VictorJuiz/thesis huggingface dataset:
Study of signal transduction in reconstituted membranes: Ras activation by SOS and RasGRP1

Cellular membranes organize signal transduction, serving as platforms for protein interactions, as well as direct modulators of enzyme function. Since many signaling reactions converge at the plasma membrane, understanding the coupling between protein/nfunction and membrane localization of signaling complex is of fundamental importance. However, a quantitative description of many of such interactions has been lacking, largely due to the difficulty in performing measurements in the complex cellular environment. Here, we reconstitute and quantitatively probe the kinetics between small GTPase Ras and its activators: Son of Sevenless (SOS) and Ras guanyl nucleotide-releasing protein/n(RasGRP) using supported membranes./nThe activation of the membrane-associated Ras by cytosolic guanine nucleotide exchange factors, SOS and RasGRP, is a key step in a plethora of receptor-mediated cell signaling pathways. Both SOS and RasGRP contain multiple domains and several of which/nare known to regulate the activation of SOS/RasGRP. In this dissertation, we study in parallel the kinetics of SOS and RasGRP-catalyzed Ras activation as well as the mechanisms that release the autoinhibition of SOS/RasGRP at single molecule level./nWe develop an assay with supported bilayers functionalized with H-Ras to monitor the enzymatic activities from hundreds of individual SOS proteins. The data reveals that SOS is dynamically heterogeneous, sampling a broad distribution of turnover rates via/nstochastic fluctuations between distinct states. The regulatory domains allosterically inhibit SOS by suppressing fluctuations to high activity states with sensitivity to both Ras nucleotide state and lipids. On the subject of Ras activation by RasGRP, the functional role of lipid interacting C1 domain of RasGRP1 has been studied. The preliminary results suggest that diacylglycerol (DAG), through the interaction with the C1 domain, regulates the function of RasGRP1 primarily by increasing its membrane localization.

Advisor: Groves, Jay T
Compton clock and recoil frequency measurements using a large momentum transfer atom interferometer

Light-pulse atom interferometers have been used as quantum inertial sensors and for precision tests of fundamental laws of physics. For higher contrast, we apply conjugate Ramsey-Borde interferometers to cancel out vibrational noise and top mirror tilting to compensate the Coriolis force. For higher sensitivity, we implement Bragg diffraction and Bloch oscillations for large momentum transfer to increase the enclosed area of our atom interferometer. We also utilize Raman sideband cooling in our experimental setup, which increases the overall signal about twentyfold, and increases the contrast by suppressing the thermal expansion of the atom cloud./nBy combining measurements of recoil frequency and a frequency comb, we present the first clock referenced to the mass of a single particle. The rest mass of a particle defines its Compton frequency, mc^2/h through relativity and quantum mechanics, and thereby sets a fundamental timescale. Our clock stabilizes a 10 MHz radio frequency signal to a certain fraction of the cesium Compton frequency. Future work could result in an elementary particle (electron) or even antimatter (antihydrogen) clock, opening up new ways to test CPT symmetry and the equivalence principle./nWe also present our progress towards a new determination of the fine structure constant. The fine structure constant value obtained by our cesium Compton clock measurement is about three times better compared with the earlier cesium recoil frequency result. After combining Bragg diffraction and Bloch oscillations, we achieved 0.33 ppb sensitivity (0.66 ppb uncertainty of the recoil frequency measurement) in 6 hours, which is about two times better than the previous best recoil frequency measurement. The leading systematic effect is also reduced by a factor of 2.75.

Advisor: Mueller, Holger
Structural and biochemical studies of ring-shaped DNA translocases

Cellular replication forks are universally powered by ring-shaped, hexameric helicases that encircle and unwind DNA. To better understand the molecular mechanisms and control of these enzymes, we used an ensemble of methods to investigate the bacterial replicative helicase, DnaB. A 3.3Å crystal structure of Aquifex aeolicus DnaB complexed with nucleotide reveals a new conformational state for this family of motor proteins. Electron microscopy and small angle X-ray scattering studies confirm the state seen crystallographically, showing that the DnaB ATPase domains and an associated N-terminal collar transition between two physical states in a nucleotide-dependent manner. Mutant helicases locked into either collar state are active, but display different capacities to support critical activities such as duplex translocation and primase-dependent RNA synthesis. Our findings establish the DnaB collar as a key auto-regulatory hub that controls the ability of the helicase to transition between different functional states in response to nucleotide and both replication initiation and elongation factors.

Advisor: Berger, James M
Bustamante, Carlos J
Uptake of Depression Treatment among Latinos in Integrated Primary Care: A mixed methods analysis

Despite high lifetime risk for depressive disorder, Latinos under-utilize mental health services as compared to non-Latino Whites, and are more likely to seek treatment for depression in primary care medical settings. Integrated behavioral health (IBH) in primary care is a promising service model for facilitating access to mental health care among Latinos. Yet, while IBH is a mandate of the Affordable Care Act (ACA), research has not addressed whether IBH facilitates entry into needed behavioral health services for Latinos. The aims of this mixed methods study are: (1) To identify specific sociodemographic and contextual factors in the referral processes that predict psychotherapy initiation for depressed Latinos within an IBH setting; and (2) To qualitatively explore why Latino patients decide to follow-up or not with behavioral health treatment upon referral. To achieve Aim 1, predictor analysis was performed on medical records data (N=431). To achieve Aim 2, qualitative semi-structured interviews were conducted with a sub-sample of depressed Latino patients (N=16) referred for IBH depression treatment. Results point to differences in treatment uptake based on referral type between English-speaking and Spanish-speaking Latinos. English-speaking Latinos were four times less likely to attend an initial visit if they received a personal introduction from their medical provider to the behavioral health provider ("warm handoff"), as compared to those who did not receive a personal introduction during referral. Qualitative findings suggest that not all warm handoff referrals are experienced as "warm", and that the strength of the patient-provider relationship is a key component affecting patients' experience of the referral, and subsequent decision to engage in depression treatment or not. Future studies should explore specific dimensions contributing to the quality of referral to better address the spectrum of psychosocial and cultural needs of depressed Latinos and engage them into care.

Advisor: Organista, Kurt C
Dialectic, Desire & Discipline: The Formation of the Philosopher on the Scene of the Platonic Dialogue

The argument explores the relationship between epistemology and ethics in the Platonic dialogues. Focusing on the drama that takes place on the scene of the dialogues, I trace Socrates' struggle to impose rules on the conversation. What I show is that though Socrates' question invites a response from his interlocutor (and so, is commonly celebrated as open-ended), the questions he asks and the rules he imposes, restricts contribution that his interlocutor can make to the dialogue. I argue that this discursive practice, the dialectic, not only imports a specific epistemology--a specific image of knowledge--but this episteme is used to interpret what Socrates' interlocutor values and desires; so the discourse brings with it a certain understanding of the form that desire should take. The epistemological assumptions, then, also assume (and endeavor to produce) a particular type of subject. A careful examination of the discursive practice by which Plato distinguishes Socrates and philosophy from other figures and practices reveals that Plato's epistemological and ethical ends are more circumscribed than is usually acknowledged. By developing a sensitivity to the struggle that takes place over method, I argue, one not only becomes sensitive to the exclusions on which philosophy is founded (e.g., the considerations deemed irrelevant to the conversation) but one also develops a sensitivity to the power dynamic that structures the relationship between interlocutors. More broadly, this raises the problem of how certain discursive practices support particular distributions of power and different ethical possibilities while suppressing others.

Advisor: Boyarin, Daniel
Bates, David W
Transcriptional Regulation of the V(D)J Recombinase (Rag)

Tight regulation of RAG activity is required for proper development of the adaptive immune system as well as prevention of genomic instability. Foxo1 and GFI family members are crucial transcriptional regulators of Rag expression. To identify the regulatory pathways activating Foxo1 for Rag expression in B cells, we generated a panel of Foxo1 mutants and assayed their ability to upregulate Rag expression. We discovered a novel residue, serine at amino acid 215 (S215), on Foxo1 that is required for transactivating Rag expression, but not most other Foxo1-regulated genes. S215 modulates Foxo1 activity, at least in part, by regulating Foxo1 binding to the Rag locus. We also identified MK5 as an activator of Rag transcription, likely by phosphorylating S215 and thereby activating Foxo1. Further, we sought to study the negative regulators of Rag transcription. Previously in our lab, GFI1B was identified as a repressor of Rag transcription. However, Gfi1b-deficient mice have no defect in Rag expression. We thus hypothesized that GFI1, a member of the same transcription factor family, may compensate for loss of GFI1B. To test this hypothesis, we generated conditional knockout mice for both Gfi1 and Gfi1b. Deleting both Gfi1 and Gfi1b in primary B cell cultures resulted in an upregulation of Rag expression. Moreover, both GFI1 and GFI1B bind directly to the Rag locus. Together, these data indicate that both family members serve redundant functions in Rag repression in developing B cells. Lastly, to study whether GFI family proteins play a role in Rag repression outside the lymphoid lineage, we utilized a V(D)J recombination reporter mouse to study the effect of Gfi1 and Gfi1b deletion in other hematopoietic lineages. We observed aberrant Rag expression in plasmacytoid dendritic cells (pDCs) when GFI family proteins were deleted in ex vivo cultures. Microarray analysis revealed that GFI family proteins regulate a diverse set of genes in pDCs, but not a lymphoid-specific transcriptional program. Together, this study identified a novel pathway and elucidated the functions of a positive and a negative regulator of Rag expression.

Advisor: Schlissel, Mark S
Applications of Integer Programming Methods to Solve Statistical Problems

Many problems in statistics are inherently discrete. When one of these problems also contains an optimization component, integer programming may be used to facilitate a solution to the statistical problem. We use integer programming techniques to help solve problems in the following areas: optimal blocking of a randomized controlled experiment with several treatment categories and statistical auditing using stratified random samples./nWe develop a new method for blocking in randomized experiments that works for an arbitrary number of treatments. We analyze the following problem: given a threshold for the minimum number of units to be contained in a block, and given a distance measure between any two units in the finite population, block the units so that the maximum distance between any two units within a block is minimized. This blocking criterion can minimize covariate imbalance, which is a common goal in experimental design. Finding an optimal blocking is an NP-hard problem. However, using ideas from graph theory, we provide the first polynomial time approximately optimal blocking algorithm for when there are more than two treatment categories. In the case of just two such categories, our approach is more efficient than existing methods. We derive the variances of estimators for sample average treatment effects under the Neyman-Rubin potential outcomes model for arbitrary blocking assignments and an arbitrary number of treatments./n/nIn addition, statistical election audits can be used to collect evidence that the set of winners (the outcome) of an election according to the machine count is correct---that it agrees with the outcome that a full hand count of the audit trail would show. The strength of evidence is measured by the p<\italic>-value of the hypothesis that the machine outcome is wrong. Smaller p<\italic>-values are stronger evidence that the outcome is correct. Most states that have election audits of any kind require audit samples stratified by county for contests that cross county lines. Previous work on p<\italic>-values for stratified samples based on the largest weighted overstatement of the margin used upper bounds that can be quite weak. Sharper $p$-values than those found by previous work can be found by solving a 0-1 knapsack problem. We also give algorithms for choosing how many batches to draw from each stratum to reduce the counting burden.

Advisor: Sekhon, Jasjeet J
Nolan, Deborah
III-V Nanostructures on Dissimilar Substrates for Optoelectronic Applications

The heterogeneous integration of optoelectronic and electronic circuits is poised to transform personal electronics because it will not only enable a vast range of otherwise unattainable capabilities, but will also reduce power consumption, weight and size. Monolithic integrations of high-quality III-V materials with single and poly-crystalline silicon are therefore highly desirable. Direct growth of III-V on silicon substrates has been very challenging because of high epitaxy temperatures that are incompatible with CMOS circuits. Moreover, the large mismatches of lattice constants and thermal expansion coefficients between III-V compounds and silicon cause compromises in reliability and performance. As for poly-silicon, the lack of long-range crystalline coherency in the substrate makes high-quality III-V epitaxial deposition impossible. As such, there has been a focus on growing three-dimensional nanostructures, which show great promise to overcome these difficulties./nIn this dissertation, a novel growth mechanism that yields catalyst-free, self-assembled, single-crystalline nanoneedles and nanopillars on dissimilar substrates will be presented. At CMOS-compatible growth temperatures (400 ~ 455 oC), single-crystalline InGaAs and InP nanostructures are grown on silicon and poly-silicon substrates via metalorganic chemical vapor deposition. Unlike nanowires synthesized with vapor-liquid-solid or selective area growth, the nanostructures expand in both axial and radial directions simultaneously. On top of silicon, these core-shell nanostructures can scale beyond a micron in diameter while maintaining pure wurtzite crystal phase. This high-quality growth is very unusual considering over 6% lattice mismatch between III-V and silicon. More surprisingly, single crystalline InGaAs nanopillars with base diameter far exceeding the substrate crystal grain size can be grown directly on poly-silicon. We study these seemingly impossible heterogeneous growths extensively by examining the crystal lattice at the hetero-interfaces via high-resolution transmission electron microscopy. Discussions on stress-relaxing mechanism, nanostructure nucleation schemes as well as alloy composition uniformity will be presented./nWith the excellent crystalline quality, InGaAs and InP nanostructures exhibit extraordinary optical properties. Lasing is achieved, for the first time, in as-grown InGaAs and InP nanopillars monolithically synthesized on silicon and poly-silicon. Nanopillar-based devices with respectable diode ideality factor and extremely low dark currents are developed directly on top of silicon. Demonstrations of optoelectronic functionalities including light emission, detection and photovoltaics will be presented. The findings in this work open up a new chapter in the heterogeneous integration of lattice-mismatched materials and their device structure design.

Advisor: Chang-Hasnain, Constance J
Modularity Conserved during Evolution: Algorithms and Analysis

Modularity is a defining feature of biological systems. This dissertation presents our work on the development of algorithms to detect modularity in protein interaction networks and techniques of analysis for interpreting the results. A multiprotein module is a collection of proteins exhibiting modularity in their interactions. Multiprotein modules may perform essential functions and be conserved by purifying selection./nA new linear-time algorithm named Produles offers significant algorithmic advantages over previous approaches. An algorithmic framework for evaluation is presented that facilitates evaluation of algorithms for detecting conserved modularity with respect to their algorithmic goals./nOptimization criteria for detecting homologous multiprotein modules are examined, and their effects on biological process enrichment are quantified. Graph theoretic properties that arise from the physical construction of protein interaction networks account for 36 percent of the variance in biological process enrichment. Protein interaction similarities between conserved modules have only minor effects on biological process enrichment. As random modules increase in size, both biological process enrichment and modularity tend to improve, though modularity does not show this trend in small modules. To adjust for this trend, we recommend a size correction based on random sampling of modules when using biological process enrichment to evaluate module boundaries./nSupporting software has been developed useful for designing high quality algorithms for detecting conserved multiprotein modularity. EasyProt is a parallel implementation of scientific workflow software designed for cloud computing that retrieves data from several sources, runs algorithms in parallel, and computes evaluation statistics. VieProt is visualization software for conserved multiprotein modularity that uses a dynamic force-directed layout and displays quality measures and statistical summaries./nWith high quality protein interaction data, it may be possible to use modules to improve the prediction of proteins that are orthologous to each other and that have maintained their function. We present statistical methods that may be useful for this purpose. The utility of these models will depend on anticipated improvements in protein interaction data quality.

Advisor: Karp, Richard M.
Scalable Statistical Methods for Ancestral Inference from Genomic Variation Data

Developments in DNA sequencing technology over the last few years have yielded unprecedented volumes of genetic data. The resulting datasets are indispensable for a variety of purposes, from understanding cancer to answering questions about evolution. Despite the ease with which one can obtain these large quantities of data, the task of extracting meaning from the data remains an open and challenging problem. In this work, we develop statistical methods to infer population genetic parameters from high-throughput sequencing data through the use of coalescent theory, which stochastically models the evolution of DNA from generation to generation. Because closed analytic formulas are unknown for many parameters of interest, computational methods such as Markov Chain Monte Carlo and Sequential Importance Sampling become particularly relevant./nWe develop a method using reversible jump MCMC to infer genome-wide variable recombination rates and apply it to data from two Drosophila melanogaster populations. Our analysis of the results reveals several interesting findings. A systematic search for hotspot regions reveals only a few occurrences along the genome, far less than that observed in human. We apply a wavelet analysis to quantify the differences between the recombination maps of the two populations, and find that although there is high variability at the fine scales, the recombination maps demonstrate general agreement at the broad scales. The correlation between various genomic features is also assessed using the wavelet analysis, and we find, in contrast to humans, a correlation between recombination and diversity./nIn addition, we describe a particle filtering method to sample genealogies from the posterior distribution. Particle filtering is a model estimation technique in the family of sequential importance sampling methods. It provides the ability to perform inference on a continuous state space where the distributions under consideration are complex enough such that exact inference is intractable. The sequentially Markov coalescent, an approximation to the coalescent model where the Markov property is imposed along the sequence, is used to decompose the likelihood of the data into the product of conditional densities and allows inference on otherwise intractably long sequences of genomic data.

Advisor: Song, Yun S
Reinventing Siam: Ideas and Culture in Thailand, 1920-1944

Abstract/nReinventing Siam: Ideas and Culture in Thailand, 1920-1944/nby/nArjun Subrahmanyan/nDoctor of Philosophy in History/nUniversity of California, Berkeley/nProfessor Peter Zinoman, Chair/nIn 1932, a small group of civilian and military bureaucrats staged a coup that deposed the Thai absolute monarchy and introduced a constitutional democracy. The dominant historiography of this event has focused on elite politics, and identified the coup as a "revolution" that fundamentally changed Thai history. My thesis, however, argues that an authoritarian political culture persisted despite the introduction of a democratic system and hence there was strong continuity between the old and new regimes. I argue that the real "revolution" of the period was intellectual and took place among middle-class society. Two more fundamental processes preceded and accompanied the irregular transition to a constitutional political system in interwar Siam, and both would be of much more profound social importance than 1932's tangled politics. "Outsiders" to the political and bureaucratic elite "insiders" developed two new discourses that challenged authoritarian politics. The first was a new conception of social integration and community that sought to end the starkly uneven development between the country and the city. Second, outsiders sought the creation of a modern self - critical, autonomous and cosmopolitan - as an agent of social welfare and enlightenment. I explain the discursive battle between insiders and outsiders and the central role of foreign ideas. Even as elite conservatism limited the new democracy, the social discourse challenged state orthodoxy and showed the young generation's assimilation and adaptation of Western ideas to push for social reform and a more inclusive society.

Advisor: Zinoman, Peter