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- Creators: Arizona State University
- Creators: School of Life Sciences
Description
Cell immunotherapies have revolutionized clinical oncology. While CAR T cell therapy has been very effective in clinical studies, off-target immune toxicity limits eligible patients. Thus, NK cells have been approached with the same therapy design since NK cells have a more favorable safety profile. Therefore, the purpose of this research project is to explore DNA nanotech-based NK cell engagers (NKCEs) that force an immunological synapse between the NK cell and the cancer cell, leading to cancer death. DNA tetrabody (TB) and DNA tetrahedron (TDN) are fabricated and armed with HER2 affibody for tight adhesion to HER2+ cancer cell lines like SKBR3. Overall, relationship between TB-NK treatment and cancer cell apoptosis is still unclear. TB-NK treatment induces an apoptotic profile similar to PMA/IO stimulation. Pilot cell assay needs to be replicated with additional controls and a shortened treatment window. For DNA TDN fabrication, HER2 affibody polishing with Ni-NTA affinity chromatography achieves high purity with 20% to 100% high-imidazole elution gradient. ssDNA-HER2 affibody conjugation is optimal when ssDNA is treated with 40-fold excess sulfo-SMCC for 4 hours. In conclusion, the manufacturing of DNA-based NKCEs is rapid and streamlined, which gives these NKCEs the potential to become a ready to use immunotherapy.
ContributorsLuca, Michael (Author) / Yan, Hao (Thesis director) / Stephanopoulos, Nicholas (Committee member) / Blattman, Joseph (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / School of Molecular Sciences (Contributor)
Created2024-05
Description
Alzheimer’s disease (AD) is projected to increase, and understanding risk and protective factors could help mitigate this increase. Deficits in Choline, a B-like vitamin, intake or issues with endogenous choline production can lead to an increased risk for AD development. To better understand the effects of endogenous choline through the lifespan in the context of Alzheimer pathology, Male and Female 3xTg-AD and NonTg mice, were aged to 16.81 ± 0.13 months. Body weight, food consumption data, and blood plasma samples were collected across the lifespan. A behavioral battery, that consisted of Rotarod, Elevated Plus Maze, and Intellicage, was performed to assess differences across a range of tasks. Hippocampal and cortical tissue were collected to assess pathology. Overall, 3xTg-AD mice had lower choline levels than NonTg at multiple timepoints and Males had higher choline than Females. Furthermore, 3xTg-AD Females had higher levels of both Aβ and Tau pathology than their Male counterparts. In the Intellicage, Females made fewer Percent of Correct Responses during Place Preference. Together these findings show that choline levels through the lifespan, impact the severity of pathology between Males and Female 3xTg-AD mice and behavioral differences between the 3xTg-AD and NonTg mouse models.
ContributorsMistry, Faizan (Author) / Velazquez, Ramon (Thesis director) / Judd, Jessica (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor)
Created2024-05
ContributorsLuca, Michael (Author) / Yan, Hao (Thesis director) / Stephanopoulos, Nicholas (Committee member) / Blattman, Joseph (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / School of Molecular Sciences (Contributor)
Created2024-05
Description
Background: Eosinophilic esophagitis (EoE) is an increasingly prevalent allergic disease characterized by eosinophilic inflammation and symptoms of esophageal dysfunction. Diagnosis and monitoring require repeated, invasive endoscopic esophageal biopsies to assess levels of eosinophilic inflammation. Recently, the minimally invasive esophageal string test (EST) has been used collect protein in mucosal secretions as a surrogate for tissue biopsies in monitoring disease activity. From the string, assessment of the eosinophil-associated proteins major basic protein-1 (MBP-1) and eotaxin-3 (Eot3) is used to assess disease activity; however, this requires measurement in a reference laboratory, for which the turnaround time for results exceeds the time required for histopathologic assessment of endoscopic biopsies. In addition, MBP-1 and Eot3 are not markers unique to eosinophils. These obstacles can be overcome by targeting eosinophil peroxidase (EPX), an eosinophil-specific protein, using a rapid point-of-care test. Currently, EPX is measured by a labor-intensive enzyme-linked immunosorbent assay (ELISA), but we sought to optimize a rapid point-of-care test to measure EPX in EST segments.
Methods: We extracted protein from residual EST segments and measured EPX levels by ELISA and a lateral flow assay (LFA).
Results: EPX levels measured by LFA strongly correlated with those quantified by ELISA
(rs = 0.90 {95% CI: 0.8283, 0.9466}). The EPX LFA is comparable to ELISA for measuring EPX levels in ESTs.
Conclusions: The EPX LFA can provide a way to rapidly test EPX levels in ESTs in clinical settings and may serve as a valuable tool to facilitate diagnosis and monitoring of EoE.
ContributorsDao, Adelyn (Author) / Lake, Douglas (Thesis director) / Borges, Chad (Committee member) / Wright, Benjamin (Committee member) / Barrett, The Honors College (Contributor) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor)
Created2024-05
Description
This project challenges the prevailing weight-centric paradigm of present-day medicine which focuses on weight as a primary indicator of health. This study aimed to understand the impact of a brief pragmatic intervention to facilitate shifting healthcare providers' clinical conceptualization, attitudes, and practices from weight-centric to weight-inclusive care. A one-hour pragmatic training was composed and presented to providers at a community health clinic. The intervention highlighted the critical gap in our understanding of health and attempted to bring attention to the intricate web of factors that play into the complexity of weight. The education also provided specific tools that providers can put into practice to better cultivate weight-inclusive care. Mixed methods were used to evaluate the acceptability and efficacy of the intervention via changes in provider attitudes, treatment behaviors, and conceptualization of patient issues. Findings reveal modest differences from pre- to post-intervention as well as a notable disconnect among providers’ understanding and application of concepts. Participants expressed significant interest in the training and weight-inclusive care.
ContributorsZach, Rose (Author) / McEntee, Mindy (Thesis director) / May, Michelle (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05
ContributorsZach, Rose (Author) / McEntee, Mindy (Thesis director) / May, Michelle (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05
ContributorsZach, Rose (Author) / McEntee, Mindy (Thesis director) / May, Michelle (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05
Description
Modified Salmonella strains and recombinant DNA in a plasmid are used to construct a
Salmonella strain that is dependent on the experimentally inserted plasmid. This construction
will be done via lab techniques such as polymerase chain reactions (PCR), transformation, and other means to create this construction. With future successful construction, the inhibition of flagella assembly, within the tumor environment, and increased synthesis of flagellin will be
possible. In the case that only assembly is prevented, then, the reliance on the lysis system to
release flagellin into the tumor microenvironment will be used as a means to induce immune
response. With the success of the self-lysis ability, these strains could be used to target these
tumor cells to deliver anticancer material as a vaccine delivery system.
ContributorsShagi, Agnel (Author) / Kong, Wei (Thesis director) / Fu, Lingchen (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2024-05
Description
Computational biophysics is a powerful tool for observing and understanding the microscopic machinery that underpins the biological world. Molecular modeling and simulations can help scientists understand a cell’s behavior and the mechanisms that drive it. Empirical evidence can provide information on the structure and organization of biomolecular machines, which serve as the backbone of biomolecular modeling. Experimental data from probing the cell’s inner workings can provide modelers with an initial structure from which they can hypothesize and independently verify function, complex formation, and response. Additionally, molecular data can be used to drive simulations toward less probable but equally interesting states. With the advent of machine learning, researchers now have an unprecedented opportunity to take advantage of the wealth of data collected in a biomolecular experiment. This dissertation presents a comprehensive review of atomistic modeling with cryo-electron microscopy and the development of new simulation strategies to maximize insights gained from experiments. The review covers the integration of cryo-EM and molecular dynamics, highlighting the evolution of their relationship and the recent history of MD innovations in cryo-EM modeling. It also covers the discoveries made possible by the integration of molecular modeling with cryo-EM. Next, this work presents a method for fitting small molecules into cryo-electron microscopy maps, which uses neural network potentials to parameterize a diverse set of ligands. The method obtained fitted structures commensurate with, if not better than, the structures submitted to the Protein Data Bank. Additionally, the work describes the data-guided Multi- Map methodology for ensemble refinement of molecular movies. The method shows that cryo-electron microscopy maps can be used to bias simulations along a specially constructed reaction coordinate and capture conformational transitions between known intermediates. The simulated pathways appear reversible with minimal hysteresis and require only low-resolution density information to guide the transition. Finally, the study analyzes the SARS-CoV-2 spike protein and the conformational heterogeneity of its receptor binding domain. The simulation was guided along an experimentally determined free energy landscape. The resulting motions from following a pathway of low-energy states show a degree of openness not observed in the static models. This sheds light on the mechanism by which the spike protein is utilized for host infection and provides a rational explanation for the effectiveness of certain therapeutics. This work contributes to the understanding of biomolecular modeling and the development of new strategies to provide valuable insights into the workings of cellular machinery.
ContributorsVant, John Wyatt (Author) / Singharoy, Abhishek (Thesis advisor) / Heyden, Matthias (Committee member) / Presse, Steve (Committee member) / Arizona State University (Publisher)
Created2024
Description
The focus of this study is on enhancing cultural competency and increasing an ethnorelative worldview perspective among instructional designers through an innovative approach that integrates global professionals and reciprocal learning. The study is grounded in the context of Arizona State University’s mission to create inclusive learning experiences, particularly in online education, confronting the challenge of effectively providing instructional design that supports a global learner. The dissertation builds upon the existing literature on instructional design, highlighting the need for cultural competency in a globalized educational context. It underscores the growing necessity for instructional designers to adapt their skills and approaches to meet the diverse needs of global learners. The research aims to achieve professional development experiences through a reciprocal learning framework involving international instructional professionals. The research questions explore the role of reciprocal learning in fostering ethnorelative worldviews and the perceived value of this learning for the professional development of instructional designers. The study addresses critical skills such as cultural empathy, active listening, self-awareness of biases, and a commitment to continual learning. The research highlights the gaps in current instructional design training, particularly in the context of global education and cultural competency, contributing to the field of instructional design by proposing a model that integrates global perspectives into the professional development of instructional designers.
ContributorsPate, Amy Loree (Author) / Basile, Carole (Thesis advisor) / Maynard, Andrew (Committee member) / Silova, Iveta (Committee member) / Arizona State University (Publisher)
Created2024