VictorJuiz/thesis huggingface dataset:
Efficient universal estimators for symmetric property estimation

Given i.i.d samples from an unknown distribution, estimating its symmetric properties is a classical problem in information theory, statistics, operations research and computer science. Symmetric properties are those that are invariant to label permutations and include popular functionals such as entropy and support size. Over the past decade, the study of time and sample complexities for estimating properties of distributions has received great attention leading to computationally efficient and sample optimal estimators for various symmetric properties. Most of these estimators were property specific and the design of a single estimator that is sample optimal for any symmetric property remained a central open problem in the area. In a seminal result, Acharya et al. showed that computing an approximate profile maximum likelihood (PML) distribution, a distribution that maximizes the likelihood of the observed multiset of frequencies, allows statistically optimal estimation of various symmetric properties. However, since its introduction by Orlitsky et al. in 2004, efficient computation of approximate PML distributions remained a well-known open problem. In our work, we resolved this question by designing the first efficient algorithm for computing an approximate PML distribution. More broadly our investigation has led to a deeper understanding of various computational and statistical aspects of PML and universal estimators. Additional results include the design of better algorithms for deterministic permanent approximation, new rounding algorithms, faster optimization methods and novel techniques for statistical analysis

Keywords: Management Science and Engineering.
Advisor: Charikar Moses
Sidford Aaron
Valiant Gregory
Eigenvalue shrinkage methods in high-dimensional estimation

This thesis studies applications of nonlinear eigenvalue shrinkage in high-dimensional estimation problems. We focus on applications in high-dimensional linear discriminant analysis and linear regression in the regime where the number of predictors and the sample size grow proportionately to infinity. Moreover, we study the problem of estimation of functions of large symmetric matrices in the presence of additive noise and provide an algorithm to approximate the optimally shrunk eigenvalues. We also study the problem of spectrum recovery, which serves as an intermediate step in the procedure that we describe

Keywords: Mathematics.
Advisor: Johnstone Iain
Ying Lexing
Candès Emmanuel J. (Emmanuel Jean)
Electromechanical phase shifters and power splitters for re-configurable integrated photonics

Photonic integrated circuits (PICs) are part of many growing applications, from LIDAR to biosensors. The complexity and functionality of these systems are only expected to become more demanding, so programmable PICs are expected to simplify the development effort by providing the same re-configurable circuit functionality as field programmable gate arrays (FPGAs) did for electronics development. The key devices for the development of programmable PICS are phase shifters and power splitters that allow for the arbitrary complex weighting and routing of optical signals on a chip. Each operation to change the state of the circuit using a phase shifter or power splitter consumes energy, so technologies that scale well in terms of power consumption are critical to achieve the necessary integration density. Unfortunately, common thermo-optic devices available in most PIC process kits will always require constant power to change and maintain the circuits configurations. A different technology that changes the paradigm is needed. Micro-electromechanical system (MEMS) based devices have emerged as such a displacing technology because they can be designed to have zero static power consumption when holding the circuit state. This dissertation provides key insights into the development of MEMS phase shifters and power splitters. Specifically, techniques for low insertion loss and process integration with silicon nitride photonics are presented. Coupled mode theory is applied to the design of the MEMS phase shifter to define a loss-loss geometry based on the orthogonality of modes. The concept is then expanded to define optimization objectives based that only require mode solver simulations. In simulation, the optimized silicon nitride designs proposed could achieve as little as 0.022dB insertion loss for a 100um long device. To experimentally demonstrate the low-loss designs, a novel silicon nitride process was developed. High aspect ratio structures needed in the design are achieved via a trench filling process. The release of the MEMS is based on XeF2 etching of silicon and not the silicon dioxide substrate or cladding of the silicon nitride photonics. The fabricated 100 um long MEMS phase shifters achieved 0.48dB zero voltage insertion loss with less than 0.05dB phase dependent loss over a pi phase range. Using the same process stack, an initial demonstration of a novel tunable power splitter based on a MEMS tunable directional coupler is made

Keywords: Electrical Engineering.
Advisor: Solgaard Olav
Miller D. A. B.
Vuckovic Jelena
Eliciting anti-tumor immunity via targeted immunostimulant therapy

Promoting immune activation within the tumor microenvironment (TME) is a promising therapeutic strategy to reverse tumor immunosuppression and elicit anti-tumor immunity. To enable tumor-localized immunotherapy following intravenous administration, we chemically conjugated a polyspecific integrin-binding peptide (PIP) to an immunostimulant (TLR9 agonist: CpG) to generate a tumor-targeted immunomodulatory agent, referred to as PIP-CpG. We demonstrate that systemic delivery of PIP-CpG induces tumor regression and enhances therapeutic efficacy compared to untargeted CpG in implanted murine breast and pancreatic cancer models. Furthermore, PIP-CpG therapy was able to inhibit tumor growth and prolong survival of MMTV-PyMT transgenic mice, which spontaneously develop multiple breast tumors. Mechanistically, PIP-CpG transforms the immunosuppressive TME into a lymphocyte-rich TME infiltrated with activated CD8+ T cells, CD4+ T cells, and B cells. This TME transformation was also observed upon treatment with intratumoral CpG but not systemic CpG, indicating that tumor-localized delivery is critical for remodeling the TME. Consistent with these findings, we show that tumor-specific effector CD8+ T cells are generated in response to PIP-CpG therapy and that T cells are required for therapeutic efficacy, demonstrating that efficient delivery of CpG to the tumor site elicits T cell-mediated anti-tumor immunity. Finally, we show that the efficacy of PIP-CpG can be enhanced using combination therapy with a T-cell-modulating anti-OX40 antibody. Overall, these results highlight the therapeutic potential of promoting immune activation in the TME and demonstrate that conjugating an immunostimulant to a tumor-targeting peptide is a viable strategy to achieve this goal

Keywords: Bioengineering.
Advisor: Bertozzi Carolyn R.
Cochran Jennifer R.
Appel Eric (Eric Andrew)
Levy Ronald
Eliminating bugs in real systems

Software is everywhere, and almost everywhere, software is broken. Some bugs just crash your printer; others hand an identity thief your bank account number; still others allow nation-states to spy on dissidents and persecute minorities. As software takes over our lives, bugs ossify and code gets older, more complicated, harder to reason about, and almost impossible to re-write from scratch. This thesis discusses how to make systems safer without requiring clean-slate re-writes: it presents systems that automatically find security bugs in large, existing, security-critical systems using techniques along the spectrum from lightweight bug finding the way to automated verification. These systems span the effort-to-payoff curve for checking and verification tools; they've found bugs in operating systems, runtime systems, and web browsers---including bugs with cash rewards (or bounties), and high-security, exploitable bugs with vulnerability designations (or CVEs)---and have verified a small portion of the Firefox browser

Advisor: Engler Dawson R. 
Boneh Dan
Stefan Deian
Elucidating mechanisms of acetyl-L-carnitine metabolism in mammalian cells

In eukaryotes carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for -oxidation. It also returns, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for post-translational protein modification to the nucleocytoplasm. Earlier work revealed that LAC supplementation has unexpected antidepressant effects in mammals while implicating an epigenetic mechanism for this property. To explain how exogenous LAC influences mammalian cell metabolism, we synthesized isotope-labeled forms of LAC and its analogs. In cultures of glucose-limited U87MG cells, exogenous LAC contributed more robustly to intracellular acetyl-CoA pools than did b-hydroxybutyrate, the predominant circulating ketone body in mammals. The fact that most LAC-derived acetyl-CoA is cytosolic is evident from strong biosynthetic labeling of fatty acids in U87MG cells by exogenous 13C2-acetyl-L-carnitine. Addition of d3-acetyl-L-carnitine increases the supply of acetyl-CoA for epigenetic uses due to its expectedly strong kinetic isotope effect on acetyl-CoA carboxylase, the first committed step in fatty acid biosynthesis. Surprisingly, whereas cytosolic carnitine acetyltransferase (CRAT) is believed to catalyze acetyl group transfer from LAC to Coenzyme A, CRAT-/- U87MG cells were unimpaired in their ability to assimilate exogenous LAC into acetyl-CoA. We identified carnitine octanoyltransferase (CROT) as the key enzyme in this process, implicating a role for peroxisomes in efficient LAC utilization. By engineering a carnitine analog with markedly superior selectivity for CROT over CRAT, our work has also opened the door to further chemical genetic investigations of a new pathway for supplying acetyl-CoA to certain glucose-starved cells

Keywords: Chemical Engineering.
Advisor: Khosla Chaitan
Abu-Remaileh Monther
Swartz James R.
Elucidation of calcineurin signaling in the context of the cell cycle, centrosomes and cilia

Calcineurin, a highly conserved Ca2+ and calmodulin-activated phosphatase, has been most extensively studied in the context of the adaptive immune response. Due to its role in activating T-lymphocytes, calcineurin inhibitors were prescribed as immunosuppressant medications long before their mechanism of action was understood. Calcineurin inhibitors, cyclosporin A and FK506, revolutionized the field of organ transplantation in the 20th century, but frequently cause adverse effects in patients due to inhibition of calcineurin in non-immune tissues. This underscores the importance of systematically determining the substrates and functions for this ubiquitous enzyme throughout the body. Calcineurin is activated by Ca2+ and calmodulin, thus signaling takes place within distinct intracellular subdomains. Through proximity-dependent biotinylation studies, we discovered that calcineurin is immediately proximal to proteins found at the cytokinesis midbody and the centrosome. We thus hypothesized that calcineurin participates in cell cycle regulation. While we were unable to reproduce previous reports that calcineurin is essential for cytokinesis and localizes to the midbody, we determined that in fact a novel calcineurin signaling subdomain exists at centrosomes and primary cilia. Calcineurin localizes to centrosomes, but this localization does not seem to depend on, nor control the timing of, the cell cycle. Instead, calcineurin presence at the centrosome allows it to interact with binding partners and potential dephosphorylation substrates such as proteome of centriole 5 (POC5). Inhibition of calcineurin causes kidney epithelial cells to lose their ability to maintain cilia length homeostasis. The precise mechanism through which calcineurin regulates cilia length maintenance remains to be uncovered. This will help us determine whether cilia abnormalities underlie some of the adverse effects that immunosuppressed patients experience

Keywords: Biology.
Advisor: Cyert Martha S.
Lewis Richard (Richard Sheridan)
Shen Kang
Stearns Tim
An embedded boundary method with smoothness guarantees and its impact on aerodynamic shape optimization with topological changes

Aerodynamic shape optimization using computational fluid dynamics (CFD) displaces the traditional aerodynamic design paradigm. Optimization algorithms automate the design generation process that is historically driven by engineering intuition, while CFD obviates the time-consuming and expensive construction of physical models. Embedded (or immersed) boundary methods (EBMs) for CFD are attractive for aerodynamic shape optimization problems characterized by large shape deformations and topology changes. They introduce a high degree of automation in the task of mesh generation and a significant flexibility in meshing complex geometries. Unfortunately, they suffer some disadvantages because they perform their computations on embedding, non body-fitted fluid meshes. In particular, they tend to generate discrete events that introduce discontinuities in the semi-discretization process and lead to unsmooth numerical solutions that are less than ideal for differentiation with respect to the evolution of a discrete, fluid/structure interface. This hinders the application of EBMs to the gradient-based solution of aerodynamic shape optimization problems. Discrete events also promote spurious oscillations in the post-processing of time-dependent results computed at the fluid/structure interface. This work addresses these issues in the context of FIVER, a comprehensive framework for developing EBMs for highly nonlinear, compressible, fluid/structure interaction (FSI) problems. It revisits the concept of the status of a node of an embedding fluid mesh and introduces that of a smoothness indicator nodal function, to eliminate discrete events and achieve smoothness in the semi-discretization process. It also introduces a moving least squares approach in the loads evaluation algorithm, to suppress spurious oscillations from integral quantities computed on the fluid/structure interface. Equipped with these enhancements, the newly created EBM FIVER$^{++}$ is shown to deliver, for three different applications, smooth, differentiable results. This work demonstrates the potential of shape-differentiable EBMs on several aerodynamic shape optimization problems. Most significantly, it showcases the optimization of a full configuration aircraft under turbulent flow, considering design spaces that involve deformations of the wing shape and airfoil section, as well as the placement of the nacelle-pylon on the wing

Keywords: Aeronautics and Astronautics.
Advisor: Farhat Charbel
Alonso Juan José
Fedkiw Ronald P.
Embodied character and the medieval novel : a study of "Lancelot" (c. 1220)

When "Lancelot" was composed in the first decades of the thirteenth century, it was the first large-scale work of vernacular prose fiction in the post-classical West. Despite its inauguration of a form which has endured for the last eight centuries, it has received scant attention from historians and theorists of the novel. This study argues for a reconsideration of its relevance, grounded in an excavation of its innovations in the treatment of character. Instead of arguing that Lancelot offers a primitive form of the characters we find in novels today, I show how its representation of human nature anchors character complexity in the body in unique ways

Keywords: Comparative Literature.
Advisor: Algee-Hewitt Mark
Starkey Kathryn
Galvez Marisa
Griffiths Fiona J.
Emergent dynamics of biological collectives

Across scales, biological systems frequently operate at the edge of chaos where they can balance competing needs for stability and adaptation. In this critical regime, details and variations at lower levels can propagate and drive behaviors at larger scales. Building understanding of how life emerges from these cross-scale interactions requires us to abstract this collective complexity into intuitive representations. But this is challenged our inability to simultaneously observe all the relevant scales driving the system's behavior. While single measurements may fail to capture all generative details of a system, dynamic trajectories can encode key information about the underlying processes. This thesis develops conceptual and technical approaches to address these challenges using dynamics data at two scales of biology. First, I study ecosystems, where species and the environment interact to create interconnected dynamic cycles. Using computational modeling and experimental data, I identify phenomenological evidence and mechanistic underpinnings by which complexity and its statistical regularity emerge from simple inter-species interactions ranging from microbial crossfeeding to the ocean food chain. Second, I study the behavior and nervous system of the planarian Schmidtea Mediterranea and demonstrate that it achieves remarkably robust memory and signal processing even as it regenerates an entire brain. By developing new high-throughput imaging platforms, analysis pipelines, and trainable neural signaling models, I find that planarians achieve their extreme behavioral robustness through overlapping networks of diffusive and synaptic interactions. The incoherent time and length scales of these different molecular signals create competitive control of firing patterns which is robust to massive structural injuries. This demonstration proposes a new principle by which neurons generate multi-scale activity patterns and opens new opportunities to explore the basis of functional neural dynamics in the planarian's structurally plastic nervous system

Keywords: Bioengineering.
Advisor: Wang Bo (Artificial intelligence scientist)
Linderman Scott
Prakash Manu
Enabling high-efficiency precision genome editing and writing through coupling of natural retron elements

CRISPR has revolutionized genome editing, but it remains challenging to incorporate desired edits with high-efficiency. Recently, a CRISPR-based technology named Cas9-Retron precISe Parallel Editing via homologY (CRISPEY) has precisely introduced thousands of specific genetic variants with each cell receiving one variant edit in a single experiment by facilitating homology-directed repair (HDR) using retrons, which are bacterial genetic elements that can produce an abundance of multicopy single-stranded DNA (msDNA) to act as donor DNA via RNA reverse transcription. However, CRISPEY is still limited by target site choices, compatible retron options, and the incorporation of longer insert lengths. To improve this system, my thesis tests the ability of a CRISPR-compatible Cas9 variant, xCas9 to cleave at NGA and NGT PAM sites, the ability of Myxococcus xanthus (Mx) retrons to produce msDNA as donor DNA to facilitate HDR, and the ability of an E. coli retron to incorporate the insertion of the NatMX6 gene in yeast cells. xCas9 showed a substantial amount of editing at NGA and NGT. The Mx retrons displayed 9% greater editing efficiency than the Ec86 retron used in the original CRISPEY construct. For the NatMX6 gene insertion, 96.9% of the cells contained the proper edit. These findings suggest a Cas9 variant that can expand target space while maintaining its functionality for the NGG PAM site is still needed. Meanwhile, the Mx retrons are shown to be promising bacterial retrons in improving editing efficiency. Additionally, the NatMX6 gene insertion showed CRISPEY has promising potential for genome writing. Improving CRISPEY will advance gene editing applications to better understand genetic outcomes and effectively develop treatments for genetic disorders.

Keywords:  Department of Biology
Biology, Molecular Genetics, CRISPR, Cas9, Retrons, Genome Editing
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Thesis
Advisor: Fraser Hunter
Qi Stanley
The energetics of split-belt walking

Split-belt treadmill walking is commonly used for stroke rehabilitation and motor learning experiments. In this dissertation, I considered split-belt walking from the perspective of mechanical energy. I first designed a split-belt rimless wheel simulation model to demonstrate how the split-belt treadmill could act as an external energy source providing power to a person during split-belt walking. I demonstrated that a split-belt rimless wheel can passively walk steadily forward on split belts, even though the same wheel would require energy to walk steadily on belts set to the same speed, known as tied belts. I then conducted a human-subject experiment measuring the energy cost of walking for a variety of both split- and tied-belt speed combinations. I found that the energy cost for human split-belt walking is similar to the cost of tied-belt walking at the average belt speed. Increasing the belt speed difference tends to increase the energy cost of walking. This suggests that people are not able to take advantage of the treadmill power to lower their energy costs. Finally, I conducted an experiment to understand why positive treadmill power during split-belt walking is not metabolically beneficial. I found that people dissipated the treadmill energy rather than using the power effectively, and the gait adjustments required to achieve net positive treadmill work caused other walking costs to increase. These energy-cost findings inform future split-belt treadmill experiments by enabling researchers to design protocols with consistent levels of energetic load. Our understanding of how people interact with positive treadmill work enables assistive device designers to analyze whether their devices provide work such that people use the work effectively rather than dissipating it

Keywords: Mechanical Engineering.
Advisor: Collins Steve (Steven Hartley)
Delp Scott
Okamura Allison