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- Creators: Barrett, The Honors College
- Creators: Wang, Xiao
Description
Recombinases are powerful tools for genome engineering and synthetic biology, however recombinases are limited by a lack of user-programmability and often require complex directed-evolution experiments to retarget specificity. Conversely, CRISPR systems have extreme versatility yet can induce off-target mutations and karyotypic destabilization. To address these constraints we developed an RNA-guided recombinase protein by fusing a hyperactive mutant resolvase from transposon TN3 to catalytically inactive Cas9. We validated recombinase-Cas9 (rCas9) function in model eukaryote Saccharomyces cerevisiae using a chromosomally integrated fluorescent reporter. Moreover, we demonstrated cooperative targeting by CRISPR RNAs at spacings of 22 or 40bps is necessary for directing recombination. Using PCR and Sanger sequencing, we confirmed rCas9 targets DNA recombination. With further development we envision rCas9 becoming useful in the development of RNA-programmed genetic circuitry as well as high-specificity genome engineering.
ContributorsStandage-Beier, Kylie S (Author) / Wang, Xiao (Thesis advisor) / Brafman, David A (Committee member) / Tian, Xiao-jun (Committee member) / Arizona State University (Publisher)
Created2018
Description
The portability of genetic tools from one organism to another is a cornerstone of synthetic biology. The shared biological language of DNA-to-RNA-to-protein allows for expression of polypeptide chains in phylogenetically distant organisms with little modification. The tools and contexts are diverse, ranging from catalytic RNAs in cell-free systems to bacterial proteins expressed in human cell lines, yet they exhibit an organizing principle: that genes and proteins may be treated as modular units that can be moved from their native organism to a novel one. However, protein behavior is always unpredictable; drop-in functionality is not guaranteed.
My work characterizes how two different classes of tools behave in new contexts and explores methods to improve their functionality: 1. CRISPR/Cas9 in human cells and 2. quorum sensing networks in Escherichia coli.
1. The genome-editing tool CRISPR/Cas9 has facilitated easily targeted, effective, high throughput genome editing. However, Cas9 is a bacterially derived protein and its behavior in the complex microenvironment of the eukaryotic nucleus is not well understood. Using transgenic human cell lines, I found that gene-silencing heterochromatin impacts Cas9’s ability to bind and cut DNA in a site-specific manner and I investigated ways to improve CRISPR/Cas9 function in heterochromatin.
2. Bacteria use quorum sensing to monitor population density and regulate group behaviors such as virulence, motility, and biofilm formation. Homoserine lactone (HSL) quorum sensing networks are of particular interest to synthetic biologists because they can function as “wires” to connect multiple genetic circuits. However, only four of these networks have been widely implemented in engineered systems. I selected ten quorum sensing networks based on their HSL production profiles and confirmed their functionality in E. coli, significantly expanding the quorum sensing toolset available to synthetic biologists.
My work characterizes how two different classes of tools behave in new contexts and explores methods to improve their functionality: 1. CRISPR/Cas9 in human cells and 2. quorum sensing networks in Escherichia coli.
1. The genome-editing tool CRISPR/Cas9 has facilitated easily targeted, effective, high throughput genome editing. However, Cas9 is a bacterially derived protein and its behavior in the complex microenvironment of the eukaryotic nucleus is not well understood. Using transgenic human cell lines, I found that gene-silencing heterochromatin impacts Cas9’s ability to bind and cut DNA in a site-specific manner and I investigated ways to improve CRISPR/Cas9 function in heterochromatin.
2. Bacteria use quorum sensing to monitor population density and regulate group behaviors such as virulence, motility, and biofilm formation. Homoserine lactone (HSL) quorum sensing networks are of particular interest to synthetic biologists because they can function as “wires” to connect multiple genetic circuits. However, only four of these networks have been widely implemented in engineered systems. I selected ten quorum sensing networks based on their HSL production profiles and confirmed their functionality in E. coli, significantly expanding the quorum sensing toolset available to synthetic biologists.
ContributorsDaer, René (Author) / Haynes, Karmella (Thesis advisor) / Brafman, David (Committee member) / Nielsen, David (Committee member) / Kiani, Samira (Committee member) / Arizona State University (Publisher)
Created2017
Description
Synthetic biology is an emerging field which melds genetics, molecular biology, network theory, and mathematical systems to understand, build, and predict gene network behavior. As an engineering discipline, developing a mathematical understanding of the genetic circuits being studied is of fundamental importance. In this dissertation, mathematical concepts for understanding, predicting, and controlling gene transcriptional networks are presented and applied to two synthetic gene network contexts. First, this engineering approach is used to improve the function of the guide ribonucleic acid (gRNA)-targeted, dCas9-regulated transcriptional cascades through analysis and targeted modification of the RNA transcript. In so doing, a fluorescent guide RNA (fgRNA) is developed to more clearly observe gRNA dynamics and aid design. It is shown that through careful optimization, RNA Polymerase II (Pol II) driven gRNA transcripts can be strong enough to exhibit measurable cascading behavior, previously only shown in RNA Polymerase III (Pol III) circuits. Second, inherent gene expression noise is used to achieve precise fractional differentiation of a population. Mathematical methods are employed to predict and understand the observed behavior, and metrics for analyzing and quantifying similar differentiation kinetics are presented. Through careful mathematical analysis and simulation, coupled with experimental data, two methods for achieving ratio control are presented, with the optimal schema for any application being dependent on the noisiness of the system under study. Together, these studies push the boundaries of gene network control, with potential applications in stem cell differentiation, therapeutics, and bio-production.
ContributorsMenn, David J (Author) / Wang, Xiao (Thesis advisor) / Kiani, Samira (Committee member) / Haynes, Karmella (Committee member) / Nielsen, David (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2018
Description
Synthetic manipulation of chromatin dynamics has applications for medicine, agriculture, and biotechnology. However, progress in this area requires the identification of design rules for engineering chromatin systems. In this thesis, I discuss research that has elucidated the intrinsic properties of histone binding proteins (HBP), and apply this knowledge to engineer novel chromatin binding effectors. Results from the experiments described herein demonstrate that the histone binding domain from chromobox protein homolog 8 (CBX8) is portable and can be customized to alter its endogenous function. First, I developed an assay to identify engineered fusion proteins that bind histone post translational modifications (PTMs) in vitro and regulate genes near the same histone PTMs in living cells. This assay will be useful for assaying the function of synthetic histone PTM-binding actuators and probes. Next, I investigated the activity of a novel, dual histone PTM binding domain regulator called Pc2TF. I characterized Pc2TF in vitro and in cells and show it has enhanced binding and transcriptional activation compared to a single binding domain fusion called Polycomb Transcription Factor (PcTF). These results indicate that valency can be used to tune the activity of synthetic histone-binding transcriptional regulators. Then, I report the delivery of PcTF fused to a cell penetrating peptide (CPP) TAT, called CP-PcTF. I treated 2D U-2 OS bone cancer cells with CP-PcTF, followed by RNA sequencing to identify genes regulated by CP-PcTF. I also showed that 3D spheroids treated with CP-PcTF show delayed growth. This preliminary work demonstrated that an epigenetic effector fused to a CPP can enable entry and regulation of genes in U-2 OS cells through DNA independent interactions. Finally, I described and validated a new screening method that combines the versatility of in vitro transcription and translation (IVTT) expressed protein coupled with the histone tail microarrays. Using Pc2TF as an example, I demonstrated that this assay is capable of determining binding and specificity of a synthetic HBP. I conclude by outlining future work toward engineering HBPs using techniques such as directed evolution and rational design. In conclusion, this work outlines a foundation to engineer and deliver synthetic chromatin effectors.
ContributorsTekel, Stefan (Author) / Haynes, Karmella (Thesis advisor) / Mills, Jeremy (Committee member) / Caplan, Michael (Committee member) / Brafman, David (Committee member) / Arizona State University (Publisher)
Created2019
Description
This thesis project was conducted to create a practical tool to help micro and small local food enterprises identify potential strategies and sources of finance. Currently, many of these enterprises are unable to obtain the financial capital needed to start-up or maintain operations.
Sources and strategies of finance studied and ultimately included in the tool were Loans, Equity, Membership, Crowdfunding, and Grants. The tool designed was a matrix that takes into account various criteria of the business (e.g. business lifecycle, organizational structure, business performance) and generates a financial plan based on these criteria and how they align with the selected business strategies. After strategies are found, stakeholders can search through an institutional database created in conjunction with the matrix tool to find possible institutional providers of financing that relate to the strategy or strategies found.
The tool has shown promise in identifying sources of finance for micro and small local food enterprises in practical use with hypothetical business cases, however further practical use is necessary to provide further input and revise the tool as needed. Ultimately, the tool will likely become fully user-friendly and stakeholders will not need the assistance of another expert helping them to use it. Finally, despite the promise of the tool itself, the fundamental and underlying problem that many of these businesses face (lack of infrastructure and knowledge) still exists, and while this tool can also help capacity-building efforts towards both those seeking and those providing finance, an institutional attitude adjustment towards social and alternative enterprises is necessary in order to further simplify the process of obtaining finance.
Sources and strategies of finance studied and ultimately included in the tool were Loans, Equity, Membership, Crowdfunding, and Grants. The tool designed was a matrix that takes into account various criteria of the business (e.g. business lifecycle, organizational structure, business performance) and generates a financial plan based on these criteria and how they align with the selected business strategies. After strategies are found, stakeholders can search through an institutional database created in conjunction with the matrix tool to find possible institutional providers of financing that relate to the strategy or strategies found.
The tool has shown promise in identifying sources of finance for micro and small local food enterprises in practical use with hypothetical business cases, however further practical use is necessary to provide further input and revise the tool as needed. Ultimately, the tool will likely become fully user-friendly and stakeholders will not need the assistance of another expert helping them to use it. Finally, despite the promise of the tool itself, the fundamental and underlying problem that many of these businesses face (lack of infrastructure and knowledge) still exists, and while this tool can also help capacity-building efforts towards both those seeking and those providing finance, an institutional attitude adjustment towards social and alternative enterprises is necessary in order to further simplify the process of obtaining finance.
ContributorsDwyer, Robert Francis (Author) / Wiek, Arnim (Thesis director) / Forrest, Nigel (Committee member) / Department of Finance (Contributor) / Department of Information Systems (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
This thesis examines the impact of price changes of select microprocessors on the market share and 5-year gross profit net present values of Company X in the networking market through a multi-step analysis. The networking market includes segments including media processing, cloud services, security, routers & switches, and access points. For this thesis our team focused on the routers & switches, as well as the security segments. Company X wants to capitalize on the expected growth of the networking market as it transitions to its fifth generation (henceforth referred to as 5G) by positioning itself favorably in its customers eyes through high quality products offered at competitive prices. Our team performed a quantitative analysis of benchmark data to measure the performances of Company X's products against those of its competitors. We collected this data from third party computer reviewers, as well as the published reports of Company X and its competitors. Through the use of a preference matrix, we then normalized this performance data to adjust for different scales. In order to provide a well-rounded analysis, we adjusted these normalized performances for power consumption (using thermal design power as a proxy) as well as price. We believe these adjusted performances are more valuable than raw benchmark data, as they appeal to the demands of price-sensitive customers. Based on these comparisons, our team was able to assess price changes for their market and discounted financial impact on Company X. Our findings challenge the current pricing of one of the two products being analyzed and suggests a 9% decrease in the price of said product. This recommendation most effectively positions Company X for the development of 5G by offering the best balance of market share and NPV.
ContributorsArias, Stephen (Co-author) / Masson, Taylor (Co-author) / McCall, Kyle (Co-author) / Dimitroff, Alex (Co-author) / Hardy, Sebastian (Co-author) / Simonson, Mark (Thesis director) / Haller, Marcie (Committee member) / School of Accountancy (Contributor) / Department of Finance (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This thesis takes the form of a market research report with the goal of analyzing the implications of the United Kingdom (UK) leaving the European Union (EU) (known as “Brexit”) on London’s office commercial real estate market. The ultimate goal of this report is to make a prediction, firmly grounded in quantitative and qualitative research conducted over the past several months, as to the direction of London’s commercial real estate market going forward (post-Brexit). Within the commercial real estate sector, this paper narrows its focus to the office segment of the London market.
Understanding the political landscape is crucial to formulating a reasonable prediction as to the future of the London market. Aside from research reports and articles, our main insights into the political direction of Brexit come from our recordings from meetings in March of 2017 with two high-ranking members of Parliament and one member of the House of Lords—all of whom are members of the Tory Party (the meetings being held under the condition of anonymity). The below analysis will be followed by a discussion of the economics of Brexit, primarily focusing on the economic risks and uncertainties which have emerged after the vote, and which currently exist today. Such risks include the UK losing its financial passporting rights, weakening GDP and currency value, the potential for a reduction in foreign direct investment (FDI), and the potential loss of the service sector in the city of London due to not being able to access the European Single Market.
The report will shift focus to analyzing three competing viewpoints of the direction of the London market based on recordings from interviews of stakeholders in the London real estate market. One being an executive of one of the largest REITs in the UK, another being the Global Head of Real Estate at a top asset management firm, and another being a director at a large property consulting firm. The report includes these differing “sub-theses” in order to try to make sense of the vast market uncertainties post-Brexit as well as to contrast their viewpoints with where the market is currently and with the report’s investment recommendation.
The remainder of the report will consist of the methods used for analyzing market trends including how the data was modeled in order to make the investment recommendation. The report will analyze real estate and market metrics pre-Brexit, immediately after the vote, post-Brexit, and will conclude with future projections encapsulating the investment recommendation.
Understanding the political landscape is crucial to formulating a reasonable prediction as to the future of the London market. Aside from research reports and articles, our main insights into the political direction of Brexit come from our recordings from meetings in March of 2017 with two high-ranking members of Parliament and one member of the House of Lords—all of whom are members of the Tory Party (the meetings being held under the condition of anonymity). The below analysis will be followed by a discussion of the economics of Brexit, primarily focusing on the economic risks and uncertainties which have emerged after the vote, and which currently exist today. Such risks include the UK losing its financial passporting rights, weakening GDP and currency value, the potential for a reduction in foreign direct investment (FDI), and the potential loss of the service sector in the city of London due to not being able to access the European Single Market.
The report will shift focus to analyzing three competing viewpoints of the direction of the London market based on recordings from interviews of stakeholders in the London real estate market. One being an executive of one of the largest REITs in the UK, another being the Global Head of Real Estate at a top asset management firm, and another being a director at a large property consulting firm. The report includes these differing “sub-theses” in order to try to make sense of the vast market uncertainties post-Brexit as well as to contrast their viewpoints with where the market is currently and with the report’s investment recommendation.
The remainder of the report will consist of the methods used for analyzing market trends including how the data was modeled in order to make the investment recommendation. The report will analyze real estate and market metrics pre-Brexit, immediately after the vote, post-Brexit, and will conclude with future projections encapsulating the investment recommendation.
ContributorsHorn, Jonathan (Co-author) / Sidi, Adam (Co-author) / Bonadurer, Werner (Thesis director) / McDaniel, Cara (Committee member) / Department of Finance (Contributor) / School of Politics and Global Studies (Contributor) / Economics Program in CLAS (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
The purpose of our research was to develop recommendations and/or strategies for Company A's data center group in the context of the server CPU chip industry. We used data collected from the International Data Corporation (IDC) that was provided by our team coaches, and data that is accessible on the internet. As the server CPU industry expands and transitions to cloud computing, Company A's Data Center Group will need to expand their server CPU chip product mix to meet new demands of the cloud industry and to maintain high market share. Company A boasts leading performance with their x86 server chips and 95% market segment share. The cloud industry is dominated by seven companies Company A calls "The Super 7." These seven companies include: Amazon, Google, Microsoft, Facebook, Alibaba, Tencent, and Baidu. In the long run, the growing market share of the Super 7 could give them substantial buying power over Company A, which could lead to discounts and margin compression for Company A's main growth engine. Additionally, in the long-run, the substantial growth of the Super 7 could fuel the development of their own design teams and work towards making their own server chips internally, which would be detrimental to Company A's data center revenue. We first researched the server industry and key terminology relevant to our project. We narrowed our scope by focusing most on the cloud computing aspect of the server industry. We then researched what Company A has already been doing in the context of cloud computing and what they are currently doing to address the problem. Next, using our market analysis, we identified key areas we think Company A's data center group should focus on. Using the information available to us, we developed our strategies and recommendations that we think will help Company A's Data Center Group position themselves well in an extremely fast growing cloud computing industry.
ContributorsJurgenson, Alex (Co-author) / Nguyen, Duy (Co-author) / Kolder, Sean (Co-author) / Wang, Chenxi (Co-author) / Simonson, Mark (Thesis director) / Hertzel, Michael (Committee member) / Department of Finance (Contributor) / Department of Management (Contributor) / Department of Information Systems (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / School of Accountancy (Contributor) / WPC Graduate Programs (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
For this thesis, the authors would like to create a hypothetical Private Equity Real Estate Investment firm that focuses on creating value for partners by taking an opportunistic approach to acquiring under-performing urban multi-family properties with large upside potential for investing. The project will focus on both the market analysis and financial modeling associated with investment strategy and transactions. There is a substantial amount of complexity within commercial real estate and this thesis seeks to offer an accurate and comprehensive documentary of the process, while simplifying it for everyday readers. Additionally, there are a significant amount of risk factors associated with investment decisions, so the best practices from the industry documented in this manuscript are valuable tools for successful investing in the future. To gain the most profound and reliable industry knowledge, the authors leveraged the experience of dozens of industry professionals through research and personal interviews. Through careful analysis, the authors were able to ascertain the current economic position in the real estate cycle and to create a plan for future investing. Additionally, they were able to identify and evaluate a specific asset for purchase. As a result, the authors found that multifamily properties are a sound investment for the next two years and that the company should slowly start to shift directions to office and retail in 2018.
ContributorsBacon, David (Co-author) / Soto, Justin (Co-author) / Kashiwagi, Dean (Thesis director) / Kashiwagi, Jacob (Committee member) / Department of Finance (Contributor) / Department of Supply Chain Management (Contributor) / Department of Marketing (Contributor) / W. P. Carey School of Business (Contributor) / School of Accountancy (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Since the passage of the Federal Election Campaign Act Amendments of 1974 (FECA) up until the most recent election in 2012, presidential campaign funds have risen over five hundred percent. While money has always been an essential and critical part of any political campaign, this rise has been drastic and continues to increase at a higher rate with every election cycle, even when the numbers are adjusted for inflation. The purpose of this paper is to examine this continuous increase in cost of presidential campaigns and to analyze the different pieces that have contributed to this rise. The main pieces include two Supreme Court cases: Buckley v. Valeo and Citizens United v. Federal Elections Commission, the rise and fall of federally regulated public funding and the various pieces of a presidential campaign that have considerably higher ticket prices with each election cycle. This paper first goes through both Buckley and Citizens, describing what each Supreme Court decision did and how they effected how much money can be spent in a presidential campaign and by whom. The paper then examines each presidential election since the passage of FECA in 1974 through the last election with President Barack Obama and Mitt Romney in 2012. Each election cycle is broken down to show how much money was spent by each candidate and the Republican and Democratic National Committees, whether or not the money was received through public funds or raised privately, and subsequently the percentages of where the money was spent. While the examination of the Court cases helps to understand why so much money can be donated and contributed directly to campaigns or spent on behalf of a presidential candidate, the breakdown of where the money is spent including advertising, travel, staff salaries etc. helps to show why a presidential campaign costs over five hundred percent more today than it did forty years ago. By understanding this increase, how it was caused and where the money is going, it is more feasible to comprehend whether or not campaign finance reform should be proposed and if so, how it should be brought about.
ContributorsColby, Mikaela Nicole (Author) / Critchlow, Donald (Thesis director) / Shair-Rosenfield, Sarah (Committee member) / School of Historical, Philosophical and Religious Studies (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05