VictorJuiz/thesis huggingface dataset:
Bioinformatics approach identifies Guanabenz as potential therapeutic for Pancreatic Ductal Adrenocarcinoma through attenuation of GPCRs and Ras Signaling

Pancreatic ductal adrenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis at time of diagnosis and high mortality due to few effective treatment options. This work seeks to show the power of bioinformatics to quickly and efficiently repurpose FDA-approved drugs for PDAC. We used a systematic drug repositioning bioinformatics approach that compared a concise and comprehensive array of gene expression profiles to identify potential FDA approved drugs. Initial screening of the top candidates by MTT survival assay narrowed the search to Guanabenz, an alpha-2 receptor (ADRA2) agonist and antihypertensive drug. MTT survival assays showed that Guanabenz significantly lowered survival of various human and mouse PDAC cell lines. Immunoblot analysis showed Guanabenz attenuating pCREB (involved in GPCR signaling) and ERK ½ kinase in the Ras signaling pathway. Mouse models treated with Guanabenz showed the drug’s tumor suppressive properties with the prevention of preneoplastic legion (PanIN) formation, a landmark precursor in tumorigenesis of pancreatitis induced PDAC. These experiments confirm the identity of Guanabenz as a novel treatment for PDAC as well as the potential in targeting the ADRA2 pathway in PDAC drug development. Further, this work confirms drug repositioning as an effective way of identifying novel treatments in PDAC.

Keywords:  Department of Biology
Drug Repositioning
DNA microarray
KRAS signaling pathway
PanINs
Pancreatic ductal adrenocarcinoma
cerulein induced pancreatitis
Guanabenz
Biology
Thesis
Advisor: Mazur Pawel
Jones Patricia
Sage Julien
Biomechanical characterization of dilated cardiomyopathy causing mutations in human beta-cardiac myosin [electronic resource]

Cardiomyopathies are diseases of the myocardium resulting in heart failure, arrhythmia, and sudden death. Cardiomyopathies represent a major cause of morbidity and mortality in all age groups and recent application of human genomic technologies has revealed thousands of gene mutations that cause inherited and sporadic cardiomyopathies. Many mutations in the beta-cardiac myosin heavy chain (beta-MHC) gene, which encodes the motor that powers ventricular contraction, have been identified to cause inherited cardiomyopathies, including dilated cardiomyopathy (DCM). However, the molecular mechanisms by which these mutations alter the force generation and kinetic properties of the myosin molecule have not been elucidated. As a result, there are no available therapies targeted toward treating the underlying cause of these diseases to date. We have successfully adapted a system to produce recombinant human cardiac myosin motor domain, known as subfragment-1 (S1), using a mammalian myoblast cell line. This technique has allowed us to obtain significant quantities of highly purified recombinant human beta-cardiac myosin S1 for in-depth functional analyses of wild type and DCM-causing mutants. Characterization of biomechanical properties of DCM causing human beta-cardiac S1 demonstrated that DCM mutations results in an overall hypo-contractile state, although the fundamental mechanistic changes that lead to decreased power output vary. In the future, more complex systems can be analyzed by performing assays with regulated thin filaments instead of actin and double-headed myosin motors to gain further insights into the effects of beta-MHC mutations on cardiac myosin function. Furthermore, using emerging induced pluripotent stem cell (iPSC) technology, insights into the effects of these mutations of myosin biomechanical function in vitro can be correlated with their effects on cardiomyocyte function at the cellular level. Further understanding of these mechanisms can guide the search for specific therapeutic targets and lead to the development of small molecules to modulate the effects of the DCM-causing mutations and potentially prevent or reverse this clinically devastating disease.

Advisor: Spudich James A.
Assimes Themistocles
Dunn Alexander Robert advisor. Thesis advisor
Giaccia Amato J. advisor. Thesis advisor
Black holes and the butterfly effect [electronic resource]

What happens if you perturb a small part of a large system, and then you wait a while? If the system is chaotic, one expects the butterfly effect to push the state far from its original trajectory. I will present an analysis of this phenomenon in the setting of a strongly interacting quantum gauge theory, using the tools of gauge-gravity duality. The original state corresponds to a black hole geometry, and the perturbation is represented by a particle falling through the horizon. As time passes, the boost of the particle grows exponentially, creating a shock wave that implements the butterfly effect. Building on this framework, I will relate and explore the dynamics of chaos and the region behind the horizon of a black hole. This thesis is based on two papers written with Stephen Shenker. It should not be cited without also referencing those papers.

Keywords: Physics.
Advisor: Susskind Leonard primary advisor. Thesis advisor
Hayden Patrick (Patrick M.) advisor. Thesis advisor
Shenker Stephen Hart
Blackboard bodhisattvas [electronic resource] : narratives of New York City teaching fellows

ABSTRACT Since the founding of Teach for America (TFA) in 1990, alternative routes to teaching have proliferated. The New Teacher Project (now TNTP), the consulting and advocacy wing of TFA, has been a key actor behind many Teaching Fellows programs in a number of settings across the U.S., the largest of which is the New York City Teaching Fellows (TNTP website). Using a life history approach (Goodson, 1992), this dissertation investigates the experiences of three New York City Teaching Fellows who have remained in the classroom for eight to thirteen years, well beyond the five-year mark by which point 50% of urban teachers quit. This dissertation argues that the inadequacy of the Fellows' preparation for taking on the challenges of urban teaching speaks dramatically to how the alternative-certification model is far more successful at recruiting and placing young, ill-prepared teachers in classrooms than it is at training or retaining good teachers, with the resulting turnover only leading, in the course of these teachers careers, to more emphasis on recruitment rather than training and retention. The three Fellows in this study, lacking the easy-exit strategy of TFA teachers (who come from the best schools), found the means of becoming better, more engaged teachers by eventually developing a personal point of connection and commitment with the students and the school system. This was despite, and not because of, the system's increasingly bureaucratic efforts at professional development for improved test results. These teachers' stories speak, not only to the difficulty of being an urban teacher in a era of accountability, but the need to provide a more supportive induction process and setting for teachers to find their places and their talents as professionals within the schools and American culture more generally.

Keywords: Education.
Advisor: Labaree David F.
Willinsky John
Kelman Ari Y.
McDermott Ray (Raymond Patrick)
Bone morphogenetic protein signaling in astrocyte maturation [electronic resource]

Astrocytes constitute a major cell population in the brain with a myriad of essential functions, yet we know remarkably little about the signaling pathways and mechanisms that direct astrocyte maturation. To explore the signals regulating astrocyte development, we prospectively purified and cultured immature postnatal rodent astrocytes. We identified fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) as robust trophic factors for immature astrocytes. We showed that astrocytes respond directly to BMPs via phosphorylation of the smad1/5/8 pathway. In vitro, BMP signaling promoted immature astrocytes to adopt multiple characteristics of mature astrocytes, including a more process-bearing morphology, aquaporin-4 (AQP4) and S100 [beta] immunoreactivity, limited proliferation, and strong downregulation of epidermal growth factor receptor (EGFR). In vivo, activation of the smad1/5/8 pathway in astrocytes was seen during early postnatal development, but inhibition of astrocyte proliferation was not observed. These insights can aid in the further dissection of mechanisms and pathways controlling astrocyte biology and development.

Advisor: Barres Ben
Elias Joshua advisor. Thesis advisor
McConnell Susan K. advisor. Thesis advisor
Talbot William
A buffer-based approach to video rate adaptation [electronic resource]

During peak viewing time, well over 50% of US Internet traffic is streamed video from Netflix and YouTube. To provide a better streaming experience, these services adapt their video rates by observing and estimating the available capacity. However, accurate capacity estimation is difficult due to highly variable throughput and complex interactions between layers. As a result, existing rate adaptation algorithms often lead to suboptimal video quality and unnecessary rebuffers. This thesis proposes an alternative buffer-based approach to adapt video rate. Rather than presuming that capacity estimation is always required, this approach starts the design by only using the playback buffer occupancy, and then ask when capacity estimation can be helpful. This design process leads to two separate phases of operation: during the steady-state phase, when the buffer encodes adequate information, we choose the video rate based only on the playback buffer; during the startup phase, when the buffer contains little information, we augment the buffer-based design with capacity estimation. This approach is tested with a series of field experiments spanning millions of Netflix users from May to September, 2013. The results demonstrate that although a simple capacity estimation is important during the startup phase, it is unnecessary in the steady state. The buffer-based approach allows us to reduce the rebuffer rate by 10-20% compared to a commercial algorithm used in Netflix, while delivering a similar overall average video rate and a higher video rate in steady state.

Advisor: McKeown Nick
Johari Ramesh
Katti Sachin
Buying suits [electronic resource] : exploring business-to-business financing of American disputes

People litigate for various reasons. Some want to right wrongs, others -- make precedents. But most, at least in the civil realm, sue to protect economic interests; and they are motivated by pragmatic considerations rather than abstract notions of justice. One fruit of the mercantile approach to civil litigation is the nascent market where third parties provide financing for litigants (or their lawyers) and profit from a successful resolution of the funded claims. Through the lens of a third-party funder, justice is a mass-market commodity, and its value depends on laws of men and laws of probability alike. The ways of litigation funders create multiple points of tension for the legal process and its participants, and laws on the book offer little guidance on how third-party interests should be treated. Resulting procedural and ethical dilemmas have stirred a debate among scholars who rushed to offer conflicting opinions and advice. Critics demand that litigation investing be banned, calling it a travesty of justice that turns courts into casinos. Enthusiasts want the practice formally recognized, asserting that it levels the playing field for weaker parties. The discussion on litigation financing does not lack vigor; but it does lack hard facts. Drawing from first-hand empirical data on the practice of litigation funding in the United States, this thesis explores and systematizes the market for legal claims, explaining how it actually works. First, it describes the entire ecosystem of actors who apply the logic of asset management to uncertainties of individual lawsuits. Second, it tackles the question of why commercial disputes get funded. Third, it provides a systematic overview of different models of financing, from secured debt to equity-style investments to attorney's fee-backed securities. Finally, it contemplates funding in the context of complex litigation, and shows various ways used by litigation stakeholders to leverage their resources. Based on the descriptive findings, I claim that modern civil litigation engages multiple, often undisclosed stakeholders with complex financial motivations. I argue that such interests should be recognized by the legal system as legitimate and ultimately regulated.

Keywords: Law JSD.
Advisor: Hensler Deborah R.
Gilson Ronald J.
Grundfest Joseph A. advisor. Thesis advisor
Candidate and proteomic approaches to study non-histone lysine methylation [electronic resource]

Lysine methylation is a chemical modification that occurs naturally in proteins. This post-translational modification is small and preserves the charge on the lysine sidechain, making relatively little chemical difference. However, misregulation of lysine methylation can cause a host of human cancers, developmental disorders, and other diseases. The most prominent example of lysine methylation occurs within histone proteins, but it can also occur on non-histone proteins. The proteomic extent of methylation and the diversity of processes it might regulate were previously unclear. The work presented here focuses on identifying the cellular "methylome" and understanding methylation signaling pathways within cells. I also examine the substrate repertoire of the methyltransferase SETMAR and identify the spliceosome component snRNP70 as a novel SETMAR substrate.

Keywords: Chemical and Systems Biology.
Advisor: Gozani Or Pinchas primary advisor. Thesis advisor
Cimprich Karlene advisor. Thesis advisor
Elias Joshua
Straight Aaron
Carbon Cycling in Organic Material Originating from Monospecific Overstories in Hawaiian Lowland Wet Forests

High levels of invasion and disturbance in the lowland wet forests of Hawaii have led to a need for novel management strategies for the conservation of biodiversity, carbon (C) storage, and other ecosystem services. The hybrid ecosystems approach represents a method by which species traits can be used in the creation of ecosystems which optimize desirable characteristics. In the lowland wet forests of Hawaii, C storage is one of these important traits, given the continual increase in atmospheric carbon and global environmental change. In this study we examined soil humus decomposition and leaf litter decomposition. We asked whether patterns seen in rates of litter turnover across nine species currently present in the lowland wet forests of the big island of Hawaii would be present in the turnover of humus originating from single species stands. We used a soda-lime absorption measurement assay to quantify soil decomposition over a period of four weeks and performed a four-month common site litter decomposition experiment. Total C efflux values for the full four week period ranged from 13.4 – 16.9 g C/kg soil, with little difference among species. Litter decomposition had greater variability. The fastest decomposition occurred in Thespesia populnea (milo) litter, with 17.6% of mass left at the end of the decomposition period, while Persea americana (avocado) litter was the slowest to decompose and maintained 78.6% of its mass. Our results suggest a decoupling of litter and humus decomposition rates. These findings provide additional understanding on the extent to which hybrid ecosystems may be able to influence C storage and turnover through species treatments.

Keywords:  Department of Biology
biology
ecology
hawaii
invasive species
carbon
soil
humus
litter
hybrid ecosystems
Stanford University Department of Biology
Thesis
Advisor: Vitousek Peter
Fendorf Scott
Cas9-Mediated Genome Editing in Mouse Primary Cells

Gene targeting through Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated homologous recombination is a novel and powerful technique with promising applications in human disease modeling and therapeutic development. However, one major factor limiting genome editing efficiency is the time and difficulty of obtaining a transgenic animal, which may require several generations of breeding and expensive maintenance. While the establishment of an animal line with endogenous Cas9 nuclease expression could potentially accelerate the study of both gene knock-out and overexpression models, particularly in primary cells, previous work has yet to test the feasibility of such a system. This project provided the first in vitro proof of concept for a Cas9 transgenic mouse line as a research tool through the generation and characterization of Cas9-expressing mouse cells. In NIH3T3 cells, constitutive expression of either the Cas9 nuclease or nickase resulted in toxicity, with high levels of wild-type Cas9 expression appearing to be lethal over time. Following delivery of a CRISPR guide RNA sequence into cultured Cas9-expressing mouse cells via lentivirus, efficient genome editing was also observed. These findings demonstrate the prospect of high-speed multiplex genome engineering in mouse primary cells with future clinical implications such as cancer modeling and gene therapy. Moving forward, the generation of an inducible Cas9 transgenic animal should be pursued.

Keywords:  Department of Biology
CRISPR
Cas9
guide RNA
genome editing
embryonic stem cells
toxicity
Biology
Stanford
Thesis
Advisor: Weissman Irving L.
Gozani Or
Catching Fish With Two Hands: Vietnam's Hedging Strategy Towards China

China’s dramatic economic growth and ascendance onto the world stage has had large implications for neighboring Southeast Asian states that, while enthusiastic about growth opportunities, are still apprehensive of Chinese dominance in the region. As a result, most scholars maintain that states in the region have chosen to “hedge” against China by cultivating positive relations with all large states involved in the region. Current literature on hedging is insufficiently nuanced since it treats hedging as a fixed foreign policy strategy in between balancing and bandwagoning. Furthermore, existing explanations generally consider only one plane of hedging, namely how small states cultivate relations with other powers to hedge against a threatening state. This paper contributes to existing literature on hedging in two ways. First, it proposes a three-dimensional approach for understanding hedging that considers how domestic, foreign, and sectoral factors affect small-states’ hedging strategy. Second, this thesis examines two cases of Vietnamese foreign policy towards China in the 21st century using this three- dimensional framework. More specifically, this paper analyzes one case study in the economic realm, bauxite mining in the Central Highlands, and one in the security sphere, the open port policy of Cam Ranh Bay. Ultimately, this thesis demonstrates the fluid processes of hedging across issues and the need for a better understanding of these dynamics in the Southeast Asian context.

Keywords: Vietnam
China
hedging
Cam Ranh Bay
bauxite
bauxite mining
Southeast Asia
Center for International Security and Cooperation
Thesis
Advisor: Emmerson Don
Cellular composition of cerebral arteriovenous malformations: determining the presence and characterization of progenitor cells

Cerebral arteriovenous malformations (AVMs), although rare, are a leading cause of intracerebral hemorrhage and stroke in young adults and children. Due to a poor understanding of the formation and cellular makeup of AVMs, available treatment options are complicated and invasive, and AVMs can regrow in some cases. Progenitor cells have been implicated in AVMs, possibly functioning in the abnormal growth characteristic of this lesion, but their physical presence has not been directly confirmed. By analyzing the protein expression in human AVM tissue in vivo and cells isolated from AVMs in vitro, this project works to clarify a potential progenitor presence and associated differentiation potential. First, Ki67 and CD133, accepted markers for cellular proliferation and stem cells respectively, were analyzed by immunohistochemistry in 29 human AVM tissue samples. In conjunction with previously identified expression patterns, the co-expression of progenitor-associated proteins in AVM tissue strongly indicates a progenitor presence. Second, two progenitor cell lines were successfully isolated from human cerebral AVMs by enrichment under progenitor conditions. The protein profile of these cell lines was then explored by immunocytochemistry to determine their in vitro differentiation potential. These cell lines maintain several characteristics of progenitor cells, including proliferation and expression of progenitor-associated proteins. Importantly, they have a unique protein signature, and the cells proliferate independently of growth factors. Additionally, human serum causes proliferation rather than differentiation. This project augments understanding of the fundamental nature of cerebral AVMs by identifying the presence of progenitor cells. Future research should extend these findings to determine the full characterization of these novel progenitors and their role in AVM formation and/or maintenance.

Keywords:  Department of Biology
Stanford University Department of Neurosurgery
Biology
Cerebral arteriovenous malformation (AVM)
progenitor cell
Thesis
Advisor: Chang Steven
Nelson William James
Simon Michael
Shoemaker Lorelei
CEO Overconfidence: An Alternative Explanation for Corporate Financing Decisions

In the well-established trade-off capital structure model, a rational CEO
chooses to issue debt and equity depending on the costs and benefits of each.
In this model, the optimal amount of debt and equity financing occurs when
the dead-weight costs of bankruptcy exactly offset the tax saving benefits of
debt. However, this rational decision-making theory does not provide an
adequate explanation for empirical findings that companies often deviate
from the presumably optimal levels of debt and equity issuance. As an
alternative explanation for these capital structures, we examine the additional
impact that CEO overconfidence appears to have on financing decisions. In
order to measure overconfidence of CEOs, we employ a measure based on
the percentage of optimistic press coverage a CEO receives relative to the
percentage of optimistic press coverage that the company itself receives. We
then gather data on net debt issuance and net equity issuance under the
governance of each CEO, and regress these financing decisions on our
measure of CEO overconfidence. We find weak evidence that what we term
overconfident CEOs deem equity financing relatively more expensive than
debt financing, and thereby maintain higher than expected leverage ratios.
We focus our data analysis on financing decision data from the decade 1997-
2007, and examine capital structure decisions arising from CEO overconfidence in conjunction with differentials by industry and the effects of the dividend tax cuts from the 2003 Jobs and Growth Tax Relief Reconciliation Act.

Keywords:  Department of Economics
Stanford Department of Economics
Thesis
Advisor: Levin Jon