Characterizing MARK2-Dependent Regulation of CBP-Mediated Acetylation in Alzheimer’s Disease
Creator:
Tabassum, Zarin
Date of publication:
October 2, 2019
Abstract Tesim:
Tau is a neuronal microtubule-binding protein that forms characteristic neurofibrillary tangles (NFT), upon hyperphosphorylation, hyperacetylation, and aggregation, which are hallmark biomarkers for Alzheimer’s disease (AD). The pathophysiological conversion of tau still remains unclear, but the regulation and synergy of tau’s post-translational modifications (PTMs) by certain enzymes can be monitored. This study investigates the interactions between two enzymes involved in regulating tau’s PTMs: the microtubule affinity-regulating kinase (MARK2) and the acetyltransferase CREB-binding protein (CBP). We performed a series of biochemical analyses, which uncovered that CBP-mediated acetylation was increased in the absence of MARK2, indicating a possible negative feedback loop, in which MARK2 is phosphorylating and thereby inhibiting CBP. Further investigation of the protein-protein interactions revealed increased acetylation of an inactive MARK2 mutant compared to wild-type MARK2 in the presence of CBP. This finding supports the idea that active MARK2 may be involved in decreasing CBP-mediated acetylation. Although the exact mechanism of this interaction and its role in tau dysfunction have yet to be determined, we have uncovered a new signaling pathway in which two enzymes may regulate each other.
Affiliation Label Tesim:
Department of Neurology and College of Arts and Sciences
A Radical Approach to Polycycles Using Carboxylic Acids
Creator:
Hunter Gadwill
Date of publication:
October 1, 2019
Abstract Tesim:
Over the nine weeks of the fellowship, two principle reagents were synthesized for application in the reaction intended with a multi-step synthesis and 24 test reactions were conducted to screen for the desired product and optimize intermediate product yield. After proton and fluorine NMR spectra were collected and analyzed to identify the compounds in the reaction mixture, GCMS was conducted during the data analysis process to verify that no desired product was formed. Although the anticipated product was not formed, a useful intermediate is formed in significant quantities, which may be used to subsequently access a known reaction that yields the desired product. The intermediate (formed from a radical transition state that readily reacts with more xanthate material) was identified through NMR spectroscopic analysis that confirmed a suspected byproduct mechanistic pathway. In the future, I would like to use known chemistry to transform the intermediate into the desired product. This multi-step synthesis would still avoid the use of transition metal catalysts, and indirectly achieve the desired reaction.
This project was an attempt to determine whether or not all of the palatal consonants in Greek share the same place of articulation by using acoustic data. The conclusion was that the all of the consonants have roughly the same effect on the formants of surrounding vowels and thus probably have roughly the same place of articulation.
Determining genetic risk for posttraumatic chronic pain and related neuropsychiatric disorders using polygenic risk scores.
Creator:
Lobo, Jarred
Date of publication:
September 30, 2019
Abstract Tesim:
Twin and family studies have reported a significant contribution of genetic factors to onset of chronic pain and related psychiatric disorders. Technological advancements now allow for the systematic testing of genetic variants across the genome for association with traits to better understand the cumulative effect of different alleles. This project aimed to determine whether a polygenic model can be used to predict genetic risk for posttraumatic chronic pain and posttraumatic stress symptom development. Polygenic risk scores were generated using GWAS discovery datasets and the target dataset consisting of European individuals between 18 and 65 years of age who presented to the ED within 24 hours of a motor vehicle collision. Phenotypes tested included pain intensity (scale from 0-10), depression (CESD scale), and PTSD (IESR scale). PRSice, polygenic risk score software, was used to calculate, evaluate, and plot the results of the analyses. The variance explained by the PRS model for moderate posttraumatic chronic pain (4-10 on pain scale) ranged from 1-3% using polygenic risk scores for back pain. As the polygenic risk score increased, the odds ratio for year 1 moderate pain generally increased. Similar results were observed when testing other GWAS discovery datasets and phenotypes. The polygenic risk scores quantify the cumulative effect of genetic variants that play a significant role in the development of posttraumatic chronic pain and related symptoms. Future research may combine these polygenic risk scores with nongenetic risk factors to predict individual susceptibility. Health care providers may use polygenic risk scores as well as nongenetic risk factors to evaluate a patient’s risk of chronic pain in order to create an individualized treatment plan.
Investigation of Listeria monocytogenes Attachment and Colonization on Plants
Creator:
Clapper, Haley
Date of publication:
September 30, 2019
Abstract Tesim:
Listeria monocytogenes (LM) is a human pathogen and agent of listeriosis, a foodborne illness that can cause severe complications and death in immunocompromised individuals such as pregnant women and the elderly. LM has one of the highest mortality rates of foodborne illnesses, with 30% of patients dying due to infection. LM occurs ubiquitously in the environment, where it can attach to crops and infect animals that are ultimately consumed by humans. LM contamination of food products not only poses a major threat to human health, but to the food industry as well, costing between $2.3 and $22 billion per year.
Current research on LM largely investigates the clinical aspects of LM infection not LM in true environmental settings. Thus, little is known about LM in the environment and how it interacts with the flora and other soil microbes. To investigate LM plant colonization, we performed a hydroponic assay in which Arabidopsis thaliana seedlings were suspended in media and inoculated with LM. We first tested a range of media and found LM readily colonizes A. thaliana in minimal media. Next, we investigated the impact of coculturing LM with other soil microbes and found that one of the organisms we tested may increase LM plant colonization. Lastly, we investigated the persistence of LM on the plant root by measuring colony-forming units (CFUs) at different time points, both in monoculture and in coculture with other soil microbes. We found that LM persists on the plant root with no significant decrease in CFUs up to 72 hours after colonization. However, further experiments are required to conclude the effects of additional soil microbes on LM persistence. These data demonstrate LM readily colonizes A. thaliana in this hydroponic assay, that LM persists on the plant root following colonization, and that coculturing with other microbes may impact LM colonization.
Developing Experimental Tools to Enable Further Study in Tardigrades
Creator:
Shaljian, Emily
Date of publication:
August 30, 2019
Abstract Tesim:
In this project, I worked to genetically manipulate the tardigrade species Hypsibius exemplaris as a means towards developing viable transgenic tardigrades. By observing the eye pigmentation pathways in the related organism Drosophila melanogaster and finding homologs of the involved genes in Hypsibius, I developed a list of target genes for RNA interference. I designed primers for the target genes, amplified them by PCR, and translated them to make dsRNAs, which were then injected into the adult tardigrade. Offspring of injected adults were observed for loss of eye pigments. This project also involved experiments to incorporate mRNA into the the body cavity of an injected adult tardigrade.
Effects of Metabolic Reprogramming Interventions on Triple-Negative Breast Cancer Cells
Creator:
Ho, Alyssa
Date of publication:
September 30, 2019
Abstract Tesim:
TNBCs comprise approximately 15-20% of all BC cases and are defined by their lack of expression of estrogen receptors, progesterone receptors, and excess HER2 protein. There are currently no approved targeted therapies available for patients with TNBC other than cytotoxic chemotherapy, resulting in elevated rates of cancer recurrence, metastasis, and mortality.
A promising area in nutrition and cancer research, with the potential to improve cancer outcomes, is dietary modification such as caloric restriction (CR) which has been shown to reduce tumor incidence, progression, and sensitization to some chemotherapeutic agents in preclinical TNBC murine models.
While dietary interventions have shown promise for improving cancer outcomes in murine models, translating these approaches to humans has proven difficult. Major issues include a low tolerance of extreme diets (feasibility) and concerns about safe use of these interventions in cancer patients. Additionally, in response to the decrease in external nutrients and pro-growth signals during a fasting or CR state, cancer cells can generate energy by breaking down damaged cellular components to maintain homeostasis and viability through the process known as autophagy. Autophagy benefits cancer cells fighting for survival in nutrient-poor conditions, promoting tumor growth and, in some cases, metastasis.
Our objective is to identify pharmacologic approaches, or metabolic reprogramming interventions (MRIs), which can be combined in innovative ways to recapitulate some or most of the beneficial effects of the previously mentioned dietary interventions. Moreover, we posit that the increased dependence on autophagy observed in fasting/CR can be exploited to improve efficacy of autophagy inhibitors – which are currently being tested in clinical trials for TNBC - and existing chemotherapies. Specifically, the purpose of this project is to examine the separate and combined effects of autophagy-inducing MRIs, autophagy inhibition, and carboplatin on murine TNBC progression.
Identification of Genes Necessary for Heat Shock Response in Tardigrades
Creator:
Barber, Heather
Date of publication:
September 30, 2019
Abstract Tesim:
This is the presentation portion of my Summer Undergraduate Research Fellowship (SURF) for the summer of 2019. I studied the heat shock response of the tardigrade Hypsibius exemplaris. I began to use RNAi to determine the effect of knockdown of suspected heat shock proteins in desiccation. I also worked on a project attempting to create transgenic tardigrades, during which I injected a tardigrade that then expressed worm proteins.
Creating More Effective Automated Feedback to Improve Web Based Learning for Low-Income Schools
Creator:
Oliver, Addison
Date of publication:
September 30, 2019
Abstract Tesim:
As a part of a larger project, this research serves to better equip the automated feedback on the web-based models that will be released for free to all schools regardless of privilege and accessibility to resources, to help engage the students in scientific discourse and improve their understanding of the science that is presented through these models.
