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Small Molecule Inhibitors of BRD4 for Treatment of Multiple Myeloma
No full textCancer is a complex disease with distinct hallmarks caused by a variety of factors. Transcription factors that normally control a large array of genes required for cell development can become oncogenes if their transcription is altered. BRD4 is a transcriptional activator that is a member of the bromodomain and extra-terminal (ET) domain (BET) family of proteins. The bromodomains of BRD4 bind to acetylated lysine residues on histones and is common among chromatin binding proteins whereas the ET domain is distinct to the BET proteins. Current BRD4- based therapeutics target the bromodomain using small molecule mimics of acetylated lysine. These inhibitors have limited efficacy because of dose-limiting toxicities due to the inhibitors targeting other proteins with bromodomains. The ET domain interacts with proteins linked to lung, breast, oral, colon, and acute myeloid leukemia (AML) cancers as well as viral integrase (IN) from murine leukemia virus (MLV). Examination of the binding interface between MLV IN and the ET domain allowed for in-silico selection of potential inhibitors. These compounds were screened in leukemia cell lines leading to selection of BETi-10.
Multiple myeloma (MM) tumors are located within the bone marrow, making it difficult to treat with limited current therapies. Using a variety of MM cell lines, BETi-10 was tested for efficacy in this hematologic cancer. In addition, a BCL-2 selective inhibitor, venetoclax (ABT-199), was chosen based on its efficacy in hematologic cancers to test synergy with BETi-10. Some MM cell lines are less sensitive to venetoclax, prompting the idea that BETi-10 could increase sensitivity to the inhibitor.
While combination of BETi-10 and venetoclax treatment did not increase sensitivity in low responding MM cell lines, a switch from venetoclax-induced necroptosis to apoptosis was observed. After investigation of the effects of BRD4 inhibition on the necroptosis pathway, it was determined that the combination of BETi-10 and venetoclax can decrease the expression of key proteins in the pathway. These results suggest a new role of BETi-10 in the switch from necroptosis to the safer apoptotic route.A three-year embargo was granted for this item.Academic Major: Biochemistr
Exploring High School Biology Teachers' Engagement with Primary Scientific Literature
Full text linkHuman Experience (The Ohio State University Denman Undergraduate Research Forum)Primary scientific literature (PSL) is a cornerstone of scientific communication, yet its integration into high school science classrooms remains poorly understood. Our study determines how teachers define PSL, how teachers use PSL, and teachers' motivations and challenges for teaching using PSL. Through an explanatory sequential mixed methods design, we combined survey data from a validated instrument with semi-structured interviews to analyze teachers' definitions, instructional practices, motivations, and challenges. Teachers consistently characterized PSL as peer-reviewed, original research published in credible journals, though their implementation varied widely. Instructional strategies included group analysis and adapting content for accessibility, though challenges and alignment with curriculum standards emerged as barriers. Teachers also emphasized a need for structured resources to support effective PSL integration. These findings highlight the gap between educators' recognition of PSL's value and their capacity to implement it consistently. Addressing this gap requires targeted professional development and curated instructional tools to reduce barriers and empower teachers to leverage PSL as a dynamic, inquiry-based learning tool. By bridging these challenges, PSL can enhance science education by immersing students in the practices and discourse of real-world research.No embargoAcademic Major: Biolog
Shared Alkaloids and Subtle Surprises in Ohio Aphaenogaster Ants
No full textAphaenogaster is an ecologically dominant ant genus found throughout the woodlands of the eastern United States. The genus is characterized by rapid nestmate recruitment and a submissive demeanor. Additionally, the mandibular and venom glands of some species contain unusual alkaloids. Alkaloids are a diverse class of heterocyclic nitrogenous compounds that are often used as a chemical defense by plants. However, they are also present in some arthropod and fungal groups. In ants, alkaloids can be found in the mandibular, pygial, and venom glands, where they are used for a variety of purposes. Aphaenogaster ants are known to contain alkaloids, but the full scope of alkaloid diversity and species-specificity within the genus remains unknown. In this paper, we investigate alkaloid presence and diversity by examining gaster and head extracts collected from five Aphaenogaster species at nine sites. Samples were analyzed using gas-chromatography mass spectrometry (GC-MS) and their Cytochrome C Oxidase Subunit 1 (COI) gene sequenced to confirm species. We compared percent abundances of frequently occurring alkaloids from the heads and gasters using a one-way permutational multivariate analysis of variance (PERMANOVA). Upon completing our analysis, we found that alkaloid presence is conserved across Ohio Aphaenogaster, but relative abundance of those alkaloids varies between species, especially those with differing natural histories. Additionally, we discovered eight frequently occurring alkaloids that have not previously been associated with Aphaenogaster ants. Lastly, we provide genetic evidence of sympatric distributions for undescribed Aphaenogaster species within the A. rudis and A. picea species complexes. This work bridges a knowledge gap in the alkaloid diversity of Aphaenogaster and provides a basis for future work to contextualize the importance of natural history, niche acquisition, and speciation on chemical evolution within Aphaenogaster.NSFURAPA three-year embargo was granted for this item.Academic Major: Evolution and EcologyAcademic Major: Entomolog
Interview of Donna McIntyre Whyte by Taylor Booghier and Joseph Yuzwa
No full textRemote interview.Donna McIntyre Whyte discusses her time at Ohio State as a student beginning in 1966. She recalls her first impressions of campus as a Black Student, her involvement as a member of the Black Student Union (BSU), and her recollections in relation to a 1968 sit-in by BSU members and others in OSU’s Administration Building. This interview was one of 15 conducted by students in English 4567 (Rhetoric and Community Service) to capture as many stories as possible from former Ohio State students associated with the sit-in at the Administration Building (now Bricker Hall) that led to the arrests of 34 Black students, now known as the “OSU 34.” She also discusses the overall inequities that Blacks faced both in her hometown of Cleveland and at OSU, and the effect her experience at OSU had on her life.
To view video recordings of 2018 interviews of four students talking about the events of 1968, please go to http://go.osu.edu/CarmenCollection1968
Investigating Synergistic Effects of PRMT5 Inhibitors Paired with BH3 Mimetics in Double-Hit Lymphoma
Full text linkDouble Hit lymphoma (DHL) is an aggressive B cell malignancy and comprises 6% of diagnoses among lymphoma cases which is estimated to reach ~2000 cases annually in the US. It primarily affects adult males in their late fifties and sixties and poses unique clinical challenges as it lacks a definitive standard of care. DHL has a poor prognosis with an overall survival ranging from 22%-43% over the span of 1.4-5.0 years. An initial response to standard chemotherapy is commonly observed, but relapse is inevitable, and to date there is no cure. DHL has a poor prognosis due to the aggressive nature of the disease and older patient demographic, which can limit their options for intensive treatment regimens. The lack of effective treatment options and inevitable fatality of a DHL diagnosis emphasize the paramount need for novel therapeutic strategies for DHL.
Our group, Baiocchi Lab, was the first to identify the overexpression of Protein Arginine Methyltransferase 5 (PRMT5) as a key driver of DHL pathogenesis. PRMT5 is an enzyme that catalyzes the methylation of arginine residues on histones and many key proteins for cell cycle progression and survival. This post-translational modification results in the silencing of tumor suppressor genes which contributes to cell transformation and cancer. In our work to explore the effects of PRMT5 inhibition and its potential to reprogram DHL cells, we have discovered that combining PRMT5 inhibition with Bcl-2 inhibition results in synergistic cell death. BCL-2 family proteins can be broadly categorized as pro- or anti-apoptotic and their relative abundances and binding interactions determine if a cell will live or die. The synergy observed between PRMT5 inhibition and Bcl-2 inhibition in other DHL cell lines made us curious about what other effects PRMT5 causes and what is the underlying reasoning for this synergy. We hypothesized that PRMT5 inhibition lowers the apoptotic threshold in DHL by modulating levels of BH3 family proteins to favor a pro-apoptotic state. Major experiments done to unfold our hypothesis were: MTS assay, which visualized our combined treatment results to see if synergy was present; Western blotting, to probe for what mechanisms were causing the synergy; and Immunofluorescence Microscopy, which allowed us to visualize changes in FOXO1 localization in DHL cell lines upon PRMT5 inhibition. Further investigation led us to believe that this upregulation in expression is because, in DHL, PRMT5 is inhibiting FOXO1 localization into the nucleus where it serves as a transcriptional factor for BH3-domain proteins. MTS assays showed that combined treatment induced synergy, especially in dosage concentrations high in PRT808 and low in Venetoclax. Western blotting revealed significant changes in abundance of pro-apoptosis proteins and BCL-2 family proteins with PRMT5 inhibition. IF confirmed upon PRMT5 inhibition via PRT808 treatment, FOXO1 is capable of localizing into the nucleus at greater quantities.
In summary, we have successfully unveiled key characteristics of DHL and began the groundwork on the journey to create a specific, effective, and targeted therapy for DHL. Let alone amongst all DHL lines, within DHL cell lines that share a differentiation state, ABC or GBC, there are profound differences in their responses to treatments and phenotypes. This further emphasizes the importance of characterizing DHL to have a greater understanding of how we can target it effectively on a case-by-case basis.Undergraduate Research ScholarshipNIH MARC T34No embargoAcademic Major: Molecular Genetic
An Empirical Exploration of Unsupervised Mobile Object Detection in a V2I Scenario
Full text linkAs object detection models for self-driving vehicles continue to advance, the scarcity of labeled training data intensifies as a bottleneck to the development process. While some methods for unsupervised learning exist, none have demonstrated sufficient performance on a vast and diverse testing set to warrant a widespread shift in approach. In this paper, we introduce UDAT (Unsupervised Detectors for Annotation and Training), a method by which roadside units (RSUs) can learn to detect mobile objects, creating labels that could be used to train vehicle detectors. The immobility of the units provides a consistency that allows for much more accurate predictions than unsupervised vehicle-mounted systems. Our approach closely mirrors the state-of-the-art MODEST[37] process, using the clustering of ephemeral points across LiDAR frames to create bounding boxes, which are then used as pseudo-labels to train an off-the-shelf detector. Multiple rounds of self-training increase the accuracy of the output annotations. We aim to demonstrate that this training regimen performs successfully enough to justify real-world viability as a roadside data annotator for the training of deep-learning vehicle detectors.No embargoAcademic Major: Computer Science and Engineerin
Understanding Career Doubling Up: Why Men Combine Legal Work and Income Generating Crime
Full text linkStudies have shown that career doublers, those who engage in income-generating crime while also working a legal job, do so because the illegal work is lucrative. Few studies research the motivations for continuing legal work and those that do tend to focus on the monetary gains and benefits associated with legitimate work. After interviewing 100 incarcerated men in Ohio, our data found that people are just as inclined to keep their legal jobs if there are intrinsic rewards associated with the work. Specific answers varied from personal pride to enjoyment of work, but they all supported the finding that money is not the sole motivation for working. Instead, identity characteristics can motivate a person to desist from future criminal activity. Previous research provides a foundation for understanding career doubling, while our study expands upon it, arguing for additional research on the connection between internal motivations for career doublers and desisting from crime.No embargoAcademic Major: Criminology and Criminal Justice Studie
Math behind Finetuning and Merging Language Models
Full text linkTo bridge this gap, fine-tuning LMs has become a critical process. By training models on domain-specific datasets or aligning them with specific objectives, organizations can improve their performance, improve accuracy, and ensure ethical considerations in their responses. Fine-tuning allows LMs to adapt to specialized use cases, whether in finance, law, healthcare, or manufacturing, making them more reliable and effective. This report explores the underlying mathematical principles of LMs, model fine-tuning, and certain model merging techniques. Using Microsoft's Phi 2 Model, we finetuned the base model on the Moral Scenarios and Professional Accounting Category of the MMLU Datasets, which a multiple choice task. We reconfigured the model output to answer multiple choice questions. Then, we merged the two fine-tuned models by averaging the weights and a sign-aware merge method. We want to show that finetuning and merging can create a model that specializes in a particular domain. In our case, we want a model that specializes in Moral Scenarios and Professional Accounting.No embargoAcademic Major: Mathematic
Pervious Concrete for Treatment of Acid Mine Drainage at a Former Strip Mine in Southeast Ohio: Removal of Metals, Total Suspended Solids, and Nutrients
Full text linkPollution resulting from ongoing and abandoned mining operations, known as acid mine drainage (AMD), is a persistent issue that causes significant ecological, human health, and financial impacts. Current AMD treatment methods are suboptimal since they (1) produce sludge as a by-product (e.g., active treatment methods such as chemical dosing) that results in costly disposal or (2) require expensive initial start-up costs and specific conditions to function optimally (passive treatment methods such as anaerobic wetlands) (Johnson & Hallberg, 2005; Skousen et al., 2016). Pervious concrete filters could provide a suitable alternative due to their low cost and ease of use in various AMD ditch, stream, or pond settings. In a previous study, pervious concrete mix designs were optimized for AMD neutralization and subsequent precipitation of heavy metals. In the current project, a pervious concrete filter was installed in an AMD-impacted stream at The Wilds near Cumberland, Ohio. Time-paced water samples were collected immediately upstream and downstream of the filter using automated samplers to assess total suspended solids (TSS), metals, and nutrients concentrations to benchmark filter effectiveness in a field-scale setting. Laboratory analysis of the samples showed significantly increased concentrations for TSS, total phosphorus (TP), and orthophosphate (PO4-P) downstream of the filter, no significant difference in concentrations between sampling locations for nitrate-nitrogen (NO3-N) and total nitrogen (TN), and significantly elevated levels of all metal concentrations downstream of the filter. Furthermore, the durability and longevity of the filter was observed to be highly susceptible to the freeze/thaw cycles common in winter in Ohio, greatly decreasing its structural integrity as a result. After one year of function, the filter suffered from severe structural integrity issues due to presumed frost heave and was no longer useful, suggesting that this type of filter may be better utilized in central latitudes. Nonetheless, data obtained from the project can be utilized to improve and further the development of novel treatment techniques for AMD-impacted waters around the world.The Ohio State University Sustainability InstituteNo embargoAcademic Major: Environmental Engineerin
Pore-Scale Mineral Accessibility and Diagenetic Controls on CO2 Reactivity in the Mount Simon Sandstone, Butler County, OH
No full textThe anthropogenic perturbation of the global CO2 cycle, driven by the continued reliance on fossil fuels, is both the unavoidable outcome of the fossil energy that we mine to maintain our current economic system as well as an ever-increasing threat to our ecological systems and our economic stability. Carbon capture and storage (CCS), from a technological and engineering perspective, has been an emerging interim solution that is allowing for the reduction of atmospheric CO2 accumulations while society transitions to energy sources that will sustain the world’s prosperity. A critical component to CCS technology is the secure storage of CO2 in deep geological formations such as the Mt. Simon Sandstone Formation in Ohio.
This study investigates how matrix mineralogy, diagenetic alteration, and pore geometry affect the Mount Simon Sandstone’s potential for CO2 storage. The primary objective is to quantify accessible reactive mineralogy exposed to pore space, with the goal to assess their contribution to long-term geochemical trapping mechanisms.
QEMSCAN mineral mapping, scanning electron microscopy (SEM), and mercury intrusion porosimetry (MICP) were integrated with advanced image segmentation techniques using ImageJ and ilastik to analyze six core sample intervals (ARM1-5 through ARM1-11). Results reveal that mineral accessibility, not total abundance, is the strongest control on potential reactivity. Specifically, feldspar and illite-rich intervals with large, well-connected pores (e.g. ARM1-7) represent an optimal zone for both injectivity and mineral trapping, while deeper, more cemented intervals may benefit as containment barriers.A one-year embargo was granted for this item.Academic Major: Earth Science