VictorJuiz/thesis huggingface dataset:
Structural response of iron oxides to irradiation

Iron oxides are ubiquitous in Earth and planetary systems and can display a variety of structures and stoichiometries. Iron oxides have several industrial applications, some of which function more efficiently when they are irradiated. One form of irradiation, swift heavy ion (SHI) irradiation, deposits large amounts of energy (> 1 MeV/u) into nano- to micrometer scale volumes. The energy is dissipated by electronic excitation along a trajectory that leaves behind tracks of damage that are several nanometers in diameter and tens of micrometers in length. Understanding the physics of ion track formation and annealing has improved our understanding of fission-track age dating and thermochronology. This work presents the effects of iron oxides’ structure and stoichiometry on their radiation stability.
Two iron oxides, hematite (α- Fe2O3, R-3c) and magnetite (Fe3O4, 𝐹𝑑-3𝑚), were irradiated with 1.7 GeV Au26+ ions at eight fluences ranging from 1011-1013 ions/cm2 at the GSI Accelerator Facility (Darmstadt, Germany). X-ray diffraction measurements showed that both iron oxides accumulate strain upon irradiation and that hematite undergoes partial phase transformation to magnetite. Fe K-edge X-ray absorption spectroscopy measurements showed disordering of the nearest neighbors around the Fe cation, along with partial reduction of Fe in both irradiated materials.

Keywords: Iron oxides
Irradiation
Swift heavy ion irradiation
Text
Thesis
Advisor: Mao Wendy
Ewing Rodney
Hok Sovanndara
Structure-based cytokine engineering

As a distributed network of cells, the immune system relies on secreted factors such as cytokines and chemokines to coordinate the induction and resolution of inflammation. Cytokine signaling is characterized by a high degree of pleiotropy in which a single cytokine acts on multiple cell types, often with countervailing effects. In many cases, this pleiotropy is critical for ensuring a robust immune response and maintaining tissue homeostasis but can present a problem for the clinical use of cytokines due to multiple responsive cell types. We applied the concept of partial agonism to two cytokines with different biological functions, interleukin 2 (IL-2) and IL-12. In the case of IL-2, we used a previously published structure of the complete IL-2 receptor complex to introduce mutations which attenuate binding to the common gamma chain and reduce receptor dimerization relative to wild-type IL-2. By profiling a diverse set of IL-2 partial agonists with reduced receptor dimerization, we identified a Treg biased agonist, IL-2-REH, which exploits two key features of Treg sensitivity to IL-2, constitutive expression of the IL-2 receptor alpha chain and reduced expression of Suppressor of Cytokine Signaling 1 (SOCS1), a negative regulator of IL-2 signaling. We sought to apply a similar concept to the heterodimeric cytokine IL-12, however, no structure of the IL-12 receptor complex was available. Using a combination of crystallography and cryo-electron microscopy, we solved structures of the IL-12 and closely related IL-23 receptor complexes. In both cases, the shared p40 subunit of IL-12/23 binds to the shared IL-12Rbeta1 receptor while unique four-helix bundles, IL-12p35 and IL-23p19, interact specifically with unique receptors, IL-12Rbeta2 and IL-23R. Guided by these structures, we generated IL-12 partial agonists with reduced binding to IL-12Rbeta1 which preserve T cell mediated anti-tumor immunity without NK cell induced toxicity relative to wild-type IL-12. Cytokine partial agonists present a path to translate structural understanding of cytokine receptor assembly to new molecules with distinct cell-type specific activity. Such agonists may have use clinically by enhancing efficacy, reducing toxicity, or both

Advisor: Garcia K. Christopher
Bollyky Paul
Ferrell James Ellsworth
Jardetzky Theodore
Structured cooperative multi-agent coordination

Reinforcement learning (RL) involves solving decision-making tasks by learning from the experience of agents without prior knowledge of the dynamics of the problems. The advances in deep neural networks and reinforcement learning have seen success in several application domains including game playing, autonomous driving, and finance. In many real-world problems, multiple entities make decisions and interact with each other within a shared environment. It is hard to model the decision-maker as a single agent in such problems. Instead, it is more natural and reasonable to model each participating entity as an agent and frame the problem as multi-agent reinforcement learning (MARL). MARL is more challenging to solve than single-agent RL due to the complexity of inter- agent interaction and limited information for each agent. The major challenges in MARL are: 1. scalability, the complexity of MARL problems grows with the number of agents; 2. partial observability, each agent lacks sufficient information to coordinate optimally due to limited local observation; 3. non-stationarity, each agent sees other agents as a part of the environment, whose evolving behavioral patterns create non-stationary environment dynamics, breaking the Markov property assumption of RL algorithms. This dissertation explores approaches to address the aforementioned challenges. We exploit the structural nature of inter-agent interaction to achieve effective coordination between agents. We use techniques from reinforcement learning and deep learning to develop efficient MARL algorithms. In the first contribution, we demonstrate solving a multi-agent problem from a single agent's perspective using utility decomposition and fusion in an approximate and decentralized way that relies on the spatial structure between agents. On top of it, we use deep Q-learning to optimize the approximate solution. In the second contribution, we use a graph structure to model the interaction between agents and use the attention mechanism to dynamically learn the graph representation. We further conduct communication of the graph to achieve multi-agent coordination. Finally, in the last contribution, we explore and analyze learning emergent discrete message communication and its interpretability. We demonstrate an explicit broadcast-based communication model and study a human-agent interaction method using discrete message communication. In summary, in this dissertation, we try to find a balanced mid-ground between the optimality and the efficiency in solving MARL problems

Keywords: Aeronautics and Astronautics.
Advisor: Kochenderfer Mykel J.
Ermon Stefano
Schwager Mac
Structure-function relationships in semiconducting polymers : new methods combining transmission electron microscopy and Monte Carlo simulations

Improving knowledge of structure-function relationships in semiconducting polymers will help design new materials that unlock new applications. This work harnesses recent advances in transmission electron microscopy of soft materials to study length scales of microstructure in these materials that have previously been difficult to probe. Further, it combines electron microscopy with structural and charge transport simulations to study the effects of mesoscale defects on charge transport in highly ordered semicrystalline polymers. Spatially resolved nanodiffraction (4D-STEM) is used to create maps of chain direction and local order in conjugated polymers. Simulations are then built upon this experimental map, first by generating molecular geometries consistent with diffraction data, then by tracking the paths of test charges across the region. A case study in this combined method is conducted using the polymer PBTTT. Short-range charge transport is shown to be more chaotic than is often pictured, with the drift velocity accounting for a small portion of overall charge motion. Local transport is sensitive to the alignment and geometry of polymer chains. At longer length scales, the curves of this PBTTT microstructure funnel charges to specific regions, creating inhomogeneous charge distributions. While alignment generally improves mobility, these funneling effects limit the overall efficiency of charge transport. The structure is modified \textit{in silico} to explore possible design rules, showing chain stiffness and alignment to be beneficial while local homogeneity has no positive effect. These observations provide direct guidance for improving mesoscale structure for future materials

Keywords: Materials Science and Engineering.
Advisor: Salleo Alberto
Lindenberg Aaron Michael
Spakowitz Andrew James
Studies on the syntheses and biophysical characterizations of archaeal tetraether lipids and the syntheses of pyrroloiminoquinone alkaloids

Archaeal extremophiles produce exotic lipid structures believed to enable survival under conditions lethal to most other life. These lipids, known as glycerol dibiphytanyl glycerol tetraethers (GDGT's), have attracted significant scientific interest. However, acquisition of these lipids from their producing organisms is not feasible. Thus, total synthesis represents the best method toward accessing these structures. Our lab has developed the shortest enantioselective synthesis of GDGT-0 relying on a global asymmetric hydrogenation and a formal macroetherification. Using this approach, we have prepared derivatives of this lipid and have begun biophysical characterizations of these compound. Furthermore, efforts are presently underway to synthesize the cycloalkane containing members of the family. The pyrroloiminoquinone alkaloids are a class of natural products principally found in marine organisms. These compounds have demonstrated a wide range of bioactivities including potent anticancer activity. Synthetic access to these structures would provide material for further investigations into their therapeutic potential. Our group developed the first catalytic asymmetric approach toward the discorhabdin pyrroloiminoquinone alkaloids. Our approach leveraged a C-H functionalization platform to rapidly assemble the core of these natural products from tryptamine. An asymmetric Morita-Baylis-Hillman strategy enabled a late-stage bromination to access these natural products in an enantioselective fashion.

Keywords: Chemistry.
Advisor: Burns Noah
Boxer Steven G. (Steven George)
Du Bois Justin
Studies toward the enantioselective synthesis of briarane diterpenes

First isolated over fifty years ago, the briaranes are a diverse family of approximately 800 diterpenoid natural products that are unified by a unique carbon skeleton which houses a trans-[8.4.0]-tetradecane ring system. This natural product family collectively possesses a broad range of interesting bioactivity and several unusual structural features, such as halogen-bearing stereocenters. This, in combination with the presence of multiple highly conserved structural features has attracted the attention of synthetic chemists for the last three decades. Despite considerable effort, no successful synthesis of any member of this family has been reported in the literature. At the outset of our work, the reports toward these natural products focused largely on the synthesis of structural motifs, rather than targeting the synthesis of any specific member. A synthesis which succeeded in establishing these important motifs in a streamlined manner as well as incorporating the rest of the carbon skeleton was completely unknown. Our group targeted a representative member, (+)-briareolide J, for synthesis, with the goal that the successful development of a route toward this member would enable the synthesis of other structurally related members which differ only by oxidation state. We developed a first-generation approach toward these natural products which hinged on the convergent coupling of two fragments using an enantioselective aldol reaction. Further elaboration of this coupled product enabled the installation of important structural motifs while incorporating necessary functionality to complete the synthesis. Ultimately, we found that our final disconnection was not able to establish the challenging trans-[8.4.0]-tetradecane ring system, leading us to revise our synthetic strategy. Targeting a redesigned second-generation synthesis, we developed a radical-polar crossover reaction to couple two enantioenriched fragments, establishing an array of important structural motifs in a single step. Further elaboration of this intermediate afforded an advanced precursor containing all the carbon atoms needed to complete the synthesis. However, we once again found that this intermediate was incapable of forming the trans-[8.4.0]-tetradecane ring system through our planned disconnection. Lastly, model studies helped to establish possible root causes of these challenges, prompting us to once again redesign our synthetic strategy. Although ultimately unsuccessful, the insights from these studies pave the way for future synthetic endeavors.

Keywords: Chemistry.
Advisor: Burns Noah
Chen James Kenneth
Du Bois Justin
Studies toward the synthesis of (+)-fomannosin

Chapter 1 introduces the protoilludane class of natural products, with an emphasis on fomannosin. Fomannosin, first isolated in 1967, deviates from other members of the protoilludane family with a unique, conjugated cyclobutene moiety and in its instability to both acid and base. This natural product is reported to have phytotoxic and antimicrobial activity, most notably against Pinus tadea seedlings and Chlorella pyrenoidosa. The isolation, structural determination, and previous synthetic efforts of this phytotoxic sesquiterpene are also outlined. Chapter 2 provides an overview of a first-generation approach to fomannosin, a collaborative effort between the Maimone group at the University of California, Berkeley, and the Burns group at Stanford University. An enolate-epoxide opening reaction forms a challenging quaternary carbon of the natural product. Furthermore, a cyclization-Ramberg--Bäcklund ring contraction cascade constructs the carbon skeleton. This allows us to access methyl-ester fomannosin. Efforts to perform a late-stage reduction to provide the primary alcohol of the natural product is detailed. Chapter 3 contains an account of our extensive synthetic efforts to access the allylic alcohol. Key transformations explored in this chapter are decarboxylative oxidative eliminations as well as decarboxylative brominations. This route permits access to 2,4-dihydrofomannosin. However, we found that early construction of cyclobutene was a liability in our efforts to access fomannosin, prompting a redesign of our synthetic strategy. Chapter 4 describes an ongoing synthetic campaign to access (+)-fomannosin asymmetrically. The current second-generation synthetic strategy hinges upon two key transformations: an asymmetric allylic alkylation to form the molecule's two contiguous stereocenters, of which one is quaternary, and a late-stage Ramberg--Bäcklund ring contraction to form the final carbon-carbon bond of the fomannosin carbon skeleton. This approach assembles the fomannosin framework in fewer steps than previously reported. Ongoing efforts toward accessing the cyclopentanone ketone and the highly strained, conjugated cyclobutene are also presented

Keywords: Chemistry.
Advisor: Burns Noah
Du Bois Justin
Maimone Thomas
Stylistic variation in a preschool classroom

This dissertation asks what young children do with style at a time when their social and linguistic worlds begin to expand beyond the home, into the peer group. Grounded in a yearlong ethnography of a preschool classroom in the San Francisco Bay Area, I show how play moved gradually from indoors to outdoors as children got older. This shift reflected increasing social and physical autonomy, bringing about new kinds of relationships—like having a best friend—and new ways of interacting with the peer group, like excluding someone, being private, and withholding information. Given expressivity's role in play, I first consider what two children did with expressive vocalizations, direct representations of internal states and moods. I find that vocalization type differed by play practice, getting us towards how speaking styles might be emerging in play at this age. From this interspeaker analysis, I then ask whether children also displayed intraspeaker variation, focusing on the role of laughter in interaction. Considering not just laughter's function but its many forms, I find that one child engaged in the most acoustically extreme types only with her best friend, compared to her interactions with adults. I argue that laughter serves an important function in peer interaction as a way of performing best friend intimacy and resisting adult authority. As this child had access to two geographic varieties of English, I expand this analysis to ask whether she showed any segmental variation alongside the already established variation in laughter. Notably, I find that she followed the same pattern, only shifting to a California dialect style with her best friend, maintaining a British English style with both an American and a British adult. This provides evidence that segmental features are implicated in structured and meaningful expressive variation at this age and calls into question the relationship between affect, style and dialect acquisition. I ask what this might tell us about the more basic social meanings underpinning linguistic variation by considering how one girl varied degree of engagement in the prenasal split—a local California feature—to take up a "playful" voice in contrast to a "bossy" voice. From here, I stay with the prenasal split to ask what a larger cohort of children did with this feature. I find that variation was conditioned not only by age and gender, but also by children's play practices. Pulling all these analyses together, I propose that development is an indexical process. Through accessing new types of affect and attitude in play, children engage in new types of relationships, which, in turn, (re)structures the emerging peer group. This expansion in the stylistic landscape brings about increasingly complex and nuanced social meanings

Keywords: Linguistics.
Advisor: Eckert Penelope
Podesva Robert
Clark Eve V.
Inoue Miyako
Submodular optimization in massive datasets

In this thesis, we study the problem of submodular maximization in various "massive data" models, namely the MapReduce, streaming, and adaptive models. For the MapReduce model, we give a simple O(1/[epsilon])-round algorithm for maximizing a monotone submodular function with respect to a cardinality constraint. This algorithm achieves an optimal 1-1/e approximation ratio, is simple to implement in practice, and removes the data duplication issue of prior works obtaining the same approximation ratio. For the streaming model, we study both the random order and the adversarial order settings. In both settings, we give the first multi-pass approximation algorithm for maximizing monotone submodular functions with respect to a matroid constraint. Our algorithms achieve 1-1/e-[epsilon] approximations in poly(1/[epsilon]) passes. For the adversarial case, it is known that our algorithm is tight -- it is impossible to achieve better than a 1/2 approximation in a single pass, and anything better than 1-1/e requires linearly many passes. Our techniques also allows us to develop single pass and multi-pass algorithms for the p-matchoid constraint, which generalizes the popular matroid (p=1) and intersection-of-matroids constraint (p=2). In the adaptive model, we study the problem of maximizing an unconstrained non-monotone submodular function. We show the following: for any problem instance, and every [delta] > 0, either we obtain a (1/2-[delta])-approximation in 1 round, or a (1/2 + [Omega]([delta]²))-approximation in [Omega](1/[delta]²) rounds. In particular (and in contrast to known lower bounds for the monotone cardinality constrained case), there cannot be an instance where (i) it is impossible to achieve an approximation factor better than 1/2 regardless of the number of rounds, and (ii) it takes r rounds to achieve a factor of 1/2-O(1/r)

Advisor: Charikar Moses
Vondrak Ján (Mathematician)
Rubinstein Aviad
Sums of singular series and the distribution of primes

The Hardy--Littlewood k-tuples conjectures generalize the twin primes conjecture by predicting the asymptotic number of twin primes less than a real number x; they go even further by predicting the number of times that any specific configuration appears in the primes, and involve important constants known as the singular series constants. The Hardy--Littlewood conjectures arise in many computations concerning the distribution of primes, including the distribution of primes in short intervals and its moments and the distribution of prime gaps. Correspondingly, understanding various sums of singular series is crucial to understanding many aspects of the distribution of primes. For example, Montgomery and Soundararajan computed the distribution of primes in short intervals by estimating lower-order terms of certain sums of singular series. We explore various refinements and generalizations of known results on sums of singular series, including better estimates for sums over sets of size k when k is odd, averages over configurations that are restricted to certain arithmetic progressions, estimates when k is large with respect to the range of the sum, and function field analogs

Keywords: Mathematics.
Advisor: Soundararajan Kannan
Bump Daniel
Fox Jacob
Supramolecular hydrogels for stability and long-term delivery of biotherapeutics

Biotherapeutics are an important category of pharmaceuticals, used to treat everything from diabetes to cancer to infectious disease. Unfortunately, biotherapeutics have unique challenges compared to other drug types when it comes to pharmaceutical formulation due to their complex, and often fragile, molecular structures. As a result, these drugs are prone to denaturation and aggregation, and in general exhibit poor stability in formulation. Further, these drugs also may not exhibit favorable pharmacokinetics, especially for treatments where the drug would be administered long-term and repeat dosing would be required to maintain therapeutic or prophylactic efficacy. My doctoral work has focused on leveraging materials science to develop biotherapeutic formulation and delivery technologies to enable new treatment approaches for a variety of target applications. In particular, I have been studying the application of injectable, supramolecular polymer-nanoparticle (PNP) hydrogels as both stabilizing excipients and drug delivery vehicles for biotherapeutic drugs. First, I will introduce the PNP hydrogel platform and a detailed protocol for how to formulate the material for different biotherapeutic delivery applications. Second, I will discuss how these hydrogels can be used to encapsulate biotherapeutics, such as insulin and monoclonal antibodies, and greatly improve their thermal stability, reducing the need for refrigerated transportation and storage. Then, I will describe our approach to engineering this supramolecular hydrogel platform as a subcutaneous drug delivery depot for sustained delivery of monoclonal antibodies for passive immunization. I have also incorporated pharmacokinetic (PK) modeling to interpret the results of in vivo studies as well as to inform the design of future biomaterials for drug delivery applications. Lastly, I describe collaborative work developing a novel amphiphilic copolymer as a "drop-in" excipient to stabilize high-concentration antibody formulations. Overall, this work illustrates both the utility of materials science in addressing pharmaceutical formulation challenges and point towards important considerations for biomaterials design for drug delivery

Keywords: Materials Science and Engineering.
Advisor: Appel Eric (Eric Andrew)
DeSimone Joseph M.
Kim Peter