VictorJuiz/thesis huggingface dataset:
Characterizing the role of UBE3C in proteasome processivity [electronic resource]

To maintain protein homeostasis, cells must balance protein synthesis with protein degradation. Accumulation of misfolded or partially degraded proteins can lead to the formation of pathological protein aggregates. Here we report the use of destabilizing domains, proteins whose folding state can be reversibly tuned using a high-affinity ligand, as model substrates to interrogate cellular protein quality control mechanisms in mammalian cells using a forward genetic screen. Upon knockdown of UBE3C, an E3 ubiquitin ligase, a reporter protein consisting of a destabilizing domain fused to GFP is degraded more slowly and incompletely by the proteasome. Partial proteolysis is also observed when UBE3C is present but cannot ubiquitinate substrates because its active site has been mutated, it is unable to bind to the proteasome, or the substrate lacks lysine residues. UBE3C knockdown also results in less substrate polyubiquitination. Finally, knockdown renders cells more susceptible to the Hsp90 inhibitor 17-AAG, suggesting that UBE3C protects against the harmful accumulation of protein fragments arising from incompletely degraded proteasome substrates.

Keywords: Chemical and Systems Biology.
Advisor: Wandless Thomas primary advisor. Thesis advisor
Ferrell James Ellsworth advisor. Thesis advisor
Meyer Tobias advisor. Thesis advisor
Wysocka Joanna
Choosing a physician depends on how you want to feel [electronic resource] : the role of ideal affect in health-related decision making

Choosing the right physician has important consequences for patient satisfaction and health outcomes. How do people decide which physician to choose? Although research has demonstrated that how people actually feel (their "actual affect") influences their health care preferences, we predicted that how people ideally want to feel (their "ideal affect") would play an even more important role. Consistent with this prediction, the more college students (Study 1) and community adults (Study 2) wanted to feel high arousal positive states on average ([ideal HAP]; e.g., excited), the more likely they were to choose a HAP-focused (vs. low arousal positive [e.g., calm] or LAP-focused) physician. Experimentally increasing the value of HAP also increased participants' choice of a HAP (vs. LAP) physician (Study 3). Wanting to feel low arousal positive states (ideal LAP) did not predict physician choice until participants were given a neutral (non-emotional) option: under these conditions, ideal LAP predicted choice of the LAP physician, and ideal HAP predicted choice of the HAP physician (Study 4). Across studies 2-4, the association between ideal affect and choice was mediated by perceived physician trustworthiness. When community adults were assigned to either a HAP or LAP virtual physician (Study 5), ideal HAP predicted greater self-reported adherence to the HAP physician's recommendations, and ideal LAP predicted greater self-reported adherence to the LAP physician's recommendations. Across all five studies, actual affect did not predict preferences for physicians. These findings suggest that people choose and listen to physicians who express the affective states that they ideally want to feel, in part because they trust those physicians more. Together, these studies demonstrate the importance of ideal affect in health-related decision making.

Keywords: Psychology.
Advisor: Tsai Jeanne Ling primary advisor. Thesis advisor
Carstensen Laura L. advisor. Thesis advisor
Thomas Ewart A. C. advisor. Thesis advisor
Chromatin remodeling factor Brg1 in embryonic development [electronic resource]

During embryonic development, dynamic remodeling of the chromatin landscape is required for the transcriptional machinery to access the genomic DNA in a spatiotemporally controlled manner. This intricate level of regulation allows precise gene regulation, necessary for complex morphogenetic processes. The Brg1/Brm-associated factor (BAF) complex is a multisubunit, ATP-dependent chromatin remodeling complex. Among the subunits, Brg1 is an ATPase that is critical for the function of the complex. Here, we study the role of Brg1 in foregut and cardiac outflow tract development. In the foregut, Brg1 functions with HDAC proteins in the ventral epithelium to regulate Nkx2-1 expression, essential for foregut septation into trachea and esophagus. In the absence of Brg1, embryos develop a single-tube foregut, reminiscent of human patients with tracheoesophageal fistula. In the developing heart, Brg1 functions in the secondary heart field-derived myocardium to control Semaphorin 3c (Sema3c) expression, essential for the outflow tract to septate into pulmonary artery and aorta. Deletion of Brg1 in the secondary heart field results in decreased neural crest cell colonization of the outflow tract, leading to a phenotype similar to the persistent truncus arteriosus pathology. Brg1 cooperates with HDAC proteins and Chd7 in the outflow tract myocardium to control Sema3c expression. These studies demonstrate novel functions and molecular mechanisms of Brg1 in foregut and cardiovascular development.

Advisor: Scott Matthew P. primary advisor. Thesis advisor
Axelrod Jeffrey (Jeffrey David) advisor. Thesis advisor
Giaccia Amato J. advisor. Thesis advisor
Koong Albert
Red-Horse Kristy advisor. Thesis advisor
CircuitBook [electronic resource] : a framework for analog design reuse

Analog IC design tools have not changed much during the past few decades. While the models and simulation methods have greatly improved in accuracy and performance, analog design still relies on manually constructed schematics and layouts. Each design needs to carry its own test routine, and the quality of the entire system depends on this custom-constructed test routine. It is common for circuits to be tested in an ad-hoc manner through some combination of SPICE decks, MATLAB calculations, and perl scripts. This test collateral is often brittle (i.e., tightly coupled to the process, circuit, and simulation environment) and archived without sufficient documentation. As a result, it is usually easier to recreate the test frame when the circuit is reused in the future. Languages like OCEAN try to address this by providing a common language that both configures the simulation environment and performs calculations. While this reduces the number of files required for a simulation and reduces the need for documentation, it does not solve the problem of tight coupling. Reuse of OCEAN scripts generally means copy-and-paste, and this duplication of code makes the test routines more difficult to debug later. We see an opportunity to improve the productivity of analog design by raising the abstraction level, at least for test construction, used by analog designers. In this work, we present the CircuitBook test framework and repository that complement existing analog design flows. Our test framework is a set of Python libraries that allow high-level specification of analog tests and an associated tool chain that executes these tests. Circuits and tests are defined against an hierarchical tree of interfaces. These common interfaces allow the reuse of tests across different circuits as well as enable faster prototyping of circuits and tests. Tests defined using the CircuitBook test framework separate the simulation directives from the results analysis. This separation of concerns avoids code duplication by separating the reusable parts of the tests from the environment-specific parts. The CircuitBook repository stores circuits, tests, and simulation results to allow designers to leverage existing circuits and tests in new designs. The objects in this repository can browsed via the interface hierarchy or through property tags of the tests. We leverage the high-level nature of the test framework and automatically generate property tags by parsing the test structure.

Keywords: Electrical Engineering.
Advisor: Horowitz Mark (Mark Alan) primary advisor. Thesis advisor
Poon Ada Shuk Yan
Wooley Bruce A.
The civic lives of immigrant-origin youth [electronic resource]

This dissertation is concerned with civic development—the process by which young people come to see themselves as part of broader society—among immigrant-origin youth in the United States. The topic is investigated through a series of three related studies. In the first paper, I show how civic motivations and barriers are derived from experiences youth have in their developmental contexts of their schools and communities. Findings point to variation in levels of civic participation and types of motivations within context. These findings have important implications for practice; opportunities can be better structured to facilitate youth civic involvement when adults understand what motivates youth toward civic participation. Findings from the second paper suggested the power of discrimination on civic development. Groups of immigrant-origin youth who perceived the highest levels of discrimination reported the lower endorsement of civic attitudes compared to groups perceiving lower levels of discrimination. At the same time, the groups perceiving the most discrimination reported the highest levels of involvement in certain types of civic activities: change-oriented activities and expressive activities. The pattern of results held true after controlling for demographics such as parental education, gender, school, and ethnicity. This is a provocative finding suggesting that the experience of racial discrimination might be both alienating and also motivating for immigrant-origin youth. The third paper tackled both methodological and conceptual issues in immigrant youth research. Measurement invariance was established for six civic attitude measures indicating that the survey instrument functions similarly for youth from different immigrant status groups. In terms of mean differences on civic attitudes, first generation youth were the most optimistic about the hypothetical functioning of the US government and American ideals; however, non-immigrants felt the most personally attached to the USA. These group differences by generational status remained after accounting for ethnicity and socioeconomic status. Together, the three papers contribute to understanding the specific experiences important in civic development among immigrant-origin youth as well as point to areas where future work is needed.

Keywords: Education.
Advisor: Damon William
Obradović Jelena (Education professor) advisor. Thesis advisor
Padilla Amado M. advisor. Thesis advisor
Classical views in geomorphology imaged and reconciled using cosmogenic isotopes, topographic analysis, and numerical modeling [electronic resource]

This thesis focuses on testing the classic conceptual end-member models of landscape evolution using cosmogenic radionuclides, topographic analysis, and numerical modeling of landscapes. The conceptual end-members of disequilibrium and equilibrium landscapes were originally proposed in the early- to mid-20th century. However, quantitative methods to test these concepts have only recently been applied to this problem. This thesis compares the predictions of variations in denudation rates and topography from these conceptual models to observations from real mountain belts. In particular, I focus on two landscapes—the deglaciated landscape of the Washington Cascades and the Mendocino Triple Junction region in northern California. In these landscapes, I measured denudation rates from cosmogenic radionuclides (10Be and 26Al) and performed topographic analysis to understand the relationship between surface processes and spatial variations of topography, tectonics, climate, and lithology. I also modeled the evolution of topography and denudation rates using a geomorphic-transport-law-based numerical model.

Keywords: Geological and Environmental Sciences.
Advisor: Chamberlain C. Page primary advisor. Thesis advisor
Hilley George E. primary advisor. Thesis advisor
Loague Keith M. (Keith Michael)
Maher Katharine advisor. Thesis advisor
Classically queer [electronic resource] : eunuchs and androgynes in rabbinic Literature

This dissertation, Classically Queer: Eunuchs and Androgynes in Rabbinic Literature, asks what we can learn about both gender and Judaism when we move beyond male and female. This study analyzes late antique legal discourse about bodies that are roughly analogous to contemporary transgender and intersex categories. The study of eunuchs and androgynes can challenge current scholarly consensus on gender in the Babylonian Talmud. The canonical status of the Talmud, and its influence on contemporary Jewish practice, means that these sixth century categories of gender continue to impact Jews today. This dissertation contextualizes rabbinic literature within the larger cultural world of late antiquity, while pairing Talmudic texts with queer theory (primarily the recent sub-field of queer temporality), intersex and transgender autobiography, and feminist scholarship on the Talmud. Feminist scholarship on the Talmud is an established sub-field, however, little of it focuses centrally on masculinity. There are excellent reasons to focus on women in rabbinic literature as a corrective to scholarship that fails to take women into account. However, the rabbinic understanding of masculinity underpins the androcentrism of the Babylonian Talmud; therefore analyses that center masculinity are crucial in fleshing out the function of gender in this canonical body of literature. This dissertation finds that the Talmud cannot be said to have a singular discourse on masculinity: from the Temple to the male householder, male bodies function as both the ideal subjects and damage-prone objects in rabbinic literature. Thus the rabbinic formulation of masculinity is fractured and multiple, and requires multiple theoretical approaches in order to produce a more nuanced portrait of the function of androcentrism. Queering gender, bodily time, and sexuality, this study argues that eunuchs and androgynes sketch the boundaries of normative masculinity in relief. In the end, far from constituting a footnote, the extended meditations in the Talmud on eunuchs and androgynes are central to the rabbinic project of (re-) imagining a gendered legal system.

Keywords: Religious Studies.
Advisor: Fonrobert Charlotte Elisheva primary advisor. Thesis advisor
Voss Barbara L.
Weitzman Steven
Classifying object-hand and object-world interactions using dynamic tactile array sensing [electronic resource]

The manipulation of objects held in a robotic hand or gripper is typically accompanied by events such as slippage, between the fingers and a grasped object or between that object and external surfaces. Humans can identify such events as occurring at one or the other of these interface using a combination of superficial and deep mechanoreceptors. These events excite the mechanoreceptors differently, allowing them to be reacted to as appropriate. In robotic systems however, slip research has primarily focused on the detection of slip occurring between the hand and the held object, without specific consideration of slip at other interfaces. In order to extend the capabilities of robotic systems, we propose two simple features which can be extracted from dynamic tactile array data and used individually to discriminate between slips occurring at these two interfaces. The first is motivated by the function and response of human mechanoreceptors, while the second is based on an analysis of the interaction between a held object in contact with a soft fingertip containing embedded sensors. The performance and generalizability of these two features are verified with extensive testing. Three separate sensing suites are used, with a total of five different sensor transduction technologies. In addition, the manipulation, texture, speed, and grip force are varied from trial to trial to attempt to capture the wide variety of conditions that can occur during general grasping and manipulation tasks. Both features demonstrate greater than 85% accuracy in identifying the location of slip, independent of these varying contact conditions.

Keywords: Mechanical Engineering.
Advisor: Cutkosky Mark R. primary advisor. Thesis advisor
Khatib Oussama advisor. Thesis advisor
Mitiguy Paul
Closed-loop oversampled D/A conversion with embedded filtering [electronic resource]

This dissertation presents an oversampled DAC based on a closed-loop architecture that consists of a hybrid cascade of a digital sigma-delta modulator and an analog quasi-sigma-delta modulator. This closed-loop approach relaxes the linearity, timing and matching required of a multi-bit D/A interface. A single-pole RC filter embedded within an analog modulation loop achieves substantial out-of-band quantization noise suppression at a significant savings in power and area because no high-performance analog low-pass filter is needed at the D/A output. An experimental prototype of the closed-loop oversampled DAC with embedded reconstruction filtering has been integrated in 0.18-um CMOS. This circuit provides multi-bit conversion without DEM, as well as 3rd-order filtering of out-of-band noise. At a sampling rate of 10MHz with an OSR of 16, the DAC achieves 61-dB SNDR, 63-dB DR, and 50-dB out-of-band noise suppression, while dissipating 22mW from a 1.2-V supply.

Keywords: Electrical Engineering.
Advisor: Wooley Bruce A.
Meng Teresa H. advisor. Thesis advisor
Su David (David Kuochieh) advisor. Thesis advisor
The co-evolution of galaxies and their surrounding environments in massive galaxy clusters [electronic resource]

A key yet poorly understood component to galaxy evolution models is the influence of the local environment, and is a particularly important aspect to understanding the evolution in galaxy clusters. Galaxy clusters are not only host to significant overdensities of galaxies, but these galaxies are embedded in a hot, diffuse Intracluster Medium (ICM). The ICM has long been observed to have important and lasting impacts on the properties of their constituent galaxies, which are commonly attributed to a number of unique astrophysical processes such as the stripping of galaxy gas by the ICM due to ram pressure and repeated tidal interactions. The galaxies in turn have also been observed to play an important role in the evolution of the ICM, especially near the centers of galaxy clusters where powerful outbursts from Active Galactic Nuclei (AGN) can provide a quasi-steady source of heating to the surrounding ICM, a process known as AGN feedback. Although great progress has been made in recent years to understand the connection between galaxies and the ICM, the precise influence of the ICM on cluster galaxies and the astrophysical processes that drive galaxy evolution in clusters are still subject to important uncertainties. It is clear from the data, however, that the predictions of the simplest models of ram pressure stripping, tidal encounters, and AGN feedback are inconsistent with observations; in particular observations taken with the modern generation of X-ray telescopes such as Chandra and XMM-Newton. These telescopes, with their superb angular resolution, large collecting areas, and wide fields of view, have revolutionized our understanding of galaxies in clusters, in particular for AGN. In this thesis, I will present a series of results regarding the nature of ram pressure stripping, harassment, and AGN feedback in cluster member galaxies driven primarily by X-ray observations. These results include multiwavelength observations of one of the most extreme cases of AGN feedback currently known, a mosaic of galaxies in the nearby Virgo Cluster which are all undergoing different variants of ramp pressure stripping, and the first set of results from one of the largest X-ray AGN surveys ever undertaken with Chandra. All of these results suggest an intricate choreography between the gas reservoirs initially hosted by galaxies and the surrounding ICM, with tests that investigate length scales ranging from 10 kpc to 1 Mpc.

Keywords: Physics.
Advisor: Allen Steven W. (Steven Ward) primary advisor. Thesis advisor
Abel Tom G.
Funk Stefan
Wechsler Risa H. (Risa Heyrman) advisor. Thesis advisor
Coherent receiver components for high frequency astrophysics applications [electronic resource]

Coherent receivers for electromagnetic radiation in the frequency band from 120 - 180 GHz and higher have many important applications for ground-based astronomy and millimeter-wave imaging, such as security screening and imaging from aircraft. This thesis reviews the development and testing of new receiver components that have enabled the design of compact and mass-producible receiver modules for instruments that require high sensitivity in this frequency band. A genetic algorithm was used to optimize a smooth-walled feedhorn antenna, which will be presented along with analysis of feedhorn efficiencies. Record low noise measurements for Monolithic Millimeter-wave Integrated Circuit (MMIC) Low Noise Amplifiers (LNAs) in this band, made possible by recent advances in High Electron Mobility Transistors (HEMTs), are also included. These devices are now being incorporated into complete receiver modules that will be used in instruments for astrophysics applications.

Keywords: Applied Physics.
Advisor: Church Sarah
Petrosian Vahe primary advisor. Thesis advisor
Cabrera Blas advisor. Thesis advisor
Combinatorial and rational approaches to engineering receptor-based antagonists of the Gas6/Axl system [electronic resource]

Ligand-receptor interactions and the specific molecular recognition events that define them govern many important physiological processes. When these interactions become dysregulated, normal physiology quickly degenerates into disease states. Nowhere is this more evident than in metastatic cancer, where aberrant signaling drives uncontrolled cell growth and systemic dissemination of disease. In spite of much effort, the management of metastatic disease has largely remained an intractable clinical challenge as effective treatment options are limited. Protein-based biologics, which leverage the inherent affinity and specificity of protein-protein interactions, offer an effective strategy for targeting and modulating dysregulated disease pathways in order to bring them under control. In this dissertation, we use combinatorial and rational protein engineering methods to develop receptor-based therapeutics that target Axl, a receptor tyrosine kinase shown to be involved in driving metastasis and disease progression in a wide range of human cancers. Using yeast-surface display and directed evolution, Axl variants were engineered for improved binding to Gas6, Axl's activating ligand. To gain an understanding of the molecular basis of the increased binding, detailed biochemical and structural studies were performed, including solving the structure of a high affinity Axl variant in complex with Gas6. When reformatted for in vivo applications, the engineered Axl decoy receptors were found to have apparent affinities to Gas6 as low as 93 fM, which are among some of the strongest protein-protein interactions ever reported. Importantly, when tested in a panel of aggressive mouse models of metastatic disease, the engineered decoy receptors showed significant efficacy, reducing metastatic disease by up to 95%. Collectively, these results validate Axl as a therapeutic target in metastatic disease and highlight the potential clinical value of the engineered Axl decoy receptors as novel anti-metastatic therapies.

Keywords: Bioengineering.
Advisor: Cochran Jennifer R. primary advisor. Thesis advisor
Giaccia Amato J. advisor. Thesis advisor
Khosla Chaitan
Smolke Christina D. advisor. Thesis advisor