VictorJuiz/thesis huggingface dataset:
Diagnostic Raman spectroscopy : from liquid phase bacterial identification to co-incubation free antibiotic susceptibility testing

Bacterial bloodstream infections account for over 40% of deaths in hospitals and are one of the most expensive medical conditions in the US. Globally, a child dies every 20 seconds due to infections. Current diagnostic methods are slow and costly, due to the long bacterial culturing step required for detection, identification, and antibiotic susceptibility testing. My work utilized Raman spectroscopy for rapid culture-free, sensitive, and specific bacterial identification and antibiotic susceptibility testing. Despite such promise, Raman's clinical translation has lagged due to reproducibility issues, bulky spectroscopy equipment needs and challenges in clinically suited sample preparation. This thesis demonstrates three major milestones to address these issues by using machine learning and nanophotonics. First, we develop a novel and robust liquid well setup for clinical sample handling with uniform Raman spectral enhancement using gold nanorods. Second, we demonstrate promising antibiotic susceptibility prediction on 100 patient derived E. coli samples with diverse response profiles to 15 major antibiotics. Third, we enable design of lower resolution more affordable spectrometers by implementing feature recognition approaches to isolate bands of spectra that are key for the accurate classifications. This work opens the door for clinical translation of novel spectroscopy based diagnostic tools for identifying bacterial infections, viral infections such as the current COVID-19 virus, early cancer detection and drug susceptibility testing by merging machine learning and nanophotonics

Keywords: Bioengineering.
Advisor: Dionne Jennifer Anne
Brongersma Mark L.
Prakash Manu
Differentiable and bilevel optimization for control in robotics

In this dissertation, we investigate an up-and-coming class of mathematical programs, bilevel optimization, and how it can be leveraged to tackle the most pressing algorithmic challenges of control in robotics. In this dissertation, we give an overview of our work on bilevel optimization, where two mathematical programs are nested into one another, and our progress on leveraging this class of problems to move us closer to computationally tractable control of nonlinear systems. Specifically, we demonstrate how it is possible to design novel solution methods that utilize advances in automatic differentiation while retaining the benefits of state of the art constrained nonlinear optimization solvers. We also demonstrate how particularly challenging problems of nonlinear control such as planning through contact, adversarial learning of value functions, and Lyapunov synthesis can all surprisingly be tackled by explicitly addressing them as bilevel optimization problems

Keywords: Aeronautics and Astronautics.
Advisor: Pavone Marco
Bohg Jeannette
Kennedy Monroe
Manchester Zachary
The differential roles of monocytes and neutrophils in inflammation-induced neurological dysfunction

Patients with inflammatory disorders frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed. There are many hypotheses as to why peripheral inflammation and neurological conditions co-occur; however, there have been few mechanistic studies demonstrating a causal relationship, and investigations of these mechanisms have yielded contradictory results. Further, neuroinflammation can exist in patients with neurological disorders who do not have a diagnosed autoinflammatory disease. Because the vast majority of studies investigating the occurrence and impact of neuroinflammation on brain function have utilized models of primary neurological disease, it is difficult to uncouple the role of the primary neurological pathology from that of inflammation. To more clearly understand the mechanisms by which peripheral inflammatory disease causes neurological symptoms, it is therefore necessary to employ models of peripheral inflammation in which the brain is not initially involved. In this thesis, I utilize a murine colitis model in which colitic mice demonstrate enhanced seizure susceptibility to untangle the differential role of monocytes and neutrophils on neurological dysfunction in the absence of a primary neurological disorder. I further present investigations into the neuroinflammatory phenotype of patients with epilepsy and pediatric acute-onset neuropsychiatric syndrome (PANS)

Keywords: Immunology.
Advisor: Engleman Edgar G.
Bendall Sean
Buckwalter Marion
Mellins Elizabeth
A dipolar quantum liquid trapped in quasi-one dimension

Highly excited eigenstates of interacting quantum systems are generically thermal; regardless of initial conditions, physical observables behave as they would in thermal equilibrium at times past the intrinsic dynamical time scale. Systems in which thermalization is absent are of great fundamental interest because they violate equilibrium statistical mechanics, and of technological interest because some quantum information encoded in these states evades decoherence. For the purpose of tackling this line of inquiry, ultracold neutral atoms in dilute gas offers a tabletop platform that is highly configurable, readily scalable, and well isolated from the environment. In this dissertation, I summarize our efforts of creating non-thermal states in a bosonic quantum gas of dysprosium, the most magnetic element, confined in quasi-one-dimensional waveguides. With long-range dipole-dipole repulsion that is two orders of magnitude stronger than alkali atoms, a highly excited super-Tonks-Girardeau gas is stabilized against collapse and thermalization. Stiffness and energy-per-particle measurements indicate that the system is dynamically stable regardless of contact strength. This metastability enables the cycling of contact interaction from weakly to strongly repulsive, then strongly attractive, and finally weakly attractive via two neighboring magnetically tuned collisional resonances. Iterating this quantum holonomy cycle constitutes an energy-space topological pump that creates a hierarchy of increasingly excited prethermal states. In addition to being the first systematic experimental investigation of a dipolar Luttinger liquid, the result opens up an unexplored regime of quantum control and may have wide-ranging implications for understanding the onset of chaos in near-integrable systems

Keywords: Applied Physics.
Advisor: Lev Benjamin L.
Bucksbaum Philip H.
Schleier-Smith Monika
Directing desire : intimacy directing, consent, and simuated sexuality on the contemporary U.S. stage

From 2016 to 2020, intimacy choreography transformed from a grassroots effort into a best practice accepted on film sets and Broadway productions. Influenced by fight choreography and movement direction, intimacy choreographers deploy a repertoire of consent-based practices to craft scenes of sex and sexuality for performance. Directing Desire analyzes the rise of intimacy choreographers in the twenty-first century as a product of colliding norms of consent culture and sex positivity. While intimacy choreography consciously emphasizes consent, the practice more subtly challenges a central assumption of sex positivity: that intimacy should express sexual interiority. Intimacy choreography separates performer and character; it creates what I term "simulated sexuality, " the iterative and citational performance of sexual desire in a theatrical frame. With this model, I advance theatrical intimacy beyond the logics of repression and liberation—what Michael Foucault calls the "repressive hypothesis"—that have governed the theater's treatment of sexuality since the advent of theatrical modernism in the United States. To ground theatrical intimacy historically, I analyze the spread of positivist models of sexuality in Stanislavskian and Method acting in the United States starting in the 1930s. Directors including Lee Strasberg and Sanford Meisner attempted to privatize theatrical intimacy as a product of the performer's individual desire. By contrast, I advance a de-privatized model of intimacy centering shared choreography and simulation, the "stylized repetition of acts" with difference. I apply this model to twenty-first-century playscripts and performances from Jeremy O. Harris, Alice Birch, Thomas Bradshaw, and Punchdrunk, among other artists. A focus on shared choreography makes intimacy more accessible to survivors of sexual violence, subjects on the asexual spectrum, and those hypersexualized and desexualized by cultural stereotypes. Beyond promoting consent, intimacy choreography can craft a "sexual commons" in which artists negotiate their relationship to intimacy in the wake of racialization and empire

Keywords: Theater and Performance Studies.
Advisor: Al-Saber Samer 
Freedman Estelle B.
Smith Matthew Wilson
Discovering RNA functions and its use in genetic interpretation

RNA has both genotype and phenotype. The production of RNA, the RNA itself, and the proteins it produces all serve important roles in the maintenance of life. RNA sequencing has allowed us to learn about the biological function and impact on human health of specific RNAs and genetic variants. Motivated by the desire to discover new chromatin-associated RNAs, chapter 2 details a biochemical and computational method to identify interactions between RNA and DNA through a novel hybrid sequencing technique. Chapter 3 focuses on the identification of mostly repetitive centromeric DNA in Xenopus laevis to permit future RNA sequencing studies with the goal of learning about the role of transcription at the centromere. Because RNA serves as a functional read-out of genomic regulatory regions and it contains information that may translate into protein coding differences, chapter 4 shares methods for diagnosing a diverse set of rare diseases from blood RNA sequencing data. Finally, chapter 5 shows that nonsense mediated decay efficiency is stable across individuals and tissues, which is useful for interpreting variants of unknown significance using predictive models or through RNA sequencing of accessible tissues or cell lines. The methods and findings throughout this thesis will allow for future advances in the use of RNA sequencing for discovering biological functions and its use in genetic interpretation

Keywords: Genetics.
Advisor: Montgomery Stephen
Bassik Michael
Fire Andrew Zachary
Vollrath Doug
Discovery and Characterization of a cGAMP-Specific ENPP1 Mutant

Cancer immunotherapy is a rapidly growing field that utilizes the body’s intrinsic ability to avert disease through adaptive and innate immunity. Recently, immunotherapy research has found that the stimulator of interferon genes (STING) pathway induces a potent antiviral and anticancer immune response through the production of interferons (IFNs), a cytokine family that amplifies the immune response. A hallmark of genomically unstable cancer cells is the shedding of self-dsDNA into the cytosol, which activates the STING pathway via cyclic GMP-AMP (cGAMP) as a second messenger. However, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) decreases the levels of extracellular cGAMP and reduces IFN production, thereby weakening the immune response. This work sought to identify a point mutation in ENPP1 that eliminates its cGAMP hydrolysis activity whilst retaining its catalytic activity for other messengers, such as ATP. The goal of this effort is to increase downstream IFN levels and stimulate an anticancer immune response. Through screening a panel of induced point mutations by enzyme kinetic experiments such as radioactive TLC and CellTiter-Glo assay, we discovered that the residue H362 is critical for cGAMP hydrolysis, but does not alter ATP hydrolysis. ENPP1 H362 mutants will be a tool to uncouple the effects of extracellular cGAMP and ATP, expand our understanding of extracellular cGAMP signaling mechanisms in cancer, and potentially serve as a noninvasive cancer therapeutic.

Keywords:  Department of Biology
Biology
cGAMP
STING
ENPP1
H362
IFN
Immunotherapy
Thesis
Advisor: Li Lingyin
Dixon Scott
Discovery and characterization of a neuroligin-3 binding partner in gliomas and oligodendrocyte progenitors

Gliomas exhibit diverse genetic aberrations, spatiotemporal growth patterns and clinical outcomes, but are commonly regulated by a dynamic and multifaceted microenvironment that includes neurons. These neurons support glioma growth in part via shed or secreted trophic factors. Neuroligin-3 (NLGN3) is one such factor that functions as a critical microenvironmental determinant of low- and high-grade glioma growth, but its cognate binding partner on glioma cells has thus far eluded identification. Here, we establish that neuronal activity-induced shedding of NLGN3 ectodomains is detected by gliomas and normal oligodendrocyte precursors via binding to chondroitin sulfate proteoglycan 4 (CSPG4). Unexpectedly, NLGN3 binding triggers CSPG4 proteolysis and intracellular signaling that promotes growth of gliomas and inhibits differentiation of healthy oligodendrocyte precursors. Our results provide insight into how glioma cells and their normal counterparts sense, translate and respond to neuronal activity in their microenvironment and suggest a way forward in therapeutically targeting this signaling axis

Advisor: Monje-Deisseroth Michelle
Ting Alice Y.
Zuchero J.
Van Rechem Capucine
Discovery and characterization of glyco-immune checkpoints

Glycans are complex polysaccharides that decorate the surface of every cell in the human body and have functions spanning many essential aspects of cell and organismal biology. Despite the importance of glycans to normal physiology and disease, relatively few drugs targeting mammalian glycans have been developed, in part due to the challenge of identifying glycans that are the causative agents of disease. In this thesis, I describe the discovery of glycans and glycan receptors that contribute to cancer and neurodegenerative disease by tuning immune cell function. Chapter 1 surveys drug development efforts in glycobiology through an historical lens and examines how identification of suitable targets is among the largest impediments to development of glycan-directed therapeutics. Chapter 2 details efforts to identify glycans that contribute to cancer growth. I find that MYC, one of the most commonly dysregulated human oncogenes, coordinates production of glycans that promote malignancy. I discover a specific glycan that facilitates tumor progression by enabling leukemia cells to engage immune cell Siglec receptors and avoid clearance by phagocytes. Chapter 3 expands on cancer glycosylation by identifying the glycolipid GD2 on neuroblastoma as an additional ligand for macrophage Siglecs. These data provide a molecular rationale for a novel immunotherapy comprising combined blockade of GD2 and CD47. Chapter 4 describes the use of CRISPR/Cas9 genetic screens to discover and characterize physiologically relevant glycan-receptor interactions. Microglia expressing the Siglec CD22 are found to have impaired phagocytic capacity which contributes to age-related cognitive decline. In sum, this dissertation identifies glycan targets in cancer and neurodegeneration, and presents a framework for further drug development efforts in glycobiology

Keywords: Chemical and Systems Biology.
Advisor: Bertozzi Carolyn R.
Chen James Kenneth
Felsher Dean (Dean Walton)
Wandless Thomas
Discovery and engineering of metabolite-based defense mechanisms in plants

Plants have developed intricate biochemical systems to detect and respond to pathogens in the environment. Improved fundamental understanding of these processes will allow us to engineer plants for improved pathogen defense, ultimately improving yields in agriculture. In this work, we discovered a new metabolite, N-hydroxy-pipecolic acid (NHP), that we found is integral to the plant defense response systemic acquired resistance (SAR). SAR is a whole-plant response that is induced at a pathogen infection site and leads to broad-spectrum disease resistance in uninfected tissues. Treatment of plants with NHP provided enhanced defense against bacterial pathogens, but not without fitness costs in certain contexts. This inability of plants to balance defense and growth led us to investigate the role of a glycosylated derivative of NHP that accumulates in Arabidopsis. We found a dedicated glycosyltransferase for NHP that is also biochemically active on the core plant defense hormone salicylic acid. We provide evidence that this enzyme acts to convert these biochemically active small molecules into their glucose conjugates to temper immune responses. Next, we discovered that several important crop species produce and respond to NHP. With this knowledge, we used metabolic engineering to overproduce NHP in tomato plants and showed that it could improve defense against a bacterial pathogen. To conclude, we provide a framework for using synthetic biology and directed evolution to engineer plant receptor systems for expanded detection and defense capabilities. This work establishes the metabolic basis for SAR in Arabidopsis and provides new insight into how plants regulate small molecule biosynthesis to tailor responses to environmental stimuli

Keywords: Chemical Engineering.
Advisor: Sattely Elizabeth
Mudgett Mary Beth
Spormann Alfred M.
Swartz James R.
Discovery and engineering of terpenoid biosynthesis in plants

Plant terpenoids are structurally complex products with important and diverse sets of bioactivities. To date, the biosynthetic route to many terpenoids remains unknown. Elucidation of a complete biosynthetic pathway to terpenoids precludes engineering efforts for production in a heterologous host or efforts for in situ production in a different plant. We address this challenge through rapid gene screening in N. benthamiana, a heterologous plant host. Here, we worked on pathways and biology for three important targets: (1) momilactones from rice, an allelopathic molecule exuded by rice roots that inhibits the growth of neighboring plants, (2) limonoids from citrus, molecules with diverse biological properties, and (3) the chemotherapeutic taxanes from pacific yew. In addition to identifying minimum set of genes for pathway reconstitution, we have engineered a plant heterologous host for increased yields. These efforts enabled isolation and purification at milligram quantities of hard-to-access pathway products and derivatives and perform biological assays and structural elucidation

Keywords: Chemical Engineering.
Advisor: Sattely Elizabeth
Abu-Remaileh Monther 
Spormann Alfred M.
Discovery of novel low dimensional and photocathode materials using materials data and simulations

Utilizing computational methods for uncovering new materials with desirable properties is a powerful tool for materials discovery. The grand goal of these approaches is to efficiently search through all of material space in order to find the best candidates for any application. Compared to traditional "trial-and-error" based materials discovery approaches, computational materials discovery allows for: i) a diverse range of materials can be explored, beyond the already successful spaces, ii) easier optimization over multiple performance metrics, and iii) statistically motivated insights into the materials space can be derived. However, discovering materials in this manner is a very difficult optimization problem that can involve assessing hundreds of thousands of candidate materials according to multiple selection criteria. Understanding how to best utilize these materials datasets is therefore an open problem that requires the development of screening methodologies. In this dissertation, I explore the use of data-driven materials discovery methods for discovering new assembly-free van der Waals heterostructures and high brightness photocathode materials. Additionally, I will discuss the development new machine-learning methodologies to improve the efficiency and success of computational-based material discovery efforts

Keywords: Chemistry.
Advisor: Reed Evan J. 
Devereaux Thomas Peter
Martinez Todd J. (Todd Joseph)
Distributed procedure call

Communication performance is a critical factor when building distributed systems; communication costs can account for a non-trivial fraction of an application's service time. This has motivated many advances in raw communication performance, including both increased throughput and decreased latency. Unfortunately, these efforts ignore a more fundamental drain on communication performance: today's most common communication patterns, which result from the use of Remote Procedure Calls (RPCs), are inefficient and create otherwise unnecessary communication. With a more flexible communication pattern, it is possible to eliminate unnecessary communication, reduce the number of network hops, and ultimately improve the end-to-end latency of distributed executions. To that end, this dissertation presents Distributed Procedure Call (DPC), a new communication primitive designed to support a "multi-hop" communication pattern for distributed systems. Multi-hop communication breaks the one-to-one mapping between requests and responses in traditional RPCs. With DPC, a server can delegate a request to one or more additional servers before responses are sent, forming a tree of requests. This allows DPC to reduce latency by eliminating messages and network hops. Compared to RPC, DPC can reduce end-to-end communication latency by 18% to 49% in a variety of applications without harming throughput. DPC makes it easy for applications to take advantage of multi-hop communication. DPC's simple and general-purpose abstraction allows applications to dynamically form distributed executions. Behind this abstraction, the DPC protocol manages the multi-hop communication, matching request and response messages, and providing DPC completion and failure detection. Furthermore, DPC can be implemented as a library. This shields applications from the complexities of multi-hop communication and allows applications to focus on the logic of their distributed execution. DPC gives developers a new tool to build and optimize distributed systems

Advisor: Ousterhout John K.
Prabhakar Balaji
Winstein Keith
Distributionally robust optimization and its applications in mathematical finance, statistics, and reinforcement learning

Distributionally robust optimization (DRO) is a zero-sum game between a decision-maker and an adversarial player. The decision-maker aims to minimize the expected loss, while the adversarial player wishes the loss to be maximized by replacing the underlying probability measure with another measure within a distributional uncertainty set. DRO has emerged as an important paradigm for machine learning, statistics, and operations research. DRO produces powerful insights in terms of statistical interpretability, performance guarantees, and parameter tuning. In this thesis, we apply DRO to three different topics: martingale optimal transport, convex regression, and offline reinforcement learning. We show how the DRO formulations/techniques improve the existing results in the literature

Keywords: Mathematics.
Advisor: Blanchet Jose H.
Glynn Peter W.
Papanicolaou George