VictorJuiz/thesis huggingface dataset:
Redefining Druggability Using Chemoproteomic Platforms

The Undruggable Proteome – those proteins which do not have a canonical small molecule binding pocket – poses one of the largest problems in modern drug discovery. The genomics revolution linked the function of thousands of proteins to corresponding diseases, but many of these disease-causing proteins are difficult or seemingly impossible to target or study with traditional small-molecule based approaches. Recently, chemoproteomics – the combination of chemical-biology methods with proteomics – has given us new tools to approach this undruggable proteome, especially in combination with covalently-acting probes or ligands. Using these emerging technologies this work shows three examples of how chemoproteomics can enable both tool development for better understanding of undruggable proteins and also allow direct engagement with such proteins for drug development./nFirstly, we show that NHS-esters are viable chemoproteomic probes, allowing the profiling of the reactivity of thousands of lysines in complex proteomes. Furthermore, scaffolds bearing an NHS-ester have surprising specificity, opening the door for covalent ligand discovery around the NHS-ester warhead. Secondly, we further highlight the efficacy of covalent molecules in targeting undruggable proteins by mapping the anti-cancer targets of Withaferin A, a natural product, with chemoproteomic methods. We show the primary target is a traditionally undruggable site on a traditionally undruggable protein, cysteine 377 on the scaffolding subunit of the phosphatase PP2A (PPP2R1A). We are then able to screen simple covalent fragments against this target, to find a small, synthetically-accessible fragment which binds same site and recapitulates the biochemical activity of Withaferin A. Lastly, we leverage similar covalent fragment screening approaches to discover a non-functional ligand against the E3 ligase RNF4. We use this ligand with success in targeted protein degradation applications, demonstrating the synergy between chemoproteomics and other emerging approaches to tackle to undruggable proteome.

Advisor: Nomura, Daniel
Learning and Logic for Formal Synthesis

Program synthesis is the use of algorithms to derive programs that satisfy given specifications. These specifications are usually given in some form of computer-understandable logic. Specifications are usually much easier to write than the programs themselves. By ‘filling in the details’ given by the specification, program synthesis opens the possibility of creating simple programs to both lay people and non-programming domain experts./nRecent work in program synthesis has used techniques from ‘exact active learning’, where learning algorithms are able to pose queries to oracles. In the case of program synthesis, these oracles are implemented by checking potential programs against the given specification or asking a user for more inputs./nAnother recent development in the field is Syntax-Guided Synthesis (SyGuS), where the space of potential programs is given by a tree-grammar (or context-free grammar). Specifications are given in the logic of SMT (satisfiability modulo theories) problems./nThis thesis further develops the theory behind exact active learning, program synthesis, and their intersection. We provide upper and lower bounds, including undecidability results, for SyGuS problems defined on various SMT theories. We introduce the subject of actively learning equational theories and show how it can be used to learn constrained EUF formulas. We expand the problem of learning symbolic automata to use different types of symbolic counterexamples. We study the problem of exact active learning of concepts that are comprised of independent components, andshow when the knowledge that components work independently can significantly reduce learning complexity. Finally, we introduce new methods for SyGuS solving with respect to cost, where the goal is to find the minimal cost program satisfying a specification.

Advisor: Seshia, Sanjit A
Co-planar Optoelectrowetting (OEW) Device for Droplet Manipulation

Lab-on-a-chip technologies have seen great advances and development over the past few decades in addressing applications such as biochemical analysis, pharmaceutical development, and point-of-care diagnostics. Miniaturization of biochemical operations performed on lab-on-a-chip platforms benefit from reduced sample, reagent and waste volumes as well as increased parallelization and automation. This enables more cost-effective operations along with higher throughput and sensitivity for faster and more efficient analysis and detection./nThe research presented in this dissertation focuses on progress achieved in optoelectrowetting (OEW), an optofluidic technology that allows for the manipulation of discrete droplets. In this work, we present a novel co-planar OEW device for droplet manipulation, which allows for faster droplet movement and a wider range of system integration capabilities than previous generations of OEW devices. First, we discuss the theory and design of the co-planar OEW device and present an optimization model that also accounts for the OEW effect on the droplet’s contact line. The OEW effect is experimentally verified by inspection of the contact angle of the droplet. We demonstrate individual and parallel droplet movement along with basic operations such as droplet merging and mixing with actuation speeds of up to 4.5 cm/s on the co-planar OEW device. Next, we investigate how experimental parameters such as applied voltage, frequency, and light intensity can be tuned for optimized OEW operation. Lastly, to showcase the co-planar OEW’s advantage for more flexible input/output configurations, we integrate the co-planar OEW platform with a droplet-on-demand dispensing system to form large scale droplet arrays with each individual droplet acting as its own unique microreaction chamber. Overall, the co-planar OEW device expands the ability for OEW technologies to serve as a versatile and adaptable lab-on-a-chip platform for a variety of biological and chemical applications.

Advisor: Wu, Ming C
Existential quantification in Tiwa: disjunction and indefinites

This dissertation examines the semantics and pragmatics of disjunction and indefinites in Tiwa, an understudied Tibeto-Burman language of northeast India. The core focus of the dissertation concerns cross-linguistic variation and its implications for semantic theory. Broadly, I address the extent to which languages encode similar meanings through the same semantic means; what mechanisms are best suited to model those meanings; and how the theory can best model what cross-linguistic variation we do find. Concretely, I provide novel cross-linguistic evidence from phrasal comparatives that disjunction is alternative-denoting, and argue that languages can employ different semantic mechanisms in deriving exceptional wide scope./nTiwa's large system of indefinites and disjunction particles, which are in part morphologically related, provide an ideal subject for exploring the logical connection between disjunction and indefinites (which amount to existential quantification over explicit and non-explicit domains respectively). While cross-linguistic studies of indefinites have seen an increase in recent years, disjunction has not received the same level of attention. In this dissertation, I provide a detailed description of the semantic and pragmatic behavior of Tiwa's various disjunction particles and their related indefinites, which, among other things, explicitly encode scope. Additionally, the dissertation contains a broader sketch of Tiwa grammar as a whole, which provides documentation and formal description of many aspects of the language. This empirical contribution is the result of original fieldwork in Assam, India, over the course of four years.

Advisor: Deal, Amy Rose
Sensitivity Simulations and Half-wave Plate Polarization Modulators for Cosmic Microwave Background Observatories

Cosmic microwave background (CMB) polarization anisotropies are at the forefront of modern cosmology, and a detection of B-mode polarization due to inflationary gravitational waves is among the most sought-after discoveries in astrophysics. Current constraints on these primordial B-modes set their amplitude at ~10 nK, posing extraordinary technological challenges to the design, characterization, and performance of today's CMB observatories. An effective CMB telescope requires both excellent sensitivity and tight control of systematic effects, and advancements in telescope instrumentation, calibration hardware, and analysis techniques are needed for a robust extraction of the inflationary signal. In this dissertation, we present two primary research products that improve the scientific prospects of today's CMB experiments. First, we describe a Python simulation code to optimize the mapping speed of both existing and future instruments. This calculator conglomerates the best aspects of several existing codes to offer a generalized, feature-filled software both for modeling future experiments and for characterizing operating ones. We discuss its use within Simons Array (SA) and Simons Observatory (SO), as well as its broader utility to upcoming experiments, including CMB-S4. Second, we present new polarization modulators for SA, including an ambient-temperature, continuously rotating half-wave plate (HWP) for POLARBEAR-2a and a cryogenic HWP for POLARBEAR-2b. Continuously rotating HWPs are powerful tools to mitigate atmospheric 1/f noise and telescope-induced intensity-to-polarization leakage, and their effectiveness is increasingly important to a precise characterization of cosmic polarization. The HWPs described in this thesis introduce several optical, mechanical, and electrical hardware advancements, and we discuss how these HWPs are paving the way for similar modulators on POLARBEAR-2c and SO's small aperture telescopes.

Advisor: Lee, Adrian
ATLAS Measurements of the Higgs Boson Coupling to the Top Quark in the Higgs to Diphoton Decay Channel

During Run 2 of the Large Hadron Collider, the ATLAS experiment recorded proton--proton collision events with a center of mass energy of 13 TeV, the highest energy ever achieved in a collider. Analysis of this dataset, which corresponds to an integrated luminosity of 139 fb$^{-1}$, has provided new opportunities for precision measurements of the Higgs boson. The interaction between the Higgs boson and the top quark, the heaviest known particle, is a fundamental probe of the Higgs mechanism, which describes how Standard Model particles obtain mass./nThe coupling of the Higgs boson to the top quark can be directly probed through the production of a Higgs boson in association with a top-antitop quark pair ($t\bar{t}H$) at the LHC. A statistical combination of ATLAS searches in multiple Higgs boson decay channels using 79.8 fb$^{-1}$ of the Run 2 dataset yielded the first observation of $t\bar{t}H$ production at the level of $6.3\sigma$./nThe Higgs to diphoton ($\gamma\gamma$) decay channel is among the most sensitive for $t\bar{t}H$ measurements due to the excellent diphoton mass resolution of the ATLAS detector and the clean signature of this decay. A powerful multivariate analysis was developed to select $t\bar{t}H(\gamma\gamma)$ events based on the momenta of jets, photons, and leptons in the final state. The $t\bar{t}H$ cross section times $H\rightarrow\gamma\gamma$ branching fraction was measured to be $\sigma_{t\bar{t}H}\times B_{\gamma\gamma} = 1.59 \; _{-0.39}^{+0.43}$ fb using the full Run 2 ATLAS dataset. Top quarks were reconstructed with high probability in selected $t\bar{t}H(\gamma\gamma)$ events./nFollowing the observation of the $t\bar{t}H$ process, a direct measurement of the CP properties of the Higgs-top interaction was carried out in the $H\rightarrow\gamma\gamma$ decay channel. A CP-sensitive multivariate categorization was developed using reconstructed top quark variables, yielding an observed $t\bar{t}H$ significance of 5.2$\sigma$ and an upper limit on the cross section of single-top-plus-Higgs ($tH$) production of 11.6 times the SM expectation. The observed data excludes a fully CP odd Higgs-top coupling at the level of 3.9$\sigma$, and the CP mixing angle is constrained to $|\alpha|>43^\circ$ at 95\% confidence level.

Advisor: Shapiro, Marjorie
Learning to Detect Geometric Structures from Images for 3D Parsing

Recovering 3D geometries of scenes from 2D images is one of the most fundamental and challenging problems in computer vision. On one hand, traditional geometry-based algorithms such as SfM and SLAM are fragile in certain environments, and the resulting noisy point-clouds are hard to process and interpret. On the other hand, recent learning-based 3D-understanding neural networks parse scenes by extrapolating patterns seen in the training data, which often have limited generalizability and accuracy./nIn my dissertation, I try to address these shortcomings and combine the advantage of geometric-based and data-driven approaches into an integrated framework. More specifically, I have applied learning-based methods to extract high-level geometric structures from images and use them for 3D parsing. To this end, I have designed specialized neural networks that understand geometric structures such as lines, junctions, planes, vanishing points, and symmetry, and detect them from images accurately; I have created large-scale 3D datasets with structural annotations to support data-driven approaches; and I have demonstrated how to use these high-level abstractions to parse and reconstruct scenes. By combining the power of data-driven approaches and geometric principles, future 3D systems are becoming more accurate, reliable, and easier to implement, resulting in clean, compact, and interpretable scene representations.

Advisor: Ma, Yi
Interactive Program Distillation

From snippets to tutorials, programmers rely on sample programs to learn and get work done. The process of creating sample programs, however, can be demanding, limiting the dissemination of programming knowledge. To enhance this process, we introduce the concept of program distillation, methods for its implementation, and usability studies verifying its power. Program distillation is the tool-assisted transformation of existing programs into simpler ones, where key ideas are emphasized, and cruft has been removed./nThree interactive tools are introduced for distilling code snippets, notebooks, and tutorials. Each tool contributes novel interactions grounded in proven program analysis techniques. CodeScoop helps programmers extract snippets from existing code through interactive program slicing and simplification. Code gathering tools let a programmer extract subsets of cells from a computational notebook that reproduce key results. And Torii provides a live programming experience for creating output-rich multi-step tutorials. Studies with users reveal that these tools satisfy important needs, support efficient sample program creation, and provide a level of expressiveness not yet available in today’s standard tools.

Advisor: Hartmann, Björn
Hearst, Marti A
Substitutional Heteroatom Doping and Topological Band Engineering in Graphene Nanoribbons

The exponentially increasing demand for smaller, faster, and more energy efficient electronic devices represents a monumental challenge in designing the next generation of post-silicon functional electronic materials. Traditionally, device architectures based on organic/inorganic semiconductors are fabricated using a top-down approach; their performance is inherently limited by the spatial resolution of photolithographic techniques. Fischer group’s goal is to understand, control, and to be able to harness the exceptional electronic/magnetic properties emerging from nanoscale graphitic materials by developing novel synthetic strategies toward graphene nanoribbons (GNR) via bottom-up synthesis from atomically defined molecular precursors. The semiconducting properties of GNRs can be modulated by varying their width, edge structure and the identity of atoms in the periodic lattice./nMy thesis work will detail the power of organic synthesis in design of molecular precursors en route to GNRs, the nanoribbon formation analysis techniques, and the outlook toward application of GNRs in a low-power, tunneling field-effect transistor device architecture (Chapter 1). A large part of my work has aimed at developing new synthetic strategies to access heteroatom-substituted GNRs. After making advances toward BN-substituted GNR precursors, I have discovered a molecular scaffold which furnishes the first example of a surface-mediated C–N bond formation in the context of a 7-AGNR segment (Chapter 2). I have also prepared a series of molecular precursors that have led to the formation of a new family of nitrogen-substituted zigzag GNRs, which possess intriguing spin-separated states along the edges (Chapter 3). In addition to exploring heteroatom substitution, I investigated all-carbon GNR scaffolds that utilize topological band engineering concepts in order to explore new variables that will allow rational tuning of electronic properties in GNRs. I have prepared multiple precursors to continue the realization of topologically protected interface states in GNRs, which are generated by construction of a superlattice of well-defined ribbon segment heterojunctions (Chapter 4).

Advisor: Fischer, Felix R
The Ties That Bind: The Internal Structures Of Law Firms And The Dynamics Of Law Firm Dissolution

Research on law firms as organizations has largely grown up in literatures that rarely, if it all, speak to one another in sustained ways. Whether drawing from economic, ecological, network, or neo-institutional frameworks, organizational scholars often use law firms as sites for research without necessarily considering the unique qualities of a professional firm (for example, their ethical responsibilities or the type of legal work they perform). Legal scholars, meanwhile, largely focus on the legal characteristics of law firms without examining how their organizational structures or broader environments influence their behavior. Dialogue between these approaches can add significant theoretical grist to the organizations literature by identifying how the rules of different fields influence organizational behavior, while at the same time deepening legal scholarship by situating study of the law firm in broader theoretical discourses./nIn this dissertation, I will review the theoretical treatment of law firms, discuss the internal structures and external environments of law firms, test whether network theories of organization explain the observed network of a professional firm, and examine the longitudinal trajectory of law firm growth and survival. To do so, I will develop novel hypotheses that integrate professional and organizational theories.

Advisor: Morrill, Calvin
Numerics and stability for orbifolds with applications to symplectic embeddings

This thesis studies the geometry of orbifolds - primarily via variation of GIT, derived category methods, and numerics - and develops connections of equivariant algebraic geometry with embedding problems in symplectic geometry, and with lattice point counting for rational polytopes. We also compile many aspects of the disparate toolkit required to rigorously study orbifolds.

Advisor: Eisenbud, David
Impacts of Native and Introduced Species on Native Vertebrates in a Salmon-Bearing River Under Contrasting Thermal and Hydrologic Regimes

As organisms undergo life history transitions, track resources, avoid stress, and evade death, they distribute themselves across landscapes. Organismal co-occurrence sets the stage for biotic interactions, which can feed back to control the distribution and abundance of interacting species in ecological communities. Classically, competition and bottom-up forces have been thought to be the most important drivers of community structure, however, examples of predation, parasitism, mutualism, and facilitation highlight the ubiquity and importance of these other interactions. In freshwaters, anthropogenic impacts, especially species introductions and climate warming, have resulted in novel species assemblages, with altered webs of interactions compared to historic conditions. Human management often seeks to provide conditions that favor native species and inhibit non-natives. Success requires an understanding species interactions and their roles in community dynamics. In my first chapter, I describe the distributional dynamics of the assemblage of aquatic fishes, reptiles and amphibians in the South Fork Eel River. In Chapter 2, I describe the seasonal migration of an introduced predatory fish, Sacramento Pikeminnow (Ptychocheilus grandis), and how climate warming and water withdrawals could increase their negative impact on rearing native salmonids and other fauna. In Chapter 3, my colleagues and I explore the positive interactions between Pacific Lamprey (Entosphenus tridentatus), juvenile Steelhead trout (Oncorhynchus mykiss), and Foothill Yellow-legged Frogs (Rana boylii). These case studies emphasize the need to consider ecological interactions, and in general, community ecology thinking, as we try to restore and manage ecosystems.

Advisor: Power, Mary E
Essays in Psychology and Economics

This dissertation establishes that loss aversion fundamentally influences the tax avoidance behavior of property taxpayers. Upon receiving notice of a new assessed value, homeowners have the option to appeal, which, if successful, could lower their tax base. I conjecture that a lagged, salient value---a property's assessed value in the previous year---serves as a natural and prominent reference point to property owners. Guided by a reference-dependent model of assessment protests, I demonstrate various predictions using a sample of 8.2 million administrative property assessment records associated with 1.6 million appeals. Foremost, loss aversion introduces an extensive margin effect around the reference point that induces property owners to disproportionately appeal assessments that have increased relative to the prior tax year. In aggregate, this leads to a sharp kink in the probability of protesting as a function of percent change in assessed value exactly at zero percent change. Additionally, homeowners not only achieve but also seek out value adjustments that result in a final assessed value precisely at the property's previous assessed value. Evidence is strongest for owner-protesters, for whom the reference point is presumably most relevant. Finally, I employ a simple counterfactual estimation strategy. It suggests that loss aversion has a sizable impact on annual household property taxes, most notably for properties constituting the top quartile of value, while also highlighting the importance of one's position in the loss domain in understanding average effect sizes.

Advisor: DellaVigna, Stefano