VictorJuiz/thesis huggingface dataset:
Engineering novel leukemia inhibitory factor inhibitors as cancer therapeutics

Pancreatic ductal adenocarcinoma (PDAC) is a devastating form of cancer, with the lowest five-year survival rate among all cancers of only 9%. Poor survival is due to late detection, limited ability to surgically resect disease, and a dearth of targeted, effective therapies. As covered in Chapter 1, numerous recent studies have identified the leukemia inhibitory factor (LIF) as a promising therapeutic target in PDAC. LIF, a member of the IL-6 family of cytokines, drives proliferation, survival, and stem-ness cellular programming via signaling though the heterodimeric receptor pair of LIF receptor (LIFR) and glycoprotein 130 (gp130). While numerous potential inhibitors of LIF have been developed, because of the high affinity of LIF for the LIFR/gp130 complex, and the shared nature of cytokine receptors, non-toxic blockade of LIF activity remains challenging. The development of novel and effective LIF inhibitors is thus sorely needed as promising therapeutics to use in the fight against PDAC. In this dissertation, I will describe our work to engineer a novel and potent type of LIF inhibitor known as a ligand trap. Ligand traps have recently emerged as a new class of inhibitors, based on the principle of using a soluble form of a receptor to bind and sequester soluble ligands from activating cellular signaling. To inhibit LIF, we engineered both LIFR and gp130 for heightened affinity to LIF using the combinatorial protein engineering techniques of yeast-surface display and directed evolution. In Chapter 2, I cover the basic principles behind determining affinity and performing affinity maturation using yeast-surface display, including numerous yeast-based characterization assays, critical for determining therapeutic efficacy. Chapter 3 describes the engineering and production of a soluble version of LIFR, called eLIFR-Fc. As a ligand trap, eLIFR-Fc possessed many desirable therapeutic properties, including very high affinity for LIF, direct competition with LIF's receptors, blockade of LIF derived signaling in cancer cells, and abrogation of PDAC growth in vivo. Chapter 4 covers potential improvements to the eLIFR-Fc design, via fusion of engineered gp130, to create a potent engineered fusion protein (eFusion-Fc). By inclusion of both of LIF's receptors, the eFusion-Fc protein eliminated LIF signaling via LIFR and gp130 in cancer cells. These engineered ligand traps are extremely potent LIF inhibitors and add to the legacy of ligand traps as an emerging class of therapeutics, while offering hope as an effective PDAC treatment

Advisor: Cochran Jennifer R.
Jackson Peter K. (Peter Kent)
Kim Peter
Sage Julien
Engineering novel peptide agonists of the glucagon-like peptide-1 receptor

Understanding the molecular operations of G-protein coupled receptors and their ligands is a central goal in the project of understanding human physiology and altering it with pharmacological agents to improve human health. Receptors in GPCR class B have pharmacological and structural features that are distinct among GPCRs because they are evolutionarily adapted to bind and respond to short, alpha-helical peptide ligands instead of small molecule ligands. The glucagon-like peptide-1 receptor (GLP-1R) is a class B G-protein coupled receptor and diabetes drug target expressed mainly in the pancreatic β-cells that, when activated by its agonist GLP-1 after a meal, triggers insulin secretion and β-cell survival and proliferation. The best-studied agonist peptides, GLP-1 and exendin-4, share sequence homology at their N-terminal region; however, modifications to this region that can be tolerated are not fully understood. In this work, I have used combinatorial peptide screening coupled with chemical exploration with non-canonical amino acid substitutions to find novel and highly active GLP-1R agonists with altered N-terminal composition and to explore the principles that govern peptide activity

Keywords: Chemical and Systems Biology.
Advisor: Cochran Jennifer R.
Chen James Kenneth
Fordyce Polly
Grimes Kevin D.
The engineering of sentiment and desire : unraveling the aestheticized politics of ideotainment in China

We are entering into a post-truth era where the divide between propaganda, news, and entertainment is increasingly blurred. With the aid of social media, propaganda seeps into the interstices of everyday life and becomes pervasive, unobtrusive, and ambient. This is especially the case in authoritarian regimes. My dissertation investigates the shifting paradigm of propaganda in China, particularly an emerging trend on social media known as ideotainment, in which ideological messages are packaged in entertaining forms such as hiphop songs, short videos, photo-editing apps, and interactive mini-games. Much of the ideotainment content is produced and/or promoted by state-run media in China. Through case studies of viral ideotainment campaigns (with up to several billion page views) and interviews with their producers in Chinese state-run outlets in 2018 and 2019, this dissertation reveals how the Party-state appropriates digital technologies and popular culture genres to reinforce the legitimacy of the political regime, incorporating entertainment and the logic of play into a process of ideological subjectification that taps into netizens' nationalist sentiment and materialistic desires. It also traces the continuity and discontinuity between the Chinese Communist Party's pre-digital propaganda arts since 1930s and social media-based ideotainment in the current era. On the one hand, this dissertation documents the Party's long tradition in utilizing cultural entertainment as a means of propaganda that thrives on different media forms and technologies; on the other hand, it examines how media convergence in China over the past decade has afforded new possibilities for the innovation of propaganda and thought work. This dissertation makes both theoretical and empirical contributions to propaganda studies, China studies, and digital journalism studies

Keywords: Communication.
Advisor: Glasser Theodore L. 
Hamilton James
Christin Angèle
Wang Ban
Engineering solid-state platforms for quantum photonics

Essential to the development of hardware for optical quantum information processing is the integration of solid-state quantum emitters into low-loss photonics. Quantum emitters provide discrete energy levels, which can be used as qubit states and driven with photons. This light-matter interaction enables the generation, manipulation, and transmission of information. Photonic devices allow us to confine light at the nanoscale to enhance the interaction between local (quantum emitter) and flying (photon) qubits. In recent years, extensive research has been conducted to find quantum emitters with narrow linewidths, high quantum efficiencies, and long coherence times. Some of the most promising quantum emitters have been incorporated into photonic devices and have facilitated fundamental studies of light-matter interactions, the development of optical control schemes, and the generation of non-classical light. These works have mostly been confined to single devices with single quantum emitters and current efforts are directed at scaling to photonic circuits connecting arrays of quantum emitters. This endeavor further increases the requirements on quantum emitters, as they have to be generated with nanoscale precision and near-identical properties across the entire chip. Clever engineering of photonics can facilitate meeting these requirements. However, the development of low-loss photonic circuits remains a challenge of its own, as the most promising quantum emitters are hosted in materials non-standard in the photonics industry. The realization of quantum photonic circuits therefore requires the simultaneous development of quantum emitters and their corresponding photonics. In my thesis, I summarize our contributions to the development of quantum photonics. I discuss how we use semiconductor quantum dots strongly coupled to photonic cavities to demonstrate the coherent generation of indistinguishable, on-demand single photons, as well as multiple photons at a time. Such systems could be used as non-classical light sources for quantum communication and measurement-based quantum computation. However, scaling from single devices to large quantum circuits is challenging, due to the prohibitively large inhomogeneous broadening and random positioning of quantum dots. In contrast, color centers are atomic-scale defects, which can be generated in site-specific locations and exhibit much smaller inhomogeneous broadening than quantum dots. We have thus worked to develop color centers in diamond and 4H-silicon carbide and their host materials into scalable quantum photonic platforms. The host materials diamond and 4H-silicon carbide are new in the field of photonics and as such required us to develop novel fabrication protocols. Leveraging these fabrication techniques and inverse-design algorithms that account for fabrication constraints, we developed photonic platforms in diamond and 4H-silicon carbide for classical, nonlinear, and quantum optics

Keywords: Electrical Engineering.
Advisor: Vuckovic Jelena
Miller D. A. B. 
Soh H. Tom
Enhancing humoral immunity with injectable hydrogel platforms for sustained vaccine exposure

Existing and emerging infectious diseases continue to threaten our population. While vaccine development has progressed over the last several decades, there is still a critical need for improving immunomodulatory technologies to guide the endogenous immune response. As our knowledge of the immune system deepens, it is becoming clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Yet, increasing the potency, quality, and durability of the vaccine response remains a challenge. Material platforms such as nanoparticles, hydrogels, and microneedles can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Given their emerging role as immunomodulatory tools, these materials have been shown to augment the vaccine immune response by improving innate immune cell activation, creating local inflammatory niches, targeting delivering to lymph nodes, and controlling the timeframe of vaccine delivery. This chapter highlights the critical biological mechanisms for developing a strong humoral immune response and explores how materials have been designed to manipulate them

Keywords: Bioengineering.
Advisor: Appel Eric (Eric Andrew) 
Pulendran B. (Bali)
Yang Fan (Bioengineering researcher and teacher)
Entering Public Markets: IPOs and New Alternatives

The IPO, or initial public offering, has long remained the dominant vehicle with which to enter pubic markets. Despite the existence of other options, few companies have considered, let alone attempted, to use an alternative mechanism. More recently, access to information and the liquidity of private markets has driven fundamental changes to how private companies raise capital, fund growth, and perceive the public markets. How have these changes transformed the growth of today’s private companies, and, as a result, altered not only how executives approach the key considerations of ‘going public’, but also how regulators govern a company’s entrance into those markets? Using historical analysis and modern case studies, I dissect the mechanics of ‘going public’, highlight the critical considerations of stakeholders, introduce pending regulatory changes to current offering mechanics, and finally present a framework through which to evaluate the future entrance of companies into the public markets.

Keywords:  Public Policy Program
Stanford University
Humanities and Sciences
Public Policy Program
Direct Listing
IPO
Public Offering
Dutch Auction
Venture Capital
Finance
Thesis
Advisor: Callander Steven
Environmental Surveillance of Typhoidal Salmonellas in the Kathmandu Valley, Nepal

Enteric Fever, the life-threatening illness resulting from infection with Salmonella Typhi and Paratyphi, is endemic throughout much of South Asia. This disease is transmitted through contaminated food and water and most prevalent in areas with poor sanitation systems. To better understand the transmission pathways of typhoid fever causing Salmonella species in the Kathmandu Valley, we have conducted environmental surveillance of both drinking water and surface water within and downstream of the Kathmandu Valley. While previous case control studies posited that household drinking water was the main exposure pathway of typhoidal bacteria in Nepal, we found less than 1% of drinking water samples were contaminated with Salmonella Typhi or Paratyphi A, while river water samples within and up to 10 kilometers downstream of Kathmandu consistently showed high levels of contamination with these disease-causing agents. These results suggest that exposure to Salmonella Typhi and Paratyphi in the Kathmandu Valley may not be caused by contaminated drinking water alone but instead could be due to direct human interaction with contaminated river water or the use of contaminated rivers to water agricultural products sold in Kathmandu markets.

Keywords: typhoid
environmental surveillance
enrichment PCR
Nepal
enteric fever
Thesis
Enzymatic and imaging based approaches to study the mammalian glycocalyx

Every cell in the human body is coated with a peripheral layer of glycosylation. These polysaccharides, glycoproteins, glycolipids, and proteoglycans organize into an extramembrane compartment termed the glycocalyx. The glycocalyx is the cell's first point of contact with the extracellular environment, and is a key regulator of cell-matrix and cell-cell interactions. Investigations into the architecture and dynamics of the glycocalyx stand to benefit from methods to (i) spatially classify glycans at relevant length scales, and (ii) selectively edit glycocalyx components. After an introductory Chapter 1, Chapter 2 describes a super-resolution microscopy based approach for quantification of glycocalyx parameters. Application of this method in the context of pancreatic cancer revealed that oncogenic KRAS changes the glycocalyx in part by promoting the biosynthesis of mucins. Mucins are a class of cell surface glycoprotein that are difficult to study and drug due to their dense glycosylation and resistance to proteases. Chapter 3 describes characterization of a mucin-selective protease derived from the human gut microbiome, which enables selective cleavage and release of mucins from live cells. This tool lowers barriers to the study of native mucin biology and represents a potential strategy for therapeutic intervention in mucin-expressing cancers. Chapter 4 describes unbiased screening in search of mammalian enzymes that proteolyze mucin domains, culminating in the observation that the human lysosomal protease cathepsin D exhibits such activity. The discovery that a human protease cleaves mucin domains without prior deglycosylation has implications for our basic understanding of human mucin catabolism and the consequences when it goes awry

Keywords: Chemistry.
Advisor: Bertozzi Carolyn R.
Cui Bianxiao
Felsher Dean (Dean Walton)
Epidemiologic approaches to investigating the relationship between insulin resistance and major depressive disorder

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders in the United States, with one in five adults experiencing the disorder in their lifetimes.1 Yet more than half of people with MDD do not achieve an adequate response to treatment with existing antidepressants, and a substantial subset of these individuals fails to respond to multiple courses of treatment. Considerable effort has been aimed at uncovering the causes of MDD and developing new strategies for treatment and prevention, but more than 90% of behavioral neuroscience results fail to translate to treatments or other effective clinical strategies to treat people with MDD. This dissertation explores whether epidemiology can facilitate this translational process by introducing strategies to evaluate the nature and plausibility of neurobiological findings before the implementation of randomized controlled trials or other expensive and time-consuming psychiatric research. We undertook this translational question by investigating the relationship between MDD and one modifiable risk factor: insulin resistance (IR). IR has been associated with several somatic disorders, including cardiovascular disease, chronic kidney disease, Alzheimer's disease, and MDD. Yet, little is understood about the nature of the relationship between IR and MDD beyond an association between the prevalence of the two conditions. Is possible that IR plays a role in the development, trajectory or treatment of MDD? Chapter 1 of this dissertation evaluated the biological plausibility of relationship between IR and MDD. Chapters 2 and 3 studied the relationship between IR and characteristics and occurrence of MDD in a Dutch cohort. Chapter 4 attempted to address a key question from Chapter 1: is it possible to intervene on the IR-MDD pathway in order to effect depression treatment response? We conducted two emulated target trials to evaluate the causal relationship between an insulin-sensitizer, pioglitazone, and the one-year risk for treatment-resistant depression. Taken together, these studies aimed to expand our understanding of the relationship between IR and MDD. At the same time, they represent an epidemiology-based strategy for gaining insight into whether promising neuroscientific findings will translate into effective clinical approaches for treating MDD

Keywords: Epidemiology.
Advisor: Simard Julia 
Baiocchi Michael
Henderson Victor W. 
Rasgon Natalie L.
Essays in behavioral market design

In this dissertation, I study how centralized systems and platforms can improve their operational efficiency by taking into account the behavior of their users. To accomplish this, I combine two key elements: (1) understand users' behavior, and (2) identify sources of inefficiency and design solutions to address them. To better understand what drives user behavior, I combine techniques from behavioral operations and economics to derive models and hypotheses of how users make decisions. Then, I use tools from the econometrics literature to test these hypotheses and validate the proposed models. Finally, I combine this knowledge with tools from market design and operations to design and implement solutions that alleviate the inefficiencies identified in these markets. In the first chapter, I analyze the effect of increasing transparency in procurement platforms. The second chapter studies how the assortment composition and the history of past usage affect users' behavior in a two-sided market, and how we can take this into account to increase the number of matches generated. Finally, in the third chapter, I study the application behavior of students in the Chilean college admissions problem and propose an estimation procedure to account for their strategic behavior

Keywords: Business.
Advisor: Saban Daniela 
Bayati Mohsen 
Somaini Paulo 
Weintraub Gabriel
Essays in empirical corporate finance

In this thesis, I study two independent but closely related topics: the impact of liquid assets on corporate investments and bank deposit funding. In the first chapter, I examine the effect of a firm's liquidity holdings on its real investments and its impact on broader outcomes. I exploit a regulation-driven supply expansion of wealth management products (WMPs) that leads to an exogenous liquidity return increase accessible to Chinese firms. WMPs are deposit alternatives issued by commercial banks outside of the regulatory purview and are the dominant form of liquidity holdings by Chinese firms. I find that in response to the regulation, firms increase their liquidity holdings and sharply reduce capital and R & D expenditures. Using exogenous variation in banks' WMP supply induced by regulation, I argue that the effect of corporate liquidity holdings on real investments is causal and not driven by changes in firms' real investment opportunities. The reduction in real investments further leads to a decrease in firm-level TFP, patent application, primary business revenue, and employment. Exploiting regional economic growth in a difference-in-difference setting that uses the same regulatory shock suggests that the growth of corporate liquidity holdings has a negative impact on local economic outcomes. Cities more exposed to the WMP supply expansion exhibit slower capital and consumption growth. My findings suggest that a firm's liquidity holding decisions have a direct impact on its real investments and broader economic activities. In the second chapter, we demonstrate the passthrough of Treasury supply to deposit funding through bank market power. We show that an increase in Treasury supply leads to a net deposit outflow. At the same time, reliance on wholesale funding decreases. The effect is heterogeneous in nature - banks in more competitive markets experience larger outflows. The explanatory power of Treasury supply is not driven by monetary policy and bank-specific investment opportunities. Our empirical findings are rationalized with a model of imperfect deposit competition. Consistent with "The Deposits Channel of Monetary Policy", the model and empirics predict the opposite effect for Fed Fund rate hikes: there is a larger response in less competitive markets. Our results also shed light on the effect of the Reverse Repurchase (RRP) Facility on monetary policy passthrough

Keywords: Business.
Advisor: Rauh Joshua 
Seru Amit 
Bernstein Shai
Blattner Laura (Finance teacher)
Krishnamurthy Arvind
Essays in empirical financial accounting

This thesis studies several topical areas in empirical financial accounting. In the first chapter, I investigate whether investors are willing to trade off wealth for societal benefits. This chapter is co-authored with my co-advisor David F. Larcker and is forthcoming in the Journal of Accounting and Economics. In the second chapter, I examine how an increase in tick size affects algorithmic trading, fundamental information acquisition, and the price discovery process around earnings announcements. This chapter is co-authored with my co-advisor Charles M.C. Lee and is forthcoming in The Accounting Review. In the third chapter, I explore the growing market for startup employee equity using proprietary data from one of the largest of these marketplaces. This chapter is under revision for submission to a top accounting or finance journal

Keywords: Business.
Advisor: Larcker David F.
Lee Charles M.
Piotroski Joseph D. (Joseph David) 
Reiss Peter C. (Peter Clemens) 
Seru Amit
Essays in financial economics

This thesis consists of three essays. The first essay, which is joint work with Steve Grenadier, develops a theoretical model of a firm's optimal capital structure decision in a framework in which it may later choose to enter either Chapter 11 reorganization or Chapter 7 liquidation. In the second essay, which is joint work with Darrell Duffie, we show in the context of a theoretical model that the now-common practice of size discovery detracts from overall financial market efficiency. In the third essay, I show that creditors lose billions of dollars every year because firms that should emerge from Chapter 11 bankruptcy are frequently liquidated instead

Keywords: Business.
Advisor: Duffie Darrell 
Grenadier Steven R. 
Bernstein Shai
Seru Amit