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Mass Spectrometry Methods For Studying Rna Modifications And Rna-Protein Interactions
Get PDFThe central dogma of biology dictates that sequence information encoded in DNA is transferred via transcription to RNA and through translation encodes a protein. While this provides one level of control, the majority of DNA, RNA and proteins are fine-tuned through chemical modifications that modulate their structure and function. Proteomics by liquid chromatography/mass spectrometry (LC-MS/MS) is an unbiased view into the world of these modifications by providing a tool to uncover their regulation and function. Specifically, the study of RNA modifications has exploded due to the parallel advancement of next generation sequencing and LC-MS/MS, but these technologies are incomplete due to the inability to capture the full depth of RNA modifications in robust manner. In this work, we designed new methods for the study of RNA modifications by creating a platform focused solely on improving the RNA MS. Separately, we have applied new methods in LC-MS/MS to virus biology to uncover how post-translational modifications (PTMs) of proteins govern RNA-protein interactions (RPIs). To this end, we investigated how PTMs are globally affected by adenovirus infection and uncovered key PTMs required for viral protein function. We identified a striking loss of arginine methylation due to the shuttling of protein arginine methyl transferase 1 (PRMT1) into the cytoplasm, away from nuclear RBPs. Overall, both works provide advances in mass spectrometry methods and illustrate their application, providing the tools to ask deeper questions about RNA and protein modifications and viral biology
Essays On Strategic Choices Over Impaired Water Quality
Get PDFThis dissertation studies the strategic choices made by both governments and private citizens in relation to impairment of water quality over both surface and drinking water in the United States. In the first chapter, I investigate whether delegating responsibility for surface water quality management to state governments generates negative externalities against downstream neighboring states. To separate the effect of state-level policy from other sources of water quality variation, I rely on the staggered roll-out of state water management programs under the Clean Water Act to conduct a difference-in-difference analysis. I find that water quality declines in downstream states in response to upstream decentralization, but that the effect is not concentrated at borders. I additionally investigate whether interstate water compacts and political cooperation reduce cross-state spillovers. I find evidence that interstate cooperative agreements have modest success in serving as a hybrid between state and federal jurisdiction: I find no evidence of political cooperation. In my second chapter, co-authored with Felipe Flores Golfin, we evaluate potential benefits of drinking water infrastructure investments in the United States. We first estimate willingness-to-pay for high-quality drinking water using consumer avoidance behavior in response to health-based drinking water quality violations. We find a modest but statistically significant increase in bottled water purchases in the year in which a county has at least one active violation. We then estimate a household-level discrete choice model of drinking water. We find that the average household is willing to pay \$162 per year to avoid a one standard deviation decrease in water quality. We additionally find that WTP for bottled water increases in income. We further discuss how our estimates suggest that consumer preferences strongly justify major increases in water infrastructure investments in the United States
Multi-Omics Integration Through Single-Cell Copy Number Analysis In Cancer
Get PDFGenetic and epigenetic alterations combine to drive cancer progression. Heterogeneous cell populations within tumors are associated with poor prognosis and outcomes. Copy number aberrations (CNAs), a genetic variant commonly occurring in tumors, are used as markers to detect subclones and reconstruct tumor phylogeny. Multi-omics integration between CNAs and other modalities on tumor subclones facilitates studying the interplay between genome and epigenome, and their effects on transcriptome. So far, there is still a lack of computational methods for the multi-omics integration of different types of single-cell and ST tumor sequencing data. Therefore, the aim of this thesis is to extract (allele-specific) CNA signals in single-cell and ST tumor sequencing data, which enables the integration of multi-omics at the subclone level. We achieved this through the development of two methods — Alleloscope (Chapter 2) and Clonalscope (Chapter 3). Alleloscope is a computational method for profiling allele-specific CNAs in single-cell DNA- and/or transposase-accessible chromatin-sequencing (scDNA-seq, ATAC-seq) data, enabling integrative analysis of allele-specific copy number and chromatin accessibility. On scDNA-seq data from gastric, colorectal and breast cancer samples, with validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multiallelic CNAs, in which cells that carry varying allelic configurations adding to the same total copy number coevolve within a tumor. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detected multiallelic copy number events and copy-neutral loss-of-heterozygosity, enabling dissection of the contributions of chromosomal instability and chromatin remodeling to tumor evolution. To detect genetically different subclones based on CNAs, we also developed Clonalscope, a subclone detection method for different single-cell and ST tumor sequencing data, which leverages prior information from matched bulk DNA-seq data. Clonalscope implements a nested Chinese Restaurant Process to model the evolutionary process in tumors. On scRNA-seq and scATAC-seq data from three gastrointestinal tumor samples, Clonalscope successfully labeled malignant cells and identified genetically different subclones, which were validated in detail using matched scDNA-seq data. On ST data from a basal cell carcinoma and two invasive ductal carcinoma samples, Clonalscope was able to label malignant spots, trace subclones between related datasets, and identify spatially segregated subclones expressing genes associated with drug resistance and survival
An Examination Of Clinical Decision Support For Discharge Planning: Systematic Review, Simulation, And Natural Language Processing To Elucidate Referral Decision Making
Get PDFStatement of the Problem: As healthcare data becomes increasingly prolific and older adult patient needs become more complex, there is opportunity for evidence-based technology such as clinical decision support systems (CDSS) to improve decision making at the point of care. Although CDSS for discharge planning is available, few published tools have been translated to new settings. Existing studies have not explored discordance between recommended and actual discharge disposition. Understanding the reasons why patients do not receive optimal post-acute care referrals is critical to improving the discharge planning process for older adults and their families. Methods: Three-paper dissertation examining CDSS. Paper 1 is a systematic review of studies with prediction models for post-acute care (PAC) destination. Paper 2 is a retrospective simulation of a discharge planning CDSS on electronic health record (EHR) data from two hospitals to examine differences in patient characteristics and 30-day readmission rates based on a CDSS recommendation among patients discharged home to self-care. Paper 3 is a natural language processing (NLP) study including retrospective analysis of narrative clinical notes to identify barriers to PAC among hospitalized older adults and create an NLP system to identify sentences containing negative patient preferences. Results: Most prediction models in the literature were developed for specific surgical populations using retrospective structured EHR data. Most models demonstrated high risk of bias and few published follow-up studies. In the simulation study, surgical patients identified by the CDSS as needing PAC but discharged home to self-care experienced adjusted 51.8% higher odds of 30-day readmission compared to those not identified. In the NLP study, the top three barriers were patient has a caregiver, negative preferences, and case management clinical reasoning. Most patients experienced multiple barriers. The negative preferences NLP system achieved an F1-Score of 0.916 using a deep learning model after internal validation. Conclusions: Future prediction modeling studies should follow TRIPOD guidelines to ensure rigorous reporting. Findings from the simulation and NLP studies suggest transportability of the CDSS to large urban academic health systems, especially among surgical patients. Incorporating natural language processing variables into CDSS tools may aid the identification of barriers to PAC
Lying, Cheating, And The Social Dynamics Of Ethical Decision Making
Get PDFUnethical behavior in organizations is pervasive. The social and economic consequences of unethical behavior are profound, and a large body of work in economics, psychology, and management has been dedicated to investigating organizational misconduct. Despite increased scholarly interest, there has been a strong methodological convergence in behavioral ethics experiments that has narrowed the scope of ethical decision-making research. In this dissertation, I use novel experimental methods to advance the study of ethical decision making both theoretically and methodologically. In Chapters 1 & 2, I highlight the limits of financially incentivized behavior and demonstrate how fear of shame and fear of embarrassment guide ethical judgment. In Chapter 1, I show that people will lie and sacrifice financial gain to avoid being embarrassed in front of others. In Chapter 2, I show that people can learn appropriate behavior from others’ expressions of shame. I find that people will avoid the behavior that elicits shame in others even when paid to engage in that behavior and when the norms surrounding that behavior are otherwise ambiguous. In Chapter 3, I draw the conceptual distinction between cheating behavior and lying behavior. While prior work has considered the terms interchangeable, by identifying the two behaviors as distinct, I reconcile conflicting findings in behavioral ethics. Together, this dissertation highlights the limitations of extant approaches and expands our understanding of ethical decision making
Essay On Sustainable Finance
Get PDFThis dissertation has three independent chapters. The first chapter investigates how the environmental liability of lenders affects debtors\u27 behavior. I use U.S. Census Bureau micro-data and the passage of the Lender Liability Act as a novel identification strategy to answer this question. Firms increase on-site pollution, cut investment in abatement technology, and incur 17.54% more environmental regulatory violations when secured lenders become less responsible for the cleanup cost of their collateral. The effects are stronger for firms close to bankruptcy or with high environmental risks. This lower environmental compliance slightly benefits employment, but does not change wages or production. Overall, financial constraints that may be alleviated due to reduced lender liability do not result in pollution mitigation investment or increased production; instead, my findings suggest that reduced lender liability lessens banks’ incentives to influence the practices of their debtors.
The second chapter studies how Private Equity (PE) firms affect firms\u27 environmental outcomes in the oil and gas industry. On average PE ownership leads to a 70% reduction in the use of toxic chemicals and a 50% reduction in satellite-based measures of CO2 emissions. However, this average effect hides significant heterogeneities. PE-backed firms increase pollution in locations and periods where environmental liability risk is low, as shown by a novel natural experiment that reduced these risks for projects located on federal and Native American territories. Overall, high-powered incentives to maximize shareholder value may benefit environmental outcomes when the risk of environmental regulation is high.
The third chapter is joint work with J. Anthony Cookson, Erik Gilje, Rawley Heimer. We study the effect of personal wealth on entrepreneurial decisions using data on mineral payments from Texas shale drilling to individuals throughout the United States. Large cash windfalls increase business formation by 0.8 to 2.1 percentage points, but do not affect transitions to self-employment. By contrast, cash windfalls significantly extend self-employment spells, but do not affect the duration of business ownership. Our findings help reconcile contrasting findings in prior work: liquidity constraints have different effects on entrepreneurial activity that may depend on the entrepreneur’s motivations
Penn Library\u27s LJS 426 - [al-Kullīyāt]. = [الكليات]. (Video Orientation)
No full texthttps://repository.upenn.edu/sims_video/1174/thumbnail.jp
Understanding Collaborative Art Degree Programs and the Recruitment of International Students
No full textInternationalization has transformed the higher education landscape in the 21st century. As a result, international student recruitment has become more important in the United States, which remains the host country for most international students, and in China, the single largest source of young people seeking to go abroad for higher education. Students from different countries bring distinct perspectives and experiences to American colleges and universities, broadening the horizons of American students and making U.S. higher education institutions (HEIs) more competitive in the global market. Various recruitment methods are used to attract international students, including collaborative degree programs that award joint and dual credentials, which are getting increasingly popular. Sixteen percent of U.S. colleges and universities were engaged in collaborative degree programs in 2016, according to the American Council on Education (ACE), compared to only 10 percent in 2011. This study analyzes why and how HEIs come together to establish collaborative degree programs, and how these programs are used to recruit international students. Specifically, this study focuses on U.S.-China higher education partnerships in the context of rapid development of art education in China, which has not been extensively researched. Adopting the Logic Model as a framework and using NVivo software for analysis, this study takes a narrative approach to provide insights into three partnerships involving six institutions, three in the United States and three in China. The selected collaborative art degree programs involve a bachelor’s level credential in theater and dance from Queens College, part of the City University of New York (CUNY) system, and the Jackie Chan Movie and Media College in Wuhan, China; a bachelor of fine arts degree offered by the School of the Art Institute of Chicago (SAIC) and the Central Academy of Fine Arts in Beijing; and a master’s degree in interactive media studies conferred jointly by the Tisch School of the Arts at New York University and New York University Shanghai, China
Aristotle on Rhetoric
No full textAristotle’s Rhetoric is a technical handbook for how to persuade a public audience about what is good, just, and noble. The goal of this dissertation is to explain why Aristotle thought this ability was a kind of knowledge, a craft (technē), distinct from both political expertise (politikē) and dialectical expertise (dialektikē). I aim to do this by giving an interpretation of the norms governing rhetorical persuasion. Like his conception of dialectic, Aristotle’s conception of rhetoric is primarily governed by epistemological norms: the excellent orator is someone who can present an audience with good reasons for believing some conclusion. But, I argue, these norms are specific to the subject matter for which rhetoric is needed: matters requiring public deliberation and judgment
Epistemic Thinking\u27s Role in Collaborating on a Wicked Problem
No full textGlobal trends such as climate change, political instability, technology, and rising inequality will radically increase the mental demands on how people know and view knowledge. One way these demands will manifest is through the need for more collaborations to address these wicked problems. Unfortunately, practitioners may be unaware of the available research to help them meet this demand by optimizing epistemic thinking within collaborations. This study addresses this problem by applying one of the more prominent theoretical frameworks within the field of epistemology, the apt-AIR model, to examine a multi-disciplinary, real-world collaborative program. Through semi-structured interviews with 20 participants in this program, the study investigates how epistemic thinking relates to a team\u27s capacity to collaborate on a wicked problem. Its findings provide critical insights into how the program can improve epistemic performance within the collaborations. The findings also offer valuable insights for practitioners designing collaborations and recommendations for making the apt-AIR model more accessible and beneficial for these designers