronic resource] : the role of the RB family in cell cycle control and differentiation
Keywords: Genetics

Embryonic stem cells (ESCs) hold great therapeutic potential, but the regulation of their self-renewal and pluripotency is still not fully understood. Furthermore, ESCs display many similarities to cancer cells, including rapid proliferation and tumorigenic potential, making it critical to understand the basic properties of these cells. The RB family, consisting of RB, p107, and p130, are critical regulators of functions such as cell cycle progression, apoptosis, and differentiation that must be tightly regulated throughout development. Here, we used loss and gain of function experiments to understand the role of the RB family in regulating key properties of ESCs. In hESCs, the RB family is critical for self-renewal and survival. hESCs overexpressing RB arrest in the cell cycle and undergo spontaneous differentiation and apoptosis. Loss of RB family function in hESCs results in decreased self-renewal ability and a loss of pluripotency, as these cells display a defect in their differentiation capacity. hESCs undergo a G2/M arrest and apoptosis through activation of the p53 pathway and the cell cycle inhibitor p21 upon loss of RB family function. In contrast to hESCs, mESCS triple knockout (TKO) for the RB family are largely normal. However, both mouse and human ESCs display genomic instability upon loss of RB family function, highlighting a key function that is conserved between both species. The RB family also regulates many functions that are critical for tumor suppression. We investigated whether RB retains its tumor suppressive ability in cancer cells by re-introducing RB into Rb-/-; p53-/- small cell lung cancer (SCLC) tumors cells. Re-introduction of RB resulted in decreased growth and an increase in differentiation, similar to that seen in hESCs. Thus, the RB pathway is an important regulator of self-renewal and differentiation in both hESCs and SCLC.
Functional heterogeneity in parietal cortex during episodic memory retrieval [electronic resource]
Keywords: Psychology

The memory for specific events and instances in time—episodic memory—is a central aspect of human cognition. It has long been thought that episodic memory is supported by a distributed network of regions in the brain, including frontal cortex and the medial temporal lobes. A growing body of neuroimaging evidence in the last several years has additionally suggested posterior parietal cortex (PPC) involvement during episodic retrieval. Several accounts have argued that the region's involvement reflects the engagement of two specific attentional processes, goal-driven and reflexive attention, distinctly residing in dorsal and ventral regions of PPC, respectively. Strict interpretations of such accounts, however, have recently been called into question, as attention- and memory-related processes might not occupy overlapping subregions of PPC. The research described here systematically assesses the anatomical and functional relationship between attention- and memory-related operations in PPC in a series of three experiments. The first experiment revealed four distinct patterns of activity across left lateral PPC—two thought to relate to mnemonic processes and two thought to relate to attention engaged during retrieval. The second experiment directly tested whether a region thought to index attention during retrieval from the first experiment was recruited in an independent attention task, with results suggesting that attention-sensitive regions are indeed engaged in a systematic manner during retrieval. The final experiment further probed the interaction between memory, attention, and decision-making processes engaged during retrieval, and replicated and extended the findings from the first experiment. Collectively, the findings from the research provide a more detailed depiction of how anatomically and functionally separable regions of PPC support distinct mechanisms of memory and attention.
Functional neural imaging of signals triggered by topologically- and genetically-specified neurons in the mammalian brain [electronic resource]
Keywords: Bioengineering.

Functional brain imaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have emerged over the last several decades as powerful methods for understanding brain function and neuropsychiatric disorders. However, due to an inability to precisely and distinctly control the heterogeneous population of circuit elements in the brain, understanding the fundamental physiological mechanisms of these imaging modalities and realizing their potential for functional brain mapping has been limited. Optogenetics is a novel technique that allows for cell-type specific, reversible focal control within the mammalian brain with millisecond-timescale precision. In this thesis, I have utilized the unique cell-type specific neuromodulatory capacity of optogenetics to demonstrate and characterize, for the first time, the effect of direct stimulation of a subclass of excitatory neurons on the in vivo functional hemodynamic response of a rodent brain as measured with functional magnetic resonance imaging (fMRI). I have then used this technique, which we have called ofMRI, to perform large-scale functional mapping of distinct neural circuits that are specified by cell-type, cell-body location, and projection topology. To complement ofMRI studies, I have also developed the use of PET imaging and the radiotracer [18F]-fluorodeoxyglucose (FDG) to further characterize the metabolic and hemodynamic response resulting from activation of genetically-specified neurons in the mammalian brain. Additionally, I have constructed an automated, parallelized all-optical ex vivo system for modulation and recording of distinct neural circuits relevant to neuropsychiatric disorders using voltage sensitive dye imaging (VSDI). Combining the highly specific and rapid control of optogenetics with the biological process sensitivity of PET, the spatial and temporal resolution of BOLD fMRI, and the neural circuit analysis capabilities of optical imaging has the potential to vastly increase our understanding of the roles of neural circuits in both normal and diseased brain states.
Futures, oil and the making of modularity in Equatorial Guinea [electronic resource]
Keywords: Anthropology

Despite radical differences between supply sites around the world, and ever-increasing technological and political challenges, hydrocarbon is reliably transformed from sub-sea and subsoil deposit into the world's most profitable commodity. How? Despite profound political, environmental, economic, and social entanglements in each and every supply site, the transnational oil industry consistently escapes consequential responsibility for local outcomes. How? This project traces the labor-intensive processes through which Equatorial Guinea's hydrocarbon resources are converted from sub-sea deposit into global futures price. I focus on the work these processes require, of labor, material infrastructures and technologies, as well as of the legal, promotional, and ethical framing processes required to lubricate the passage of oil to market. Based on fourteen months of fieldwork in Equatorial Guinea, I explore the idea that the offshore oil and gas industry in Equatorial Guinea is a modular capitalist project: a bundled and repeating set of technological, social, political, and economic practices aimed at profit-making that materialize in diverse ways wherever the industry finds commercially viable hydrocarbon deposits. I argue that the considerable work put into the making of modularity intends to disentangle the production of profit from the place in which the industry happens to find itself, to structure liability and responsibility in such a way that the industry can remove itself from the social, legal, political, and environmental entanglements in supply sites. This argument finds empirical traction through chapters on offshore infrastructures and labor regimes; Equatorial Guinea's "new" national economy in the wake of oil; Production Sharing Contracts and subcontracting arrangements; and the industry's corporate and residential enclaves. Modularity is a work-intensive, asymptotic process in which messy engagement with difference is the assumed starting point; the hoped-for framing requires massive logistical, financial, and infrastructural investment; and the intended disentanglement is compromised at its core, as the oil industry can only animate the repeating techniques and technologies widely accepted as standardized by seeping into every crevice of Equatorial Guinea's daily life.
Galaxy formation and mergers with stars and massive black holes [electronic resource]
Keywords: Physics

While mounting observational evidence suggests the coevolution of galaxies and their embedded massive black holes (MBHs), a comprehensive astrophysical understanding which incorporates both galaxies and MBHs has been missing. To tackle the nonlinear processes of galaxy formation, we develop a state-of-the-art numerical framework which self-consistently models the interplay between galactic components: dark matter, gas, stars, and MBHs. Utilizing this physically motivated tool, we present an investigation of a massive star-forming galaxy hosting a slowly growing MBH in a cosmological LCDM simulation. The MBH feedback heats the surrounding gas and locally suppresses star formation in the galactic inner core. In simulations of merging galaxies, the high-resolution adaptive mesh allows us to observe widespread starbursts via shock-induced star formation, and the interplay between the galaxies and their embedding medium. Fast growing MBHs in merging galaxies drive more frequent and powerful jets creating sizable bubbles at the galactic centers. We conclude that the interaction between the interstellar gas, stars and MBHs is critical in understanding the star formation history, black hole accretion history, and cosmological evolution of galaxies. Expanding upon our extensive experience in galactic simulations, we are well poised to apply this tool to other challenging, yet highly rewarding tasks in contemporary astrophysics, such as high-redshift quasar formation.
Gallium nitride epitaxy by a novel hybrid VPE technique [electronic resource]
Keywords: Materials Science and Engineering

Gallium nitride is an important material for the production of next-generation visible and near-UV optical devices, as well as for high temperature electronic amplifiers and circuits; however there has been no bulk method for the production of GaN substrates for device layer growth. Instead, thick GaN layers are heteroepitaxially deposited onto non-native substrates (usually sapphire) by one of two vapor phase epitaxy (VPE) techniques: MOVPE (metalorganic VPE) or HVPE (hydride VPE). Each method has its strengths and weaknesses: MOVPE has precise growth rate and layer thickness control but it is slow and expensive; HVPE is a low-cost method for high rate deposition of thick GaN, but it lacks the precise control and heterojunction layer growth required for device structures. Because of the large (14%) lattice mismatch, GaN grown on sapphire requires the prior deposition of a low temperature MOVPE nucleation layer using a second growth process in a separate deposition system. Here we present a novel hybrid VPE system incorporating elements of both techniques, allowing MOVPE and HVPE in a single growth run. In this way, a thick GaN layer can be produced directly on sapphire. GaN growth commences as small (50-100 nm diameter) coherent strained 3-dimensional islands which coalesce into a continuous film, after which 2-dimensional layer growth commences. The coalescence of islands imparts significant stress into the growing film, which increases with the film thickness until catastrophic breakage occurs, in-situ. Additionally, the mismatch in thermal expansion rates induces compressive stress upon cooling from the growth temperature of 1025°C. We demonstrate a growth technique that mitigates these stresses, by using a 2-step growth sequence: an initial high growth rate step resulting in a pitted but relaxed film, followed by a low growth rate smoothing layer. As a result, thick (> 50 [Mu]m) and freestanding films have been grown successfully. X-ray rocking curve linewidth of 105 arcseconds and 10K PL indicating no "yellow" emission indicate that the material quality is higher than that produced by conventional MOVPE. By further modifying the hybrid system to include a metallic Mn source, it is possible to grow a doped semi-insulating GaN template for use in high frequency electronics devices.
Gei Debyuu [electronic resource] : desire among Japanese and non-Japanese men in Tokyo, Japan
Keywords: Anthropology

Abstract: This project is a cultural analysis of sexuality and race in Tokyo, Japan. Through an ethnographic study of Japanese and non-Japanese gay men who are interested in having international romantic relationships, I investigate how gay men, both Japanese and non-Japanese, become a part of Tokyo's gay social network and appropriate, manipulate, and amplify ideas of race to understand and explain their sexual activity and desires. Informants were drawn from an English language class organized for gay men and from Japanese and non-Japanese men who regularly patronized three foreigner-friendly bars in Shinjuku Ni-chome, Tokyo's largest gay bar area. An historical survey, an analysis of contemporary media, and ethnographic data collected over eighteen months (2006-2007) are presented to demonstrate the micro-processes of cultural construction of sexual and racial identity in Tokyo, particularly in relation to contemporary Japanese LGBT identity formation.
General existence theorems in moduli theory [electronic resource]
Keywords: Mathematics

In this thesis, we prove that there is an algebraic stack parameterizing all curves. The curves that appear in this algebraic stack are allowed to be arbitrarily singular, non-reduced, disconnected, and reducible. We also prove the boundedness of the open substack parameterizing reduced and connected curves with fixed arithmetic genus g and at most e irreducible components. We also show that for essentially any algebraic stack, there is an algebraic stack, the Hilbert stack, parameterizing quasi-finite maps to the stack. The technical heart of this result is a generalization of formal GAGA to a non-separated morphism of algebraic stacks, something that was previously unknown for a morphism of schemes. We also employ derived algebraic geometry, in an essential way, to prove the algebraicity of the Hilbert stack. The Hilbert stack, for algebraic spaces, was claimed to exist by M. Artin (1974), but was left unproved due to a lack of foundational results for non-separated algebraic spaces. Finally, we generalize the fundamental GAGA results of J. P. Serre (1956) in three ways---to the non-separated setting, to stacks, and to families. As an application of these results, we show that analytic compactifications of the moduli stack of smooth curves possessing modular interpretations are algebraizable.
Genetic studies of endocrine function and metabolic regulation by the corpora cardiaca cells in Drosophila melanogaster [electronic resource]
Keywords: Developmental Biology.

In humans, the hormones insulin and glucagon are the principal regulators of blood sugar homeostasis. In the fruit fly, Drosophila melanogaster, the regulation of circulating sugar levels is similarly controlled by insulin-like and glucagon-like factors. Insulin signaling in Drosophila has been studied intensively; by contrast, relatively little is known about the genetic regulation of Drosophila Adipokinetic hormone (Akh), the polypeptide with glucagon-like functions, and the corpora cardiaca (CC) cells that produce Akh. Here I describe the use of an enhancer trap screen that led to the identification of a novel regulator of CC function, the homeodomain transcription factor unplugged (unpg). Knocking down unpg in the CC cells results in decreased Akh transcript levels and reduced circulating glucose and trehalose. I also describe the identification of a number of enhancer traps that are capable of driving GFP expression in the CC cells, suggesting a role for the associated genes in CC cell function. As in human diabetes, insulin deficiency in the fruit fly elevates circulating glucose levels and impairs triglyceride regulation. Reduced insulin signaling in Drosophila also increases expression of the adipokine Akh, a phenotype reminiscent of the excessive glucagon signaling that accompanies human diabetes. Thus, it remains unclear if insulin deficiency or adipokine excess is the primary basis for diabetic phenotypes in flies lacking insulin-producing cells. Here I show that simultaneous targeted ablation of cells producing Drosophila insulin and adipokinetic hormone results in hypoglycemia. Mutation of the gene encoding the Akh receptor (Akhr) reduces circulating glucose levels in adult Drosophila lacking insulin, arguing that excessive Akh signaling is the basis for hyperglycemia in insulin-deficient flies. Simultaneous attenuation of insulin and Akh synthesis also produced hypoglycemic flies. Similar approaches revealed triglyceride imbalance from insulin deficiency requires Akh. Thus adipokines like Akh, not insulin, may be the principal hormonal regulators of glucose and lipid balance in some non-mammalian animal classes and states of insulin deficiency.
Genetics and genomics of mammalian pigment patterns [electronic resource]
Keywords: Genetics

Hundreds of coat color loci have been cloned and studied in the laboratory mouse, and most aspects of the mouse pigmentary system are conserved in other mammals. However, comparative zoologic studies suggest that some components of mammalian pigmentation are not represented as coat color mutations in laboratory mice. This dissertation aims to advance our molecular understanding of mammalian pigmentation, and strives to identify novel components of the genetic toolkit involved in generating the diverse array of coat color patterns found in nature. In the Syrian hamster, X-linked inheritance of the Sex-linked yellow (Sly) mutation results in irregular patches of black and yellow hair in heterozygous females. Femalespecific variegation of black and yellow coat color is also present in the domestic cat, but curiously absent from other vertebrate species. Using a combination of comparative genomics and linkage mapping, I made key contributions towards defining a candidate interval for the Sly mutation and discovering that the hamster and cat mutations lie in non-homologous regions of the X chromosome. Periodic color patterns on animal skin, such as cheetah spots and zebra stripes, are evident across the mammalian phylogeny, but their molecular basis remains a mystery. Taking advantage of improvements in ultra high-throughput sequencing technologies, I developed a methodology called EDGE, or EcoP15I-tagged Digital Gene Expression, that is well suited for gene expression profiling in non-model organisms. Applying EDGE to black spot and yellow background regions of cheetah skin, I discovered that localized differences in Endothelin-3 expression is likely to be responsible for maintaining black spotting through a pigment-type switching mechanism in hair follicle melanocytes. The use of EDGE and other genomic approaches to generate comparative molecular profiles of mammalian skin patterns is likely to open new avenues of research into mammalian pigment patterning and initiate a molecular renaissance for a set of questions that has mostly resided in the area of theoretical biology for the past few decades.
Genome level analysis of protein evolution in Drosophila [electronic resource]
Keywords: Biology.

Recent advances in technology have unleashed a breathtaking amount of genome sequence data. My doctoral research builds on the resulting opportunities of whole genome sequence data and analysis in a quest for gaining new insights into molecular evolution, and in particular molecular evolution and adaptation of proteins. Chapter One of my dissertation is focused on methodology, specifically the impact that the choice of multiple sequence alignment procedure has on the inference of positive selection. I find that selection inference is highly dependent on the choice of alignment procedure. Furthermore, in the case of the 12 Drosophila genomes proteins and commonly used alignment programs, most of the inferences are false positives, caused by misaligned codons. These results put into question the reliability of some of the previously reported conclusions on adaptation in these proteins, as well as in similar studies of other species. The second chapter relates these alignment errors to specific regions in the proteins, the so-called intrinsically disordered protein regions. Disordered protein regions do not have a stable fold in native physiological conditions, and therefore do not fit the standard assumptions made in codon-based evolutionary analyses about structure and folding constraints. My findings indicate that in the case of the false-positively inferred positively selected sites, as well as in general throughout the alignments, most alignment errors and ambiguities originate in disordered regions. Indels in the alignments also appear predominantly in those regions. Examination of widely used alignment benchmarks indicates that disordered regions have mostly been excluded from the benchmarks. I discuss implications of these findings for both evolutionary research and development of alignment software. The last chapter of my dissertation characterizes the evolution of disordered regions in Drosophila. I survey protein substitution and polymorphism patterns in D. melanogaster and D. simulans, and find that relative to structured regions, disordered ones have multiple-fold higher rates of replacement polymorphisms and substitutions, as well as fewer rare polymorphisms. Structured regions appear to be significantly more impacted by both positive and purifying selection, contrary to indications from previous reports where within-species data was not incorporated in the analysis.
Geometric transitions [electronic resource] : from hyperbolic to Ads geometry
Keywords: Mathematics

We introduce a geometric transition between two homogeneous three-dimensional geometries: hyperbolic geometry and anti de Sitter (AdS) geometry. Given a path of three-dimensional hyperbolic structures that collapse down onto a hyperbolic plane, we describe a method for constructing a natural continuation of this path into AdS structures. In particular, when hyperbolic cone manifolds collapse, the AdS manifolds generated on the "other side" of the transition have tachyon singularities. The method involves the study of a new transitional geometry called half-pipe geometry. We also discuss combinatorial/algebraic tools for constructing transitions using ideal tetrahedra. Using these tools we prove that transitions can always be constructed when the underlying manifold is a punctured torus bundle.