ScholarWorks shares over 50,000 articles, working papers, chapters, presentations, posters, theses, historical documents and other items submitted by members of the IU Indianapolis campus community.
Get started! Login with your IU credentials to share freely with 2 million readers per year.
Communities in ScholarWorks
Select a community to browse its collections.
Recent Submissions
Endophenotypes of Late‐Onset Alzheimer's Disease in Mouse Models Expressing IL1RAP Risk Alleles
(Wiley, 2025-12-23) Kotredes, Kevin P.; Pandey, Ravi S.; Sasner, Michael; Oblak, Adrian L.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Carter, Gregory W.; Lamb, Bruce T.; Howell, Gareth R.; Radiology and Imaging Sciences, School of Medicine
Background:
It is estimated that by 2050 the number of Alzheimer's disease (AD) patients will exceed 12 million, 95% of which are sporadic, late‐onset AD (LOAD). Without novel therapeutics, unlike other age‐related disorders, LOAD mortality will continue to increase. But as next‐generation‐sequencing technologies improve, human disease risk factors are emerging, correlated to the prevalence and severity of disease. Alterations in the IL1RAP gene are found to be a strong risk factor for amyloid accumulation in LOAD patients. IL1RAP is a membrane‐bound IL‐1ß receptor expressed in most tissues, including CNS‐specific astrocytes, microglia, and neurons, relaying immune signals via NF‐κB and MAPK transcription factors. Further, a neuron‐specific isoform, IL1RAPb, has been identified and found to disrupt MYD88 scaffolding. As a suspected regulatory mechanism for IL‐1ß vulnerability, IL1RAP may prove to be a potential target for intervention against AD.
Methods:
Mouse models of LOAD are underutilized and in short supply. Most popular AD strains express amyloid‐related, familial AD transgenes and fail to address the heterogeneous disregulation observed in human disease. For better preclinical models of LOAD, MODEL‐AD has developed novel mouse strains incorporating genetic and environmental risk factors identified from human data sets. To investigate how IL1RAP specifically impacts disease, we have designed two strains expressing loss‐of function Il1rap transcripts‐ a whole body Il1rap knockout and a neuron‐specific Il1rapb conditional knockout.
Results:
We generated mouse strains on a LOAD‐relevant genetic background (APOEε4, Trem2*R47H, and humanized App) and knocked‐out Il1rap or I1rapb transcripts which produced gene expression signatures in the brain more similar to those seen in human AD patients. To exacerbate this phenotype, we utilized sterile‐infection and high‐fat diet insults which produced normal immune responses evidenced by increases in plasma TNFα, IL‐6, and IL1RAP agonist, IL‐1ß. Both strains also showed an increase in peripheral biomarker neurofilament light chain (NfL), suggesting downstream neuronal injury. More detailed, CNS‐specific characterization of the many aspects of IL1RAP function are still in progress.
Conclusion:
Here we present two novel mouse strains of LOAD, expressing human‐relevant genetic backgrounds aimed at investigating IL1RAP function as a model of human disease and potential target for therapeutic intervention against neurodegeneration.
Domain Formation in Model Membranes: Insights from MD Simulations
(2025-12) Kelley, Patrick; Wassall, Stephen; Petrache, Horia; Liu, Jing; Vemuri, Gautam; Joglekar, Yogesh
Numerous health benefits are associated with dietary consumption of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFA) abundant in fish oils. Incorporation into membrane phospholipids and regulation of the size of lipid rafts is a potential underlying mechanism. These ordered domains enriched in sphingolipid and cholesterol floating in a surrounding sea of disordered lipid are purported to serve as the platform for signaling proteins. In this work, we used coarse grained (CG) MD simulations to study lateral organization in bilayer membranes comprised of mixtures of DHA-containing 1-palmitoyl-2-docosahexaenoylphosphatidylcholine (PDPC) with raft-forming N-palmitoylsphingomyelin (PSM) and cholesterol. An analysis that applies a sliding window approach to assign lipids to raft-like PSM-rich/cholesterol-rich domains based on local lateral density was developed. Two projects are described.
In the first project, we compared mixtures of PSM and cholesterol with polyunsaturated PDPC and/or monounsaturated 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). Substituting PDPC for POPC was seen to promote the formation of larger raft-like PSM-rich/cholesterol-rich domains in simulations that were initially assembled as homogeneously mixed bilayers. The greater size was attributed to the larger difference in order between raft-like and non-raft environments due to disordering of the non-raft region produced by PDPC. This observation supports a role for DHA in controlling the size of lipid rafts and potentially the activation cell signaling proteins when rafts coalesce.
In the second project, we studied where α-tocopherol (αtoc) prefers to locate in simulations run on a bilayer composed of PSM, cholesterol and PDPC begun as a homogeneously mixed bilayer that then separated into PSM-rich/cholesterol-rich domains surrounded by a PDPC-rich environment. αToc, the biologically active form of the essential micronutrient vitamin E, is a membrane soluble antioxidant that prevents oxidative damage of lipids. The simulations reveal that almost all αtoc resides in the disordered PDPC-rich environment, which we attributed to incompatibility with the high concentration of cholesterol or the associated high order in PSM-rich/cholesterol-rich domains. By co-localizing αtoc with PDPC, protection of polyunsaturated phospholipids that are highly vulnerable to oxidation is optimized. Both projects demonstrate the utility of CG MD simulations that enable observation of the formation of nm-sized domains in membranes.
Exploring the Effects of RNase H2 Regulation and Protein Lysine Acetylation on Genomic Stability
(2025-12) Battapadi, Tripthi; Balakrishnan, Lata; Berbari, Nicolas F.; Perrin, Benjamin J.; Turchi, John J.
Maintenance of genomic integrity during DNA replication requires precise coordination of multiple enzymatic processes. The antiparallel nature of the duplex DNA necessitates asymmetric replication, where the leading strand is synthesized continuously while the lagging strand is synthesized discontinuously as Okazaki fragments. In human cells, approximately 50 million Okazaki fragments are generated per replication cycle and must be matured and seamlessly joined to produce an intact lagging strand. Defects in this process contribute to genomic instability and have been implicated in cancer development. The Okazaki fragment maturation (OFM) process involves a coordinated action of several key enzymes: DNA Polymerase δ (Pol δ) synthesizes and displaces the preceding fragment creating a flap, which is then processed by flap endonuclease 1 (FEN1) and the remaining nick is sealed by DNA LigI. Additionally, despite their high fidelity, replicative polymerases can occasionally incorporate ribonucleotides during synthesis, which is processed by Ribonuclease H2 (RNase H2) in the ribonucleotide excision repair (RER) pathway. Central to both pathways is proliferating cell nuclear antigen (PCNA), a sliding clamp that mediates these activities through protein-protein interactions via PCNA-interaction peptide (PIP) domains. The fidelity and efficiency of lagging strand synthesis therefore depend critically on the sequential handoff of DNA substrate between these coordinated enzymes. This study investigates two regulatory mechanisms that modulate protein function and influence pathway efficiency and overall genome stability. First, we examined RNase H2’s role as a potential coordinator linking OFM and RER pathways. Our results reveal bidirectional stimulatory interactions between RNase H2 and key downstream enzymes - Pol δ, FEN1, and DNA LigI, suggesting a coordinated regulatory network. Second, we investigated how lysine acetylation, a dynamic post-translational modification, affects the enzymatic activity of RNase H2, Pol δ, and RPA. In vitro acetylation studies demonstrate enhanced enzymatic activity for all three proteins, indicating that this modification may serve as a governing mechanism controlling OFM efficiency. Collectively, our findings suggest that these protein interaction networks, and regulatory mechanisms offer potential therapeutic targets for cancer and other diseases associated with genomic instability.
Treatment patterns, health care resource utilization, and costs of heavily treatment-experienced people with HIV in the United States
(Academy of Managed Care Pharmacy, 2025) Gupta, Samir; Cappell, Katherine; Coaquira Castro, JeanPierre; Mezzio, Dylan; Bonafede, Machaon; Gruber, Joshua; Park, Seojin; Navadeh, Soodi; Price, Kwanza; Sedgley, Robert; Segal-Maurer, Sorana; Medicine, School of Medicine
Background: Although advancements in antiretroviral therapy (ART) have significantly improved outcomes for people with HIV (PWH), there remains a subset of PWH who are heavily treatment experienced (HTE) and at increased risk for poor outcomes, including AIDS-related complications and mortality.
Objective: To describe the clinical characteristics, treatment patterns, health care utilization, and costs associated with HTE among PWH.
Methods: Treatment-experienced PWH who had at least 2 ART lines of therapy (LOTs) between January 1, 2015, and December 31, 2022, were identified from the Veradigm Network electronic health record (EHR)-linked claims database. HTE PWH met at least 1 of 4 HTE-defining criteria based on ART indication and exposure, evidence of viremia, and/or ART resistance (index date = earliest criterion met). Patients were eligible for study inclusion if they were aged 18 years or older, had a prior HIV diagnosis, and had continuous claims enrollment and EHR activity for at least 6 months before and after the index date. A matched comparator group of treatment-experienced non-HTE PWH was also identified. Treatment patterns were measured for HTE PWH in a variable follow-up period lasting until the end of continuous enrollment or December 31, 2022. HIV-related clinical measures in the 6-month follow-up, and health care resource utilization and costs in the variable-length follow-up, were measured for both HTE PWH and non-HTE PWH.
Results: Among the 19,221 HTE PWH identified in the Veradigm dataset, 2,507 met all remaining study criteria. On average, HTE PWH were aged 50.6 years and predominantly male (63.3%), Black (43.6%), and insured through Medicaid (56.7%). Over a mean 3 years of follow-up, more than 50% of HTE PWH had ART on hand for at least 75% of the follow-up period (median percentage of days = 75.4%); however, treatment modifications were common, as 58.1% had at least 3 LOTs during follow-up. Although the majority of HTE PWH avoided gaps in ART, 26.5% to 32.5% of people in each LOT experienced a gap in ART of at least 45 days. Mean (SD) annualized all-cause and HIV-related health care costs for HTE PWH vs non-HTE PWH were $69,529 ($156,077) vs $51,726 ($89,179) (P < 0.001) and $40,082 ($91,703) vs $30,717 ($66,926) (P < 0.001), respectively. Pharmacy costs and outpatient costs were the largest factors contributing to increased costs for HTE PWH.
Conclusions: HTE PWH experienced frequent changes to their ART regimens, and they had higher disease burden, health care utilization, and health care costs compared with PWH who do not meet the criteria of HTE, suggesting an unmet need in this population.
Device-Related Adverse Events and Modes of Failure in Renal Denervation Systems: Insights From the Food and Drug Administration Manufacturer and User Facility Device Experience (FDA MAUDE) Database Analysis
(Springer Nature, 2025-11-13) Jasti, Manasa; Kumar, Ashish; Nanjundappa, Aravinda; Kalra, Ankur; Paul, Timir; Medicine, School of Medicine
Renal denervation (RDN) therapy has emerged as a device-based treatment option for patients with resistant hypertension. There are currently two Food and Drug Administration (FDA) approved RDN systems in the United States: the ParadiseR RDN system (Recor Medical, Palo Alto, California) and the Symplicity SpyralTM RDN system (Medtronic, Minneapolis, Minnesota). There are limited data on commonly reported adverse events and failure modes associated with these devices. Our objective is to assess the frequently reported adverse events and modes of failure for RDN therapy with the two FDA-approved devices by analyzing data from the FDA Manufacturer and User Facility Device Experience (MAUDE) database. The MAUDE database was queried for the terms "renal denervation", "Symplicity Spyral", and "Paradise renal" for reports received by the FDA to yield a total of 61 results (44, 17, and 0 results, respectively), with the earliest event from November 9, 2016, to the latest on January 5, 2024. After adjusting for duplicates and excluding results unrelated to RDN therapy (n = 38), a total of 23 results pertaining to 13 cases were identified. All the events that resulted from the MAUDE database were Medtronic Symplicity SpyralTM-related. The most common complication reported was renal artery perforation or dissection (n = 7), of which five were intraprocedural vessel dissection and two were postprocedurally identified vessel perforation. Among the five intraprocedural vascular dissections, four were secondary to the guide wire. Other complications (n = 3) included intraprocedural bradycardia requiring atropine (n = 1) and postprocedural bleeding at the right groin access site (n = 2). Reported modes of failure for the RDN system were damage of the device component (n = 2) and device entrapment (n = 1). MAUDE database analysis to date has shown that the most common complication with the RDN system is renal artery dissection or perforation. RDN-related complications appear to be rare. These data provide valuable insight to both operators and manufacturers in further optimizing device performance and enhancing clinical outcomes. Further real-world data/clinical trials are needed to assess implications at a larger scale.