VictorJuiz/thesis huggingface dataset:
The calcium channel CACNA1C gene [electronic resource] : multiple proteins, diverse functions

Abstract : Voltage-gated calcium channels are an important route of calcium entry into cells and are essential for converting electrical activity into biochemical events. In neurons these channels are vital for synaptic vesicle release and have been implicated in almost every activity-dependent process including survival, dendritic arborization, synaptic plasticity, and gene expression. One of the ways in which these channels regulate cellular behavior is by regulating gene expression but the mechanisms that link calcium channels to the transcription machinery are not well understood. In this thesis I show that a C-terminal fragment of CaV1.2, an L-type voltage-gated calcium channel, translocates to the nucleus and regulates transcription. I show that this calcium channel associated transcription regulator (CCAT), binds to a nuclear protein, associates with an endogenous promoter, and regulates the expression of a variety of endogenous genes that are important for the function of neurons and muscle cells. The nuclear localization of CCAT is regulated by changes in intracellular calcium on a time scale of minutes, suggesting that CCAT integrates information about the electrical activity of the cell. Together these findings reveal an entirely unexpected function for a well-characterized calcium channel. This works also addresses the question of how CCAT is generated. I show that CCAT is not released from proteolysis of full-length Cav1.2 channel but is generated from an mRNA that is transcribed from the 3' end of the Cav1.2 gene (CACNA1C). Consistent with this, I find that CCAT expression is independent of full-length channel protein and that exon 46 of the CACNA1C gene contains a promoter whose transcriptional activity is required for the expression of CCAT. Activity at this promoter, and consequently CCAT expression, is regulated spatially and temporally in the brain having highest expression during embryonic stages and in regions of the brain rich in inhibitory neurons. Analysis of 5' transcriptional starts from CACNA1C and Cap Analysis of Gene Expression (CAGE) tags from genome-wide studies show at least two mRNAs one of which encodes CCAT in vivo and a second transcript that is predicted to encode a membrane bound CCAT containing a voltage sensor. These findings reveal an unexpected mechanism by which CCAT is generated in neurons and provide a unique example by which two proteins with distinct biologic functions can be derived from a single gene. Such transcriptional phenomena may be at play in many other genes throughout the genome and has far reaching implications for prediction of gene products and interpretation of phenotypes in gene mutations and knockout studies.

Keywords: Chemical and Systems Biology.
Advisor: Dolmetsch Ricardo E. primary advisor. Thesis advisor
Clandinin Thomas R. (Thomas Robert)
Crabtree Gerald R. advisor. Thesis advisor
Meyer Tobias advisor. Thesis advisor
Carbon nanotube synthesis, device fabrication, and circuit design for digital logic applications [electronic resource]

Carbon Nanotube Field Effect Transistor (CNFET) technology has received a lot of attention in the past few years as a promising extension to silicon-CMOS for future digital logic integrated circuits. While recent research has advanced CNFET technology past many important milestones, robust and scalable solutions must be developed to realize the full potential of CNFETs. Thus, this thesis aims to develop a suite of techniques, spanning from material synthesis to circuit solutions, compatible with very-large-scale integration (VLSI). Specifically, to enable the real-world engineering of carbon nanotube integrated circuits, this thesis presents (1) wafer-scale aligned CNT growth, (2) wafer-scale CNT Transfer, (3) wafer-scale device and circuit fabrication techniques, and (4) ACCNT, a VLSI-compatible circuit design solution to surmounting the problem of metallic CNTs. These techniques culminated in the successful demonstration of CNT transistors, inverters, and NAND logic gates on a wafer scale. Furthermore, this thesis sheds light on important design considerations for the demonstration of a simple CNT "computer" and suggests a few critical directions for future work in the field of carbon nanotube technology. In contributing the above, this thesis hopes to propel carbon nanotube technology forward towards the vision of robust, large-scale integrated circuits using high-density carbon nanotubes.

Keywords: Electrical Engineering
Advisor: Wong Hon-Sum Philip
Mitra Subhasish advisor. Thesis advisor
Nishi Yoshio
Careers in a changing landscape [electronic resource] : specialist behavior and lateral mobility within the legal profession

The flattening of organizational hierarchies and the concomitant growth in flexible working practices have meant that increasing numbers of people pursue careers that are characterized by lateral labor markets. The structure of these lateral labor markets is often based upon specialist fields or practice areas. My research attempts to model the labor market structure of the legal profession in California and discern how it affects the careers of private practice lawyers. I find that, in general, the extent of specialization has increased for lawyers, regardless of firm size or position. In addition, my research indicates that the relationship between firm size and number of specialized fields is an inverted U-shape, with lawyers in large and small firms having fewer specialist fields than those in medium-sized firms. Moreover, in my analysis of changes in specialist behavior, I find that the patterns of lateral mobility between specialist fields are dependent on the size of the firm in which a lawyer works and the career stage he or she is in. My results on career outcomes indicate that early specialization predicts promotion to partner in large firms, but not in small firms. In sum, these findings suggest that specialization is having notable effects on the opportunity structures of the California bar.

Keywords: Sociology.
Advisor: Powell Walter W. primary advisor. Thesis advisor
Granovetter Mark S. advisor. Thesis advisor
Sandefur Rebecca
Cartesian feedback control for MRI transmitter array systems [electronic resource]

Accurate control of the radio-frequency (RF) electromagnetic fields in Magnetic Resonance Imaging (MRI) is necessary to ensure patient safety and provide high-quality diagnostic capabilities. Precise control is however becoming increasingly difficult to achieve, given the recent trends toward high fields and transmitter array systems. At high fields, imaging is performed in a frequency regime where the wavelength is on the order of, or smaller than, the dimensions of the human body. This leads to prominent wave behavior, non-uniform field patterns, and increased power deposition. Multi-element transmitter array systems with independent phase and amplitude control of their elements support methods that can mitigate these problems. However, in turn, they demand high fidelity RF reproduction and may lead to undesired electromagnetic interactions between elements of the arrays and with interventional devices. Frequency-offset Cartesian feedback can be used to address all of these issues. In combination with the use of polyphase error amplifiers (to implement a low-IF control bandwidth), Cartesian feedback can be used with MRI power amplifiers and transmit coils to increase the fidelity of RF reproduction, without the in-bandwidth DC-offsets and quadrature mismatches that may lead to imaging artifacts such as bright spots and ghosting. In addition, the control system, which includes autotuning circuitry for stability and vector multipliers circuitry for feedback manipulation, can be used to tune the series output impedance of these amplifiers, thereby reducing the likelihood of interactions between elements of transmit array systems. Furthermore, a miniaturized variation of the control system (called Active Cable Trap) can be used on guidewires to suppress undesired currents elicited by coupling with the RF fields of the transmit coils. In an era of rapid progress in high field MRI for clinical applications, the frequency offset Cartesian feedback method and system thus promises to address many of the challenges faced by designers of multi-element transmitter array systems.

Keywords: Electrical Engineering
Advisor: Pauly John (John M.) primary advisor. Thesis advisor
Lee Thomas H. 1959- advisor. Thesis advisor
Scott Greig Cameron
Cascading effects of a plant community shifts across ecosystem boundaries [electronic resource]

This dissertation is organized around the effects and mechanisms of a plant community shift, from a mixed species forest to largely monodominant stands of coconut palm (Cocos nucifera), in the Line Island chain in the Central Pacific Ocean. The cause and effects of this plant community shift transgress both ecosystem and conceptual boundaries. This dissertation thus likewise moves across multiple systems and topics notably including: ecosystem connectivity, indirect effects of introduced species, and resource partitioning.

Keywords: Biological Sciences
Advisor: Dirzo Rodolfo primary advisor. Thesis advisor
Hadly Elizabeth Anne
Micheli Fiorenza advisor. Thesis advisor
Vitousek Peter Morrison advisor. Thesis advisor
"Cast in later Grecian mould", Quintus of Smyrna's reception of Homer in the posthomerica [electronic resource]

This dissertation examines the relationship between the Homeric epics, the Iliad and the Odyssey, and Quintus of Smyrna's Posthomerica, a 14-book epic of the third century CE. It argues that Quintus bridges the narratives of the Iliad and the Odyssey and redeploys Homeric style in order to re-activate the cultural power of Homer under the Roman Empire. The first chapter analyzes Quintus' depiction of the Muses. The ways in which the goddesses are represented encodes the contemporary conflict of constructing a Greek identity as panhellenic or epichoric in the language of the past. This demonstrates the Posthomerica's deep engagement with the position of Hellenism and its connection to the past. The lack of an opening invocation to the Muses is part of Quintus' strategy for tapping into Homeric power: he connects the Iliad with the Posthomerica but also respects the boundaries of the Homeric text. The second chapter explores how Quintus occasionally draws his audience's gaze away from the primary narrative of the heroic past and towards their own present. This is done through landscapes, a simile involving the arena, Odysseus' testudo maneuver, and Calchas' prophecy about the Roman empire. These passages fuse the two time-frames together, which implicates the past in the construction of the present. In the third chapter specific nodes of intertextuality between the Posthomerica and the Iliad/Odyssey are the primary focus. It is argued that the intertextual web is incomplete, and that the audience must engage their education (paideia) to fill in the narrative gaps. This engages them in creating a Hellenic identity from the narratives of the past with knowledge derived from the present. The fourth chapter contextualizes Quintus with other hexameter poets of the first through fourth centuries CE who treated the Trojan War narrative, including Nestor and Pisander of Laranda, Triphiodorus, and hexameter papyrus fragments.

Keywords: Classics
Advisor: Martin Richard P. primary advisor. Thesis advisor
Parker Grant Richard
Stephens Susan A. advisor. Thesis advisor
Cell cycle exit in G1 and differentiation independent of the Retinoblastoma gene family during development [electronic resource]

The ability of stem/progenitor cells to exit the cell cycle is essential for proper embryonic development, but the mechanisms governing cell cycle exit are still not fully understood. Correct regulation of G1 is critical for ensuring proper organismal development, tissue homeostasis, and tumor suppression. The Retinoblastoma (Rb) gene family is composed of three genes, Rb, p107, and p130, which are collectively thought to serve as essential regulators of the G1 phase of the cell cycle in most proliferating cell types. The Rb family has also been implicated in promoting the gene expression of several differentiation programs in different cell lineages. However, due to the overlapping and compensatory functions among the Rb family members, a complete understanding of how the Rb family controls the cell cycle and differentiation programs within a cell remains unclear. Furthermore, it has not yet been tested whether the Rb family members are the only mediators of these cellular processes, or if there are alternative mechanisms for cell cycle exit and differentiation in mammalian stem and progenitor cells. Here we tested the requirement for the Rb protein and its family members p107 and p130 in G1 arrest and differentiation in mammalian cells. We employed several strategies to conditionally remove the Rb family genes in entire embryos and in specific neural lineages, as well as multiple differentiation systems in vitro. We found that Rb family triple knock-out (TKO) mouse embryos survive until days 9-11 of gestation, with similar patterning and organogenesis as seen in wild type embryos. Strikingly, a number of TKO cells, including in the neural lineage, are able to exit the cell cycle in G1 and fully differentiate in vivo and in culture. This ability of TKO cells to arrest in G1 is associated with the repression of key cell cycle target genes for E2F and Myc transcription factors. Thus, G1 arrest can be achieved independently of Rb family members, illustrating the robustness of cell cycle regulatory networks during embryogenesis, and identifying a novel program that regulates cell cycle exit in G1 in mammalian cells.

Keywords: Cancer Biology.
Advisor: Sage Julien primary advisor. Thesis advisor
Artandi Steven E. advisor. Thesis advisor
McConnell Susan K. advisor. Thesis advisor
Wong Albert J. advisor. Thesis advisor
Cell-free methods to engineer therapeutic proteins [electronic resource] : improving the efficacy of epidermal growth factor

Protein-protein interactions such as ligand-receptor interactions mediate cell signaling and can be used to control and modulate cell behavior. Despite their effectiveness in natural settings, protein ligands require optimization of properties such as homogeneity, lack of immunogenicity, potency, or stability to be used in therapeutic applications. Multiple combinatorial and rational protein engineering techniques have been developed to improve therapeutic proteins. However, these methods have been limited by the lack of a robust, high-throughput system for the expression of complex mammalian proteins. In this dissertation, cell-free protein synthesis (CFPS) was applied to fill this void, and the potential of this approach was demonstrated with epidermal growth factor (EGF). EGF binds to the EGF receptor (EGFR) and stimulates cell proliferation, migration, and differentiation. EGF has been pursued for wound healing and tissue engineering applications, thus EGF mutants with enhanced biochemical and biophysical properties are of great biomedical interest. The primary goal of this thesis research was to create a directed evolution platform to screen protein libraries based on biological function, an objective not feasible with other protein engineering approaches. We developed methods to fully express mutated protein libraries and to determine the efficacy of each individual member by employing a high-throughput protein product assay followed by a cell-based functional assay conducted with uniform dosage. Using this platform, we discovered the first known EGF mutants with enhanced mitogenic activity compared to wild-type EGF despite many previous attempts. These mutants bound EGFR with approximately ten-fold weaker binding affinity than wild-type EGF and reduced depletion of soluble EGF and cell surface EGFR when cells were treated with EGF. Second, we employed CFPS to rapidly characterize an array of EGF mutants and rationally engineered mutants with ideal biochemical properties for EGFR activation. It is important to note that all of these studies can be carried out without the need for protein purification from the CFPS reaction mixture, significantly increasing the number of mutants that can be analyzed. Finally, we site-specifically incorporated non-natural amino acids into EGF by CFPS and demonstrated accessibility by conjugating EGF to polyethylene glycol (PEG), a polymer that has been shown to improve protein retention and stability. These improvements to EGF highlight the advantages of cell-free methods compared to other protein engineering strategies, and advance EGF's potential for therapeutic use. Furthermore, the techniques developed here can be extended to improve the biological efficacy of other clinically-relevant proteins.

Keywords: Bioengineering.
Advisor: Cochran Jennifer R. primary advisor. Thesis advisor
Swartz James R. primary advisor. Thesis advisor
Quake Stephen Ronald advisor. Thesis advisor
Cenozoic landscape evolution of the Northern Sierra Nevada and western Basin and Range [electronic resource] : implications for tectonics, climate, and topography

The Sierra Nevada of California reflects a complex tectonic history of late Mesozoic-early Cenozoic convergence along the western margin of North America, subsequent Laramide batholith unroofing, and Neogene-Quaternary extension and translation on the eastern edge of the range. Although long thought to be the product of very recent uplift, recent studies indicate that the Sierra Nevada has persisted as an elevated topographic feature throughout the Late Cretaceous and Cenozoic. This ancestral Sierra Nevada is now widely regarded to have formed the western edge of a high elevation plateau -- the 'Nevadaplano' that covered much of what is now Nevada and western Utah -- similar to the Andean Altiplano-Puna. The topography, extent, and drainage of this plateau remain uncertain, and questions persist as to the tectonic history, paleo-elevations, erosional patterns, and drainage system of the ancestral range. Cenozoic gold-bearing fluvial deposits are locally exposed in the northern part of the range, overlain by a sequence of Oligocene ignimbrites originally sourced from central Nevada. These geologic units provide an important record of the topographic and geomorphic evolution of the range during a controversial time period in the history of the region. Paleo-landscape reconstructions based on sedimentology, stratigraphy, geochronology, geochemistry, and geologic mapping provide both a detailed reconstruction of the evolution of the ancestral Sierra Nevada drainage system and multiple lines of evidence to support the conclusion that the northern range likely acted as the steep western flank of a gradually sloping high-elevation plateau in the Oligocene. Miocene to Recent extension lowered elevations across what is now the western Basin and Range, possibly associated with gravitational spreading of overthickened, magmatically and radiogenically heated crust.

Keywords: Geological and Environmental Sciences.
Advisor: Graham S. A. (Stephan Alan)
Chamberlain C. Page advisor. Thesis advisor
Lowe Donald R.
Centriole assembly regulation by Plk4 [electronic resource]

Regulation of centriole number is important to ensure proper cell division and formation of the correct number of cilia, a signaling organelle. Activity of the polo-like kinase Plk4 regulates the number of centrioles formed each cell cycle. To study Plk4 function and the mechanism of centriole assembly we developed a system in Xenopus laevis egg extract, where we show Plx4 (Xenopus Plk4) overexpression drives de novo centriole assembly. Centriole assembly regulation in this system mimicked regulation of centriole duplication in somatic cells, suggesting that mechanisms identified in the egg extract would apply to centriole formation in general. By analyzing the functionality of Plx4 mutants we determined that Plx4 activity is not regulated by proteolysis in vitro in the extract, and likely not in vivo during early embryogenesis. To identify potential Plk4 regulators and effectors we took two approaches in egg extract: 1) chemical genetics to specifically modify Plk4 substrates in egg extract, and 2) pull-down and mass spectrometry identification of co-purifying proteins. Using the second approach we identified an interaction between Plx4 and the centrosomal protein Cep152. We found that Cep152 directly interacts with human Plk4, and that Cep152 is required for centriole duplication and Plk4-based centriole amplification. Cep152 is required to recruit the early centriole assembly protein Sas-6, but not Plk4, to the centriole. Finally, Cep152 was phosphorylated by Plk4 in vitro, suggesting that Cep152 acts with Plk4 to initiate centriole formation.

Keywords: Biology
Advisor: Stearns Tim primary advisor. Thesis advisor
Cyert Martha S.
Ferrell James Ellsworth advisor. Thesis advisor
Nelson W. J. (W. James) advisor. Thesis advisor
Challenges to drawing generalized causal inferences in educational research [electronic resource] : methodological and philosophical considerations

This work is concerned with external validity in educational research. The first part is an empirical work that examines the levels of two kinds of bias that can figure into the estimate of a program effect, where the intervention is being administered at multiple sites. The first (Bias 1) is due to differences in average performance between sites in the absence of treatment, the second (Bias 2) is due to variation in the treatment effect across sites. Data from the Tennessee STAR multisite trial of the effects of reduced class size is used to investigate both forms of bias. Findings include that both kinds of bias are significantly different from zero, Bias 1 is larger than Bias 2, regression adjustments are more effective at reducing Bias 1 than Bias 2, and in the case of reading but not math outcomes, certain covariates account for both forms of bias. The main conclusion is that both types of bias are large and difficult to reduce to a level where a local school official can feel confident that the impact estimates based on information from other location apply locally. The second work is a critique of the heterogeneity of replication approach to establishing generalized causal inferences. The argument is made that generalized causal inferences stemming from meta-analyses of randomized trials of nominally the same intervention are deficient for several reasons, the main one being that they ignore context. The empirical nature of causal generalizations in the social sciences makes them tentative and more akin to working hypotheses than immutable laws. Alternatives are considered, and the argument is made for an approach that admits a broader range of evidence for seeking appropriate and adequate warrants for drawing generalized causal inferences.

Keywords: Education.
Advisor: Reardon Sean F. primary advisor. Thesis advisor
Bhattacharya Jay advisor. Thesis advisor
Phillips D. C. (Denis Charles)
Shavelson Richard J.