VictorJuiz/thesis huggingface dataset:
Pricing and rollout of durable product versions in the presence of maintenance costs [electronic resource]
Keywords: Business.

In many durable good contexts, firms have the opportunity to price discriminate on quality by charging higher prices for the latest functionality. In the software good market, on the other hand, we often do not observe price discrimination on the latest versions, despite new versions being introduced over time. I propose that the software firm's ability to price discriminate on latest functionality is restricted by two factors: (1) the extent to which different consumer types appreciate the innovation from one version to the next and (2) the extent to which legacy software products are costly for the firm to maintain. To analyze this question, I use a unique dataset on individual consumer subscriptions to a Fortune 500 firm's software products. The firm releases new product versions each year, but allows consumers to adopt the latest functionality for free. Despite this policy, descriptive analysis reveals that consumers frequently choose not to upgrade, electing to renew legacy versions of the product instead. To distinguish between the different factors driving this pattern, I develop a dynamic model of consumer choice of different product versions, renewal opportunities and upgrades. This model allows me to separately account for version usage utility, non-monetary costs of purchasing and upgrading and the heterogeneity therein. The estimates of the model reveal that although the majority of the consumers value the new versions, the high value, price insensitive consumers do not, causing it to be un- profitable for the firm to price latest functionality at a premium. Using the estimates and the structure of the model, I then show that if high value consumers were to sufficiently appreciate the firm's innovation, it would be profitable for the firm to charge a fee for the new functionality; however, sufficiently high costs of maintaining legacy versions eliminate such incentives. The final counterfactual allows me to calculate the minimum legacy version cost that would cause the firm to shift from releasing distinct intertemporal versions to maintaining one continuously upgraded version of the product.
PriMagic: Component-Based Synthesis of Loopy and Non-Loopy Programs
Keywords:  Department of Computer Science
PriMagic
program synthesis
component-based synthesis
loops
Department of Computer Science
honors thesis
Thesis

Previous works in component-based synthesis have struggled to synthesize loops and other control structures. We present PriMagic, a new approach to component-based synthesis that can synthesize loopy programs from input-output examples. Our approach first mines primitives: by generating random straight-line programs and remembering those that are consistent with many input-output examples, we can obtain a set of code fragments that are likely to be useful for synthesis. Then, we randomly generate programs where we leave control structure conditions blank. We evaluate these partial programs using the idea of magic conditions, where we analyze the different code flows to determine if it is possible for the partial program to pass all test cases. In the last step, we resolve the magic conditions by filling them with random Boolean expressions. We demonstrate that PriMagic can synthesize short but interesting loopy programs within several minutes, and that it can be a useful tool for API translation.
Probing ultrafast electron dynamics in atoms and molecules [electronic resource]
Keywords: Physics.

This dissertation explores two major lines of research concerning ultrafast electron dynamics in atoms and molecules. The first part investigates the dynamics of photoionization in intense laser fields on the attosecond time scale. A new technique using a weak probing field at half the frequency of the strong ionizing laser field reveals attosecond delays in the above-threshold ionization process. We observe the influence of the combined Coulomb-laser potential on the spectral phase of the photoelectron. In the second part, an experiment which imaged the uncoupling of electron motion from the molecular frame in rotating molecules is described. A coherent wave packet in the 4f Rydberg manifold of molecular nitrogen is created and its motion is probed in time. This allows for a direct observation in the time domain of a non-Born-Oppenheimer regime, known as the l-uncoupling regime, that up until now has only been inferred from spectroscopic data.
The problem of epistemic relevance [electronic resource]
Keywords: Philosophy.

Does being in a position to know P require information that rules out every possible way in which P is false? Traditional arguments for skepticism apparently assume a 'yes' answer. A relevant alternatives (RA) theorist answers 'no'. In this dissertation, I bypass prominent objections to relevant alternatives theory with a novel and precise version thereof called resolution theory. Resolution theory marries the old with the new. On the epistemic side, it claims that to be in a position to know proposition P is to have empirical information that discriminates P from not-P (a degenerate case: if P is a priori, discrimination requires no empirical information). Thus, resolution theory develops a key claim in the groundbreaking work of early RA advocate Alvin Goldman (in concert with ideas from another key progenitor: Fred Dretske). On the semantic side, it claims that the truth of "a knows that φ" requires that a be positioned to know that each proposition in a certain set is false: namely, a set of defeaters generated by the subject matter of φ in coordination with its Fregean guise. Thus, we capitalize on recent insights on how the meaning of "a knows that φ" interacts with the meaning of φ, building mainly on David Chalmers, Jonathan Schaffer and Stephen Yablo. Despite these many debts, resolution theory is a novelty, contrasting with its forerunners in critical ways. I argue that resolution theory overcomes objections that many RA theories fall prey to: Schaffer's problem of missed clues; the closure dilemma; and worries concerning ad hocness. In particular, these objections apply, to varying extents, to the theories we draw inspiration from. Among other consequences, resolution theory motivates a novel framework for epistemic logic, broadly situated in the modal tradition.
Production and sensing of natural products in Saccharomyces cerevisiae [electronic resource]
Keywords: Biochemistry.

Natural products broadly refer to organic compounds formed in living organisms, but are usually taken to mean small molecule metabolites that are not required for growth and development. More than half of FDA-approved antibiotics and anticancer drugs are natural products (NPs) or their derivatives. In particular, fungi produce a wide range of bioactive compounds such as penicillin and lovastatin. Recent genomic DNA sequencing efforts yielded a surprise in NP research: Many NP gene clusters could be readily identified based on homology, but no associated NP could be identified as being produced by the organism, and often the genes were not even expressed. Even for the most well studied fungal strains, only 10% of the identified clusters are expressed under laboratory conditions. Tens of thousands of NP clusters that may encode a wealth of unknown natural products with attractive bioactivities have been identified but are yet to be explored. Difficulties in culturing and genetically manipulating the host organisms of natural products, and inducing the expression of NP genes, are the major obstacles in studying these gene clusters. To circumvent these problems, researchers have pioneered heterologously expressed them in various model organisms, among which S. cerevisiae has emerged as a powerful host. However, the limitations on synthetic biology technologies and our understanding of yeast as a host for heterologous natural products production have constraint the discovery of novel NPs. In this thesis project, I further developed yeast as a producer of fungal natural products by streamlining assembly and characterization process that enabled discovery of novel NPs. I then dissected how yeast responded to NPs through the highly conserved pleiotropic drug resistance (PDR) mechanism, identified multiple novel regulators of this process, and connected this drug response to cell cycle regulation. I further demonstrated coupled production and sensing of natural products in a single yeast cell, providing new tools to study and generate new NPs based on the heterologously expressed fungal NP clusters. My thesis work revolved around production and sensing of natural products in Saccharomyces cerevisiae, and took advantage of recent advances in DNA sequencing, synthesis and engineering. On the natural products front, this work provides an efficient alternative to traditional natural product chemistry that have increased the repertoire of currently available natural products, and may lead to further development of new compounds with interesting bioactivities. Towards the front of understanding yeast as a host, this work uncovers novel control mechanism of the yeast pleiotropic drug resistance, a vital process in the drug response, and its connection to cell cycle regulation. With more knowledge on both fronts, the utilization of yeast PDR transcription response as biosensor systems illustrates the potential of an untapped resource for future biological and biotechnological applications.
A programmable alternative splicing platform for regulating protein diversity [electronic resource]
Keywords: Bioengineering.

Nature offers enormous functional diversity that is largely untapped in engineered biological systems. Given its roots in bacterial transcriptional gene networks, synthetic biology has yet to develop a comprehensive set of tools that harness the complexity and biological regulation prevalent in mammalian cells. A critically important mechanism in mammalian cells, alternative splicing, increases the coding capacity of genomes to generate several proteins from an individual gene. Few engineered genetic devices utilizing alternative splicing mechanisms have been described, and existing approaches are limited to turning on or off the expression of a gene coupled to a splicing regulatory component. A novel alternative splicing platform has the potential to broaden the current regulatory capabilities of genetic devices by providing a strategy to program protein function. We describe the design and implementation of an intron framework for controlling the mutually exclusive alternative splicing of exons in a four exon-three intron system, wherein the exon sequences can be recoded. The coding capacity of the genetic device is increased by the mutually exclusive nature of the alternative splicing event, as one of two internal exons is incorporated into a mature mRNA, thereby resulting in multiple isoforms. RNA profiling and protein expression assays established that these devices effectively spliced to produce the expected dominant isoform. Systematic tuning of consensus sequence element activity in the intron framework revealed the ability to modify isoform profiles and favor alternate isoform production from a splicing device. Furthermore, we conducted an exploratory study of intronic regulatory elements for controlling and predicting mutually exclusive alternative splicing events within the context of the intron framework. Finally, we applied this intron framework to program transcription factor activity by encoding domains of modular transcription factors in synthetic RNA splicing devices, modifying domain functionality through alternative splicing, and producing precise transcription factor profiles that control downstream gene expression patterns. Our work highlights the first demonstration of an intron framework design that leverages a complex mode of alternative splicing to program protein diversity with synthetic RNA splicing devices. Continued development of such foundational frameworks in mammalian synthetic biology will enable increasingly sophisticated devices that expand the capabilities of genetic engineering for tackling critical global challenges in health and medicine.
The programmed cell death protein 1 (PD-1) pathway in cancer [electronic resource] : engineering protein therapeutics and exploring a novel role for PD-1 on tumor-infiltrating macrophages
Keywords: Molecular and Cellular Physiology.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells to induce tolerance.1,2 Tumor cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), allowing escape from the immune system.3,4 Several monoclonal antibodies blocking PD-1/PD-L1 are clinically approved, and lead to remarkable efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small cell lung cancer, and Hodgkin's lymphoma.5-10 However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1 directed immunotherapy could be improved with smaller, non-antibody therapeutics, I used directed-evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high affinity PD-1 was effective in treating both small (50 mm3) and large tumors (150 mm3), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, I found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, non-antibody therapeutics for enhanced cancer immunotherapy and immune diagnostics. Although it is well-established that PD-1/PD-L1 blockade activates T cells, little is known about the role that this pathway may have on tumor-associated macrophages (TAMs). As such, I also investigate a functional role for PD-1 on TAMs. I show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models, and with increasing disease stage in primary human cancers. TAM PD-1 expression negatively correlates with phagocytic potency against tumor cells, and blockade of PD-1/PD-L1 in vivo increases macrophage phagocytosis, reduces tumor growth, and lengthens survival in mouse models of cancer in a macrophage-dependent fashion. My results suggest that PD-1/PD-L1 therapies may also function through a direct effect on macrophages, with significant implications for treatment with these agents.
Programming heterogeneous systems from an image processing domain specific language [electronic resource]
Keywords: Electrical Engineering.

The performance and energy efficiency of image processing tasks are becoming increasingly important as cameras become ubiquitous, and as our ability to extract information from images improves. These tasks are extremely computationally intensive, requiring trillions of operations per second to fulfill the performance requirements of applications in computer vision, computational photography, and augmented reality. Therefore, specialized hardware accelerators are necessary to deliver the performance and energy efficiency required by these important applications. However, creating, "programming, '' and integrating this hardware into a hardware/software system is difficult. We address this problem by extending the image processing language, Halide, so users can specify which portions of their applications should become hardware accelerators, and then provide a compiler that uses this code to automatically create the accelerator along with the "glue" code needed for the user's application to access this hardware. Starting with Halide not only provides a very high-level functional description of the hardware, but also allows our compiler to generate a complete software application, which accesses the hardware for acceleration when appropriate. This system also provides high-level semantics to explore different mappings of applications to a heterogeneous system, including the flexibility of being able to change the throughput rate of the generated hardware. We demonstrate our approach by mapping applications to a commercial Xilinx Zynq system. Using its FPGA with two low-power ARM cores, our design achieves up to 6x higher performance and 38x lower energy compared to the quad-core ARM CPU on an NVIDIA Tegra K1, and 3.5x higher performance with 12x lower energy compared to the K1's 192-core GPU.
Propagation in multi-dimensional Fisher-KPP equations [electronic resource]
Keywords: Mathematics.

Advection-reaction-diffusion equations (ARD) are non-linear elliptic or parabolic equations that are used to model a variety of systems in natural sciences and engineering, ranging from biological (population dynamics) to chemical and astrophysical systems (reactions in a fluid). They describe the evolution of a normalized quantity, such as a local density of a population or a temperature, as a result of three processes: transport inside the domain (advection), creation or depletion due to an energy source (reaction), and spatial movement (diffusion). These equations exhibit interesting behaviors such as growth/decay, spreading and mixing. Over the past decades there has been significant progress towards understanding and quantifying the behavior of ARD equations. A great focus was shown in equations of biological invasions, more specifically in the phenomenon of spreading, which happens as a result of the invasion of an unstable equilibrium state by a positive stable one. There are two main threads of research in this field: (1) front-like spreading, which leads to the study of traveling fronts, their speeds of propagation and stability properties, and (2) multi-directional spreading, arising from initial data that have compact support or fast decay in every direction. In this thesis we study the problem of spreading rates for the Cauchy problem in multi-dimensional periodic Fisher-KPP equations. Localized initial data give rise to an invasion that will happen typically at different speeds and profiles in each unit direction, but independent on the size and distribution of the original mass. The main result will be on precise asymptotics for the location of level sets of solutions for these data. The trajectory of the thesis will be as follows: In the first part, after a brief introduction of the problem and past results, we study the linearized Dirichlet equation in a half space moving at a constant speed derived from the slowest traveling fronts. This provides intuition for the location of the fronts in the compactly supported case, as well as concrete bounds that can be compared to the solution of the original problem. In the second part we prove the main result by controlling the propagation of the Fisher-KPP solution using sub- and super-solutions constructed from the linearized fronts.
Public deliberation and participation through a comparative lens [electronic resource] : attitudes, behaviors, and institutions
Keywords: Communication.

Ordinary people have been increasingly engaging in policy deliberations around the world. This dissertation studies the democratic potential of public deliberation; in particular, whether such practices live up to normative standards and benefits, and how to situate them in broader social and political contexts. The first part of the dissertation examines the psychological processes of attitudinal and behavioral changes through democratic deliberation. In a California-wide Deliberative Poll and a participatory budgeting project in a Chinese neighborhood, I find that democratic dialogues on the basis of balanced information, respect, and mutual justification nurture sophisticated public opinion and better citizenries, and such democratic merits hold true across political contexts. The second part of the dissertation studies the intriguing marriage of deliberative democracy and authoritarianism with a focus on the "socialist deliberative democracy" in China. Combining evidence from field study and national-scale data, I have shown that China has adopted consultative institutions in order to maintain social stability. Democratic deliberation is compatible with authoritarianism, though the forms and functions integrate with the native political culture and institution. Local political elites perceive and practice deliberative democracy according to their inherent democratic orientations, which may open up a promising ground for public participation, or turn it into window dressing.
Quantitative functional oncogenomics [electronic resource] : translational methods to study tumor initiation, progression, and metastasis in vivo
Keywords: Genetics.

Cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors. The functional importance of the vast majority of these alterations, both alone and in combination, remains unknown and largely uninvestigated due to lack of tools enabling high-throughput interrogation of coincident genetic alterations in vivo. This thesis describes a method that integrates tumor barcoding with CRISPR/Cas9-mediated genome editing and ultra-deep barcode sequencing (Tuba-seq) to interrogate multiple tumor genotypes simultaneously in autochthonous mouse models of human cancer. I demonstrate the quantification of the effects of eleven of the most frequently inactivated genes in human lung adenocarcinoma and uncover the methyltransferase Setd2 and the splicing factor Rbm10 as novel suppressors of lung cancer growth. By quantifying the in vivo fitness advantage conferred by inactivation of each of these eleven genes in combination with inactivation of p53 or Lkb1, we identify unexpected context-dependent tumor suppression. I further demonstrate the ability of tumor barcoding to investigate clonal relationships between tumors and metastases, as well as uncover potential drugs to inhibit metastatic progression. These approaches will redefine our ability to understand how tumor suppressor inactivation impacts tumor initiation, growth, malignant transformation, and ultimately lead to the identification of therapy responses. Specifically, we can begin to investigate genotype specific drug responses and hope to inform a more precise and personalized era of patient care.