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In eukaryotes, most messenger RNA precursors (pre-mRNA) undergo extensive processing, leading to the cleavage of the transcript followed by the addition of a poly(A) tail. This process is executed by a large complex known as the Cleavage and Polyadenylation Complex (CPC). Its central subcomplex, the Cleavage and Polyadenylation Specificity Factor (CPSF) complex is responsible for recognizing a short hexameric element AAUAAA located at the 3’end in the nascent mRNA molecule and catalyzing the pre-mRNA cleavage. In the round nematode C. elegans, the cleavage reaction is executed by a subunit of this complex named CPSF3, a highly conserved RNA endonuclease. While the crystal structure of its human ortholog CPSF73 has been recently identified, we still do not understand the molecular mechanisms and sequence specificity used by this protein to induce cleavage, which in turn would help to understand how this process is executed in detail. Additionally, we do not understand in additional factors are needed for this process. In order to address these issues, we performed a comparative analysis of the CPSF3 protein in higher eukaryotes to identify conserved functional domains. The overall percent identities for members of the CPSF complex range from 33.68% to 56.49%, suggesting that the human and C. elegans orthologs retain a high level of conservation. CPSF73 is the protein with the overall highest percent identity of the CPSF complex, with its active site-containing domain possessing 74.60% identity with CPSF3. Additionally, we gathered and expressed using a bacterial expression system CPSF3 and a mutant, which is unable to perform the cleavage reaction, and developed an in vitro cleavage assay to test whether CPSF3 activity is necessary and sufficient to induce nascent mRNA cleavage. This project establishes tools to better understand how CPSF3 functions within the CPC and sheds light on the biology surrounding the transcription process as a whole.
ContributorsGallante, Christina (Author) / Mangone, Marco (Thesis director) / Sharma, Shalini (Committee member) / Hrach, Heather (Committee member) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
The successful reduction of CO2 and protons by a light-induced cobalt porphyrin/cytb562 hybrid metalloenzyme in water is reported. Incorporation of the porphyrin into a protein scaffold results in increases in CO and H2 production over naked porphyrin. Rational point mutations to the CoPPIX binding site of cytb562 modulate production, indicating possible further improvements in catalytic activity.
ContributorsGwerder, Noah D (Author) / Ghirlanda, Giovanna (Thesis director) / Williams, Peter (Committee member) / Mangone, Marco (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease which occurs in approximately 1 in 3,500 male births. This disease is characterized by progressive muscle wasting and causes premature death. One of the earliest symptoms of this disease is mitochondrial dysfunction. Dystrophin is a protein found under the sarcolemma. The N terminus binds to actin and the C terminus binds to dystrophin glycoprotein complex (DGC). DMD is caused by mutations in the dystrophin gene. C. elegans possess an ortholog of dystrophin, DYS-1. Though there is evidence that C. elegans can be used as a model organism to model DMD, nematode DGC has not been well characterized. Additionally, while we know that mitochondrial dysfunction has been found in humans and other model organisms, this has not been well defined in C. elegans. In order to address these issues, we crossed the SJ4103 worm strain (myo-3p::GFP(mit)) with dys-1(cx18) in order to visualize and quantify changes in mitochondria in a dys-1 background. SJ4103;cx18 nematodes were found to have less mitochondrial than SJ4103 which suggests mitochondrial dysfunction does occur in dys-1 worms. Furthermore, mitochondrial dysfunction was studied by knocking down members of the DGC, dys-1, dyb-1, sgn-1, sgca-1, and sgcb-1 in SJ4103 strain. Knock down of each gene resulted in decrease in abundance of mitochondria which suggests that each member of the DGC contributes to the overall health of nematode muscle. The ORF of dyb-1 was successfully cloned and tagged with GFP in order to visualize this DGC member C. elegans. Imaging of the transgenic dyb-1::GFP worm shows green fluoresce expressed in which suggests that dyb-1 is a functional component of the muscle fibers. This project will enable us to better understand the effects of dystrophin deficiency on mitochondrial function as well as visualize the expression of certain members of the DGC in order to establish C. elegans as a good model organism to study this disease.
ContributorsObrien, Shannon Nishino (Author) / Mangone, Marco (Thesis director) / Newbern, Jason (Committee member) / Hrach, Heather (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
While non-invasive breast cancer treatments may be considered less costly in the short-term, over the course of a lifetime, a more aggressive treatment can be overall less costly, especially with recurrence cases; however, these more aggressive treatments are not necessarily covered by insurance and are difficult to discuss in the short amount of time in physician consultations. This analysis studied data from 982 women diagnosed with breast cancer over a five-year period to evaluate monetary costs associated with treatment options and incorporated five in-depth interviews to understand experiences and non-monetary costs. Data showed the most expensive option was a unilateral mastectomy with radiation therapy and the least costly option was breast conserving surgery. Interviews determined each woman evaluated the monetary costs with each treatment but most heavily focused on personal values, biases and recommended opinions when deciding on a treatment. The use of prompt sheets before physician appointments and consultations, along with the addition of financial counselor meeting with each patient can improve patient satisfaction and alleviate stress by simplifying a woman's choice in deciding a treatment. In addition, increased insurance coverage to include every treatment chosen by women (rather than on a case-by-case basis), specifically contralateral prophylactic mastectomy and additional screening options, could decrease long term costs \u2014 both monetarily and in quality of life for patients.
ContributorsOsumi, Alana (Author) / LaRosa, Julia (Thesis director) / Sivanantham, Jai (Committee member) / Barrett, The Honors College (Contributor) / W.P. Carey School of Business (Contributor)
Created2018-12
Description
Cleavage and polyadenylation is a step in mRNA processing in which the 3’UTR is cleaved and a polyA tail is added to create a final mature transcript. This process relies on RNA sequence elements that guide a large multimeric protein complex named the Cleavage and Polyadenylation Complex to dock on the 3’UTR and execute the cleavage reaction. Interactions of the complex with the RNA and specific dynamics of complex recruitment and formation still remain largely uncharacterized. In our lab we have identified an Adenosine residue as the nucleotide most often present at the cleavage site, although it is unclear whether this specific element is a required instructor of cleavage and polyadenylation. To address whether the Adenosine residue is necessary and sufficient for the cleavage and polyadenylation reaction, we mutated this nucleotide at the cleavage site in three C. elegans protein coding genes, forcing the expression of these wt and mutant 3’UTRs, and studied how the cleavage and polyadenylation machinery process these genes in vivo. We found that interrupting the wt sequence elements found at the cleavage site interferes with the cleavage and polyadenylation reaction, suggesting that the sequence close to the end of the transcript plays a role in modulating the site of the RNA cleavage. This activity is also gene-specific. Genes such as ges-1 showed little disruption in the cleavage of the transcript, with similar location occurring in both the wt and mutant 3’UTRs. On the other hand, mutation of the cleavage site in genes such as Y106G6H.9 caused the activation of new cryptic cleavage sites within the transcript. Taken together, my experiments suggest that the sequence elements at the cleavage site somehow participate in the reaction to guide the cleavage reaction to occur at an exact site. This work will help to better understand the mechanisms of transcription termination in vivo and will push forward research aimed to study post-transcriptional gene regulation in eukaryotes.
ContributorsSteber, Hannah Suzanne (Author) / Mangone, Marco (Thesis director) / Harris, Robin (Committee member) / LaBaer, Joshua (Committee member) / School of Life Sciences (Contributor, Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
In 2016, in the United States alone, the cosmetics industry made an estimated 62.46 billion dollars in revenue (Revenue of the Cosmetic Industry in the U.S. 2002-2016 | Forecast). With a consistent increase in sales in the last several years, the industry has reached continued success even during times of hardship, such as the Great Recession of 2008. The use of Corporate Social Responsibility (CSR), external campaigns, and thoughtful packaging and ingredients resonates with targeted consumers. This has served as an effective strategy to maintain growth in the industry. Cosmetic companies promote their brand image using these sustainability tactics, but there seems to be a lack of transparency in this unregulated industry. The purpose of this thesis is to determine if the cosmetics industry is a good steward of the sustainability movement. Important terms and concepts relating to the industry will be discussed, then an analysis of sustainability focused cosmetic brands will be provided, which highlights the extent to which these brands engage in activities that promote sustainability. This is followed by an application of findings to a company that could benefit from using such practices. Overall, the analysis of the different brands proved to be shocking and disappointing. This is due to the sheer amount that scored very poorly based on the sustainability criteria developed. The cosmetics industry is too inconsistent and too unregulated to truly act as a good steward for sustainability. Though some companies in the industry succeed, these accomplishments are not consistent across all cosmetic companies. Hence, the cosmetics industry as a good steward for sustainability can only be as strong as its weakest link.
ContributorsMamus, Sydney Wasescha (Author) / Ostrom, Amy (Thesis director) / Kristofferson, Kirk (Committee member) / Department of Marketing (Contributor) / W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This report was commissioned to provide an analysis and evaluation of consumer perceptions and branding as it relates to the political and social climate in America. To be able to do this, the paper analyzes shifts in the external environment as well as researching case studies and online consumer perception surveys. Overall, this paper aims to examine the distributed survey and attempt to correlate and identify how branding, consumer perceptions, and social and political issues all can work and affect one another. Through the administration of this survey, we were able to formulate a conclusion that points towards the importance of brands actively adhering to changing consumer preferences, ideals, and expectations.
ContributorsClark, Sydney (Co-author) / Loera, Carolina (Co-author) / Montoya, Detra (Thesis director) / Samper, Adriana (Committee member) / W.P. Carey School of Business (Contributor) / Department of Marketing (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The use of generalized linear models in loss reserving is not new; many statistical models have been developed to fit the loss data gathered by various insurance companies. The most popular models belong to what Glen Barnett and Ben Zehnwirth in "Best Estimates for Reserves" call the "extended link ratio family (ELRF)," as they are developed from the chain ladder algorithm used by actuaries to estimate unpaid claims. Although these models are intuitive and easy to implement, they are nevertheless flawed because many of the assumptions behind the models do not hold true when fitted with real-world data. Even more problematically, the ELRF cannot account for environmental changes like inflation which are often observed in the status quo. Barnett and Zehnwirth conclude that a new set of models that contain parameters for not only accident year and development period trends but also payment year trends would be a more accurate predictor of loss development. This research applies the paper's ideas to data gathered by Company XYZ. The data was fitted with an adapted version of Barnett and Zehnwirth's new model in R, and a trend selection algorithm was developed to accompany the regression code. The final forecasts were compared to Company XYZ's booked reserves to evaluate the predictive power of the model.
ContributorsZhang, Zhihan Jennifer (Author) / Milovanovic, Jelena (Thesis director) / Tomita, Melissa (Committee member) / Zicarelli, John (Committee member) / W.P. Carey School of Business (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This research aims to look at the lower level collegiate athletics, Intramural sports and club sports, in comparison to Division 1 varsity athletics to see how their sport lives differ and why they are still competing when the reward does not seem as grand as the Varsity athletics. The findings show that the socially ingrained aspect of sports is the reason that most lower level athletes keep competing.
ContributorsHarvey, Abigail (Author) / Jonsson, Hjorleifur (Thesis director) / Jackson, Victoria (Committee member) / School of Human Evolution and Social Change (Contributor) / W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This report will provide an analysis of frontier market equity-based investment funds with respect to bivariate correlation analysis, global integration analysis, and US optimized portfolio statistics. My analysis has indicated strong diversification benefits of including frontier market equities in a US portfolio, given its low correlation to US equity concentrated portfolios especially portfolios that would consist of midcap and smallcap stocks. With the drawbacks of the bivariate correlation test, an additional global integration analysis has been included to reaffirm the value frontier markets offer in the form of integration. Integration is a second layer of the diversification analysis. I find that when analyzing frontier markets (FM) against developed markets (DM) there exhibits significantly less integration as compared to emerging markets against developed markets. This analysis goes one step further and quantifies integration of specific frontier market funds against the broader emerging and developed markets. This study finds that iShares MSCI frontier 100 ETF (Ticker: FM) exhibits the least integration amongst Guggenheim Frontier Markets ETF (Ticker: FRN), Templeton Frontier Markets A (Ticker: TFMAX), and Morgan Stanley Frontier Emg (Ticker: MFMIX). Lastly, this analysis covers the inadequacy with using Sharpe ratios and minimum volatility parameters to achieve portfolio optimization under a Monte-Carlo style 1000 portfolio simulation with frontier market funds in a broader US equity portfolio but finds better results when using a US equity and US bond combination portfolio. Overall, this analysis of frontier markets and frontier market funds has shown there still exists significant diversification benefits to US Investors when they engage in FM investments, specifically through diversified FM investment funds.
ContributorsHardy, Gunner Laine (Author) / Pruitt, Seth (Thesis director) / Brada, Josef (Committee member) / W.P. Carey School of Business (Contributor) / Economics Program in CLAS (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05