VictorJuiz/thesis huggingface dataset:
Glucocorticoids and Metabolic Disorders

Glucocorticoids (GC) are steroid hormones that exert necessary metabolic adaptation under stress, such as fasting/starvation, for the survival of mammals. To maintain blood glucose level during stress GC suppress insulin actions to promote hepatic gluconeogenesis and inhibit glucose utilization in muscle and adipose tissues. Chronic and/or excess GC exposure, however, leads to various metabolic disorders such as insulin resistance, dyslipidemia. Notably, the molecular mechanisms of GC- induced metabolic disorders are largely unclear. In this dissertation, we focus on two GC primary target genes: Angptl4 and Pik3r1 to study their roles in GC induced physiological/metabolic changes and insulin resistance in vivo./nIn Chapter I, we identified a Glucocorticoids-Angiopoietin-like 4- ceramide axis as a mechanism for GC induced hepatic insulin resistance. Under Dex treatment, wild type mice developed hepatic insulin resistance with high hepatic ceramide level, increased expression of several ceramide synthesis associated genes, and increased PP2A and PKCζ activity. However, all these observations can be reversed by Angptl4 depletion in Angptl4 null mice./nIn Chapter II, we found that Pik3r1 plays roles in the process to recruit PKA toward lipid droplet for Plin1 phosphorylation. Therefore, Pik3r1 knockout does not impair the activation of cytosolic HSL and PKA, but does impair the phosphorylation of Plin1 on lipid droplet. Therefore, less phosphor-HSL (the activated HSL) can be recruited to lipid droplet to mediate lipolysis. As a consequence, under Dex treatment, with less lipolysis, the adipose tissues specific Pik3r1 knockout (AKO) mice shown reduced fatty liver and dyslipidemia compared to wild type mice./nIn Chapter III, we found that the expression of Pik3r1 is regulated by GC in skeletal muscle in vivo. In the molecular level, the GC induced Pik3r1 expression is mediated by p300 induced histone H3 and H4 acetylation. In the physiological level, the Pik3r1 expression in muscle is important for GC induced insulin resistance. Therefore, muscle specific Pik3r1 knockout (MKO) mice show improved glucose tolerance under Dex treatment. This result is consistent with the findings in vitro using C2C12 myotubes./nIn total, this dissertation demonstrated that Angptl4 and Pik3r1 are two important genes mediating GC-induced metabolic disorders including insulin resistance, fatty liver and dyslipidemia.

Advisor: Wang, Jen-Chywan
Mechanisms of RNA sorting into exosomes

Exosomes are vesicles that are released by cells into the extracellular environment and populate all bodily fluids. These vesicles contain molecular cargo, including RNA, proteins and lipids and therefore may serve as vehicles for intercellular communication by transferring unconventional signals between cells. Despite widespread scientific interest in the physiological role of exosomes in health and disease, little is currently known about how molecules are selectively sorted into exosomes./nIn the work described herein, I used biochemical approaches to purify exosomes from cells grown in culture and identify microRNAs that are selectively sorted into exosomes. I then developed a cell-free reaction that reconstitutes the selective sorting of microRNA into exosomes in vitro. The reaction was then utilized to identify an RNA binding protein, Y-box Protein I (YBX1), that is required for sorting an exosomal microRNA. Next, I used the cell-free reaction as the basis for a selection strategy (termed Exo-SELEX) to identify primary RNA sequence motifs that act as positive and negative sorting signals in vitro. Finally, I used a high throughput RNA sequencing approach (TGIRT-seq) that allowed for a comprehensive transcriptome analysis (including highly structured or modified transcripts) of purified exosomes from normal and YBX1 knockout cells. TGIRT-seq analysis revealed that the most abundant transcript biotypes in exosomes are tRNA followed by other small non-coding RNA species. The abundant small non-coding RNA (tRNA, Y-RNA and Vault RNA) were strongly depleted in YBX1 knockout exosomes while sequences representing long non-coding RNA and protein coding genes were unaffected, indicating that these are sorted through a separate mechanism and allowing for broad classification of exosomal RNA based on YBX1-dependence or independence. In sum, this work provides a preliminary mechanistic understanding of the process of RNA sorting into exosomes and establishes multiple tools for the continued dissection of these pathways.

Advisor: Schekman, Randy W
Essays on Technology Adoption and Provision Efficiency in Development Projects

In many development projects, technologies with potential to improve welfare are under adopted and under-utilized once adopted. One possible cause for this inefficiency is ignoring fit risk (the risk the technology may not meet the needs of the potential adopter). This dissertation attempts to introduce fit risk in the development context and develops a framework to analyze resource misallocation when fit risk is not addressed by project donors and managers. We examine strategies to reduce fit risk, like pre-purchase demonstration to reduce waste and enhance intake. The dissertation analyzes when it is worth to incur costly demonstration of the technology that eliminates fit-risk, and shows that the economic net benefit of costly demonstration is non-monotone in the probability of technology fit. Demonstration is not worthy when the probability of non-suitability of the technology is either too high or too low. Even if well-implemented demonstration eliminates fit-risk and improves project value, it does not necessarily increase take-up of the technology. Ignoring fit-risk or misunderstanding demand in the presence of fit-risk can lead to miscalculating project values in development projects and to making wrong support decisions. The predictions of the model are tested using a randomized controlled trial (RCT) in the case of vision aid technology (eyeglasses) in rural Cambodia. The analysis recognizes heterogeneity among individuals with respect to the benefit from glasses where eyesight is the proxy variable for different levels of likelihood of fit. Our empirical study shows that a one-week free trial (a type of demonstration) increased the take-up rate for the middle-fit group (mild vision impairment), while it decreased for the high-fit group (substantial vision impairment). While overall intake of the eyeglasses did not change much, people who purchased eyeglasses after the one-week free trial tended to use their eyeglasses more frequently than people who purchased the eyeglasses after only a single, ten-minute fitting process. This implies that such marketing efforts can lead to better allocation of technology and improve technology provision efficiency even if they do not necessarily increase take-up.

Advisor: Zilberman, David
Infinitary Limits of Finite Structures

We study three distinct ways of assigning infinitary limits to classes of finite structures. We are primarily concerned with logically motivated questions about these limit objects and their theories, as well as connections and analogies between them./nIn the first part, we consider limits of sequences of finite structures which converge with respect to densities of quantifier-free formulas, generalizing the dense graph limits and similar structural limits studied in combinatorics. A convergent sequence determines, as a limit object, a certain kind of probability measure on the space of countable structures with domain $\omega$, which we call an ergodic structure. After developing the background theory, we take up the case of properly ergodic structures, which do not assign full measure to any single isomorphism class. The main result is a purely logical characterization of those theories in countable fragments of $L_{\omega_1,\omega}$ which arise as the theories of properly ergodic structures./nIn the second part, we study categories consisting of finite structures and certain ``strong" embeddings between them. We identify a necessary and sufficient condition for the well-definedness of strong embeddings between infinite direct limits from the category. This allows us to develop the natural generalization of classical Fra\"iss\'e theory in this context, with a focus on topology and genericity, in the sense of Baire category, in the space of direct limits with domain $\omega$. We elaborate on an analogy between these generic limits and the measure limits in the first part, and we examine model-theoretic properties of generic limits./nIn the third part, we take up logical limits, in the sense of ultraproducts and zero-one laws. In contrast to the first two parts, the limit theories here are always pseudofinite. We focus on countably categorical theories, which are essentially generic theories of small Fra\"iss\'e classes, and we show that higher amalgamation properties (disjoint $n$-amalgamation for all $n$) are sufficient to prove pseudofiniteness by a probabilistic argument. We examine relationships between pseudofiniteness, higher amalgamation, and model theoretic dividing lines, especially simplicity and NSOP$_1$. Our hope is that in ``purely combinatorial" situations, pseudofiniteness should always be explained by randomness, via higher amalgamation; in an attempt to isolate these situations, we define the class of primitive combinatorial theories.

Advisor: Scanlon, Thomas
Printed Organic Thin Film Transistors, Photodiodes, and Phototransistors for Sensing and Imaging

Light and image sensors are ubiquitous and used in a wide variety of applications ranging from consumer products to healthcare and industrial applications. The signal-to-noise ratio (SNR) from a photodetector element increases with larger photoactive area, which is costly to scale up using silicon wafers and wafer-based microfabrication. On the other hand, the performance of solution-processed photodetectors and transistors is advancing considerably. It is proposed that the printability of these devices on plastic substrates can enable low-cost areal scaling for high SNR light and image sensors./nThis thesis advances the performance of printed organic thin film transistor (OTFT), pho- todiode (OPD), and phototransistor (OPT) devices optimized for light and image sensing applications by developing novel printing techniques and creating new device architectures. An overview is first given on the essential figures of merit for each of these devices and the state of the art in solution-processed image sensors. A novel surface energy-patterned doc- tor blade coating technique is presented to fabricate OTFTs on flexible substrates over large areas. Using this technique, OTFTs with average mobility and on-off ratios of 0.6 cm^(2)/Vs and 10^(5) are achieved, which is competitive with amorphous silicon TFTs. High performance OPDs are also fabricated using doctor blade coating and screen printing. These printing processes give high device yield and good controllability of photodetector performance, enabling an average specific detectivity of 3.45×10^(13) cm·Hz^(0.5)·W^(-1) that is higher than silicon photo- diodes (10^(12-13)). Finally, organic charge-coupled devices (OCCDs) and a novel OPT device architecture based on an organic heterojunction between a donor-acceptor bulk heterojunction blend and a high mobility semiconductor that allows for a wide absorption spectrum and fast charge transport are discussed. The OPT devices not only exhibit high transistor and photodetector performance, but are also able to integrate photogenerated charge at video frame rates up to 100 frames per second with external quantum efficiencies above 100%. Applications of these devices include screen printed OTFT backplanes, large-area OPDs for pulse oximeter applications, and OPT-based image sensors.

Advisor: Arias, Ana Claudia
Methods for Optimal Stochastic Control and Optimal Stopping Problems Featuring Time-Inconsistency

This thesis presents novel methods for computing optimal pre-commitment strategies in time-inconsistent optimal stochastic control and optimal stopping problems. We demonstrate how a time-inconsistent problem can often be re-written in terms of a sequential optimization problem involving the value function of a time-consistent optimal control problem in a higher-dimensional state-space. In particular, we obtain optimal pre-commitment strategies in a non-linear optimal stopping problem, in an optimal stochastic control problem involving conditional value-at-risk, and in an optimal stopping problem with a distribution constraint on the admissible stopping times. In each case, we relate the original problem to auxiliary time-consistent problems, the value functions of which may be characterized in terms of viscosity solutions of a Hamilton-Jacobi-Bellman equation.

Advisor: Evans, Lawrence C
Reactivating Latent HIV-1

Complete eradication of HIV-1 infection is impeded by the existence of cells that harbor chromosomally integrated but transcriptionally inactive provirus. These latently-infected cells can persist for years without producing viral progeny, rendering them refractory to immune surveillance and antiretroviral therapy and providing a permanent reservoir for the stochastic reactivation and reseeding of HIV-1. Strategies for purging this latent reservoir are thus needed to eradicate infection. Here we show that engineered transcriptional activation systems based on CRISPR/Cas9 can be harnessed to activate HIV-1 expression in cell line models of latency. We utilized two distinct CRISPR transcriptional activation systems, dCas9-VP64 and the synergistic activation mediator (SAM) complex, to target numerous sites across the HIV-1 long terminal repeat (LTR) promoter and observed robust expression from the full-length HIV-1 promoter in multiple cell line models of HIV-1 latency. We further demonstrated that complementing Cas9 activators with latency-reversing compounds can enhance latent HIV-1 transcription and that epigenome modulation using CRISPR-based acetyltransferases could also promote viral gene activation. Finally, we showed that latent HIV-1 expression could also be stimulated by CRISPR-mediated activation of endogenous factors not previously implicated in HIV-1 pathogenesis but whose expression could nonetheless reactivate viral gene expression. Collectively, these results demonstrate that CRISPR systems are potentially effective tools for inducing latent HIV-1 expression and that their use, in combination with antiretroviral therapy, could lead to improved therapies for HIV-1 infection.

Advisor: Schaffer, David V
Earth versus Neutrinos: Measuring the total muon-neutrino-to-nucleon cross section at ultra-high energies through differential Earth absorption of muon neutrinos from cosmic rays using the IceCube Detector

The IceCube Neutrino Detector at the South Pole was constructed to measure the flux of high-energy neutrinos and to try to identify their cosmic sources. In addition to these astrophysical neutrinos, IceCube also detects the neutrinos that result from cosmic ray interactions with the atmosphere. These atmospheric neutrinos can be used to measure the total muon neutrino-to-nucleon cross section by measuring neutrino absorption in the Earth. The measurement involves isolating a sample of 10,784 Earth-transiting muons detected by IceCube in its 79-string configuration. The cross-section is determined using a two-dimensional fit in measured muon energy and zenith angle and is presented as a multiple of the Standard Model expectation as calculated by Cooper-Sarkar, Mertsch, and Sarkar in 2011. A multiple of 1.0 would indicate agreement with the Standard Model. The results of this analysis find the multiple to be 1.30 (+0.21 -0.19 statistical) (+0.40 -0.44 systematic) for the neutrino energy range of 6.3 to 980 TeV, which is in agreement with the Standard Model expectation.

Advisor: Shapiro, Marjorie D.
Klein, Spencer R.
Base(ic) Transfigurations: Race and the Cultural Logics of Flow Along US Bases in Okinawa

What happens when concepts of “security” that circulate at a more global level consolidate around concepts of race, gender, or other factors at the local level in Okinawa and how and what precipitates the fragmentation of those consolidated imaginaries for US Americans in Okinawa? With the ever increasing consolidation of joint US-Japanese military power in Okinawa and the attempts to secure the narratives to frame “sacrifice” and “global security,” how do those people most vulnerable to these discursive claims — specifically women, children, mixed race Okinawans, and military personnel of color, and economically insecure military personnel — find ways to maneuver from these interpellations? And more importantly, how do they shift the discourse that thrives on postcolonial states of exception?/nThis research project focuses on how people craft themselves as globally flexible in these local “in-between” militarized sites to restructure their own resistance and modes of knowledge-making against what sometimes seems to be insurmountable militarized conditions. This project explores how these flexibilities are shaped, 1) spatially at the interstices of binaries marked as on/off base spaces, 2) in circulating discursive maneuvering by long-term expatriates and military personnel living in Okinawa, 3) by mixed race Okinawans and Black soldiers whose histories are indelibly marked within Okinawan spaces of coloniality, and 4) by artists and performers attempting to shape concepts of friendship, flow and hybridity with alternative discourses, all of which are strongly linked to the maintenance of security imaginaries on the island./nI argue that life situated within Okinawan partial sovereignty, is always affected by the rubric of national security that attempts to bridge the temporal gap between WWII and the more ambiguous, global “war on terror.” Therefore, alternative trajectories for pushing past the cultural logics that deem Okinawans as simply stuck “in the middle” of a geopolitical situation require savvy interlocutors who can flexibly and delicately dodge the disciplining effects of state power and transnational security imaginaries. I argue these actors rewrite cultural codes of “flow” and commercialized hybridity that weave together perspectives of the insecurely rooted, the routinely racialized via security talk, and the globally and locally dislocated subjects in uneven spaces of privilege at the Okinawan fencelines.

Advisor: Graburn, Nelson
Fast Randomized Algorithms for Convex Optimization and Statistical Estimation

With the advent of massive datasets, statistical learning and information processing techniques are expected to enable exceptional possibilities for engineering, data intensive sciences and better decision making. Unfortunately, existing algorithms for mathematical optimization, which is the core component in these techniques, often prove ineffective for scaling to the extent of all available data. In recent years, randomized dimension reduction has proven to be a very powerful tool for approximate computations over large datasets. In this thesis, we consider random projection methods in the context of general convex optimization problems on massive datasets. We explore many applications in machine learning, statistics and decision making and analyze various forms of randomization in detail. The central contributions of this thesis are as follows:/n(i) We develop random projection methods for convex optimization problems and establish fundamental trade-offs between the size of the projection and accuracy of solution in convex optimization./n(ii) We characterize information-theoretic limitations of methods that are based on random projection, which surprisingly shows that the most widely used form of random projection is, in fact, statistically sub-optimal./n(iii) We present novel methods, which iteratively refine the solutions to achieve statistical optimality and enable solving large scale optimization and statistical inference problems orders-of-magnitude faster than existing methods./n(iv) We develop new randomized methodologies for relaxing cardinality constraints in order to obtain checkable and more accurate approximations than the state of the art approaches.

Advisor: Wainwright, Martin J
El Ghaoui, Laurent
Hierarchical Urban Transit System Design for Reducing Greenhouse Gas Emissions and Societal Costs

Public transit systems with efficient designs and operating plans can reduce greenhouse gas (GHG) emissions relative to low-occupancy transportation modes, but many current transit systems have not been designed to reduce environmental impacts. This motivates the study of the benefits of design and operational approaches for reducing the environmental impacts of transit systems. For example, transit agencies may replace level-of-service (LOS) by vehicle miles traveled (VMT) as a criterion in evaluating design and operational changes. Previous studies have demonstrated in an idealized single-technology transit system the potential of reducing GHG emissions by lowering the transit level-of-service (LOS) provided to the users./nIn this dissertation, I extend the analysis to account for a more realistic case: a transit system with a hierarchical structure (trunk and feeder lines) providing service to a city where demand is elastic. By considering the interactions between the trunk and the feeder systems, the study provides a quantitative basis for designing and operating integrated urban transit systems that can reduce GHG emissions and costs to both transit users and agencies. The study shows that highly elastic transit demand may cancel emission reduction potentials resulting from lowering LOS, due to demand shifts to lower occupancy vehicles, causing unintended consequences. However, for mass transit modes, these potentials are still significant. Transit networks with buses, bus rapid transit or light rail as trunk modes should be designed and operated near the cost-optimal point when the demand is highly elastic, while this is not required for metro. I also find that the potential for unintended consequences increases with the size of the city. The results are robust to uncertainties in the costs and emissions parameters./nThe study also includes a discussion of a current transit system. Since many current transit systems have not yet been optimally designed, it should be possible to reduce their GHG emissions without sacrificing the LOS. A case study of the MUNI bus system in San Francisco is used to validate this conjecture. The analysis shows that reductions in GHG emissions can be achieved when societal costs are reduced simultaneously. The cost-optimal MUNI bus system has a societal cost of 0.15 billion $/year and emits 1680 metric tons of greenhouse gases. These figures only amount to about half of the cost and a third of the emissions in the current MUNI bus system. The optimal system has a lower spatial availability but a higher temporal availability of bus service than the current system, which highlights the potential benefits of providing more frequent express bus services.

Advisor: Madanat, Samer
Horvath, Arpad