Open Access Policy Articles

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The IUPUI Faculty Council adopted an open access policy on October 7th, 2014 (available from: https://openaccess.indianapolis.iu.edu/). This policy shows IUPUI's commitment to disseminating the fruits of research and scholarship as widely as possible. Open access policies increase authors’ rights, readership and citation rates for scholarly articles. The opt out provision ensures that all faculty authors have the freedom to publish in the journal of their choice.

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Digital Light Processing 3D Bioprinting of Gelatin-Norbornene Hydrogel for Enhanced Vascularization
(Wiley, 2023) Duong, Van Thuy; Lin, Chien-Chi; Biomedical Engineering, Purdue School of Engineering and Technology
Digital light processing (DLP) bioprinting can be used to fabricate volumetric scaffolds with intricate internal structures, such as perfusable vascular channels. The successful implementation of DLP bioprinting in tissue fabrication requires using suitable photo-reactive bioinks. Norbornene-based bioinks have emerged as an attractive alternative to (meth)acrylated macromers in 3D bioprinting owing to their mild and rapid reaction kinetics, high cytocompatibility for in situ cell encapsulation, and adaptability for post-printing modification or conjugation of bioactive motifs. In this contribution, the development of gelatin-norbornene (GelNB) is reported as a photo-cross-linkable bioink for DLP 3D bioprinting. Low concentrations of GelNB (2-5 wt.%) and poly(ethylene glycol)-tetra-thiol (PEG4SH) are DLP-printed with a wide range of stiffness (G' ≈120 to 4000 Pa) and with perfusable channels. DLP-printed GelNB hydrogels are highly cytocompatible, as demonstrated by the high viability of the encapsulated human umbilical vein endothelial cells (HUVECs). The encapsulated HUVECs formed an interconnected microvascular network with lumen structures. Notably, the GelNB bioink permitted both in situ tethering and secondary conjugation of QK peptide, a vascular endothelial growth factor (VEGF)-mimetic peptide. Incorporation of QK peptide significantly improved endothelialization and vasculogenesis of the DLP-printed GelNB hydrogels, reinforcing the applicability of this bioink system in diverse biofabrication applications.
Evaluating a Virtual Reality Game to Enhance Teen Distracted Driving Education: Mixed Methods Pilot Study
(JMIR, 2024-11-26) Peterson, Colleen M.; Visclosky, Timothy; Flannagan, Carol A.; Mahajan, Prashant; Gabanyicz, Andrew; Bouchard, Jean-Jacques; Cervantes, Vincent; Gribbin, William; Nobuhide Hashikawa, Andrew; Medicine, School of Medicine
Background: Inexperienced adolescent drivers are particularly susceptible to engaging in distracted driving behaviors (DDBs) such as texting while driving (TWD). Traditional driver education approaches have shown limited success in reducing motor vehicle crashes among young drivers. Objective: We tested an innovative approach to help address the critical issue of DDB among teenagers. We investigated the effectiveness of using a novel virtual reality (VR) game "Distracted Navigator" to educate novice teenage drivers about DDB. Methods: The game consisted of maneuvering a spaceship around asteroids while engaging in simulated DDB (eg, inputting numbers into a keypad). A physician-facilitated discussion, based on the theory of planned behavior, linked gameplay to real-life driving. Teenagers were recruited for the in-person study and randomly assigned at the block level to intervention (VR gameplay or discussion) and control groups (discussion only), approximating a 2:1 ratio. Unblinded, bivariate statistical analyses (all 2-tailed t tests or chi-square tests) and regression analyses measured programming impact on TWD-related beliefs and intentions. Content analysis of focus group interviews identified thematic feedback on the programming. Results: Of the 24 participants, 15 (63%) were male; their ages ranged from 14 to 17 (mean 15.8, SD 0.92) years, and all owned cell phones. Compared to the control group (n=7, 29%), the intervention group (n=17, 71%) was more likely to report that the programming had positively changed how they felt about texting and driving (?218=-8.3; P=.02). However, specific TWD attitudes and intentions were not different by treatment status. Irrespective of treatment, pre- and postintervention scores indicated reduced confidence in safely TWD (ie, perceived behavioral control; β=-.78; t46=-2.66; P=.01). Thematic analysis revealed the following: (1) the VR gameplay adeptly portrayed real-world consequences of texting and driving, (2) participants highly valued the interactive nature of the VR game and discussion, (3) both the VR game and facilitated discussion were deemed as integral and complementary components, and (4) feedback for improving the VR game and discussion. Conclusions: Our findings show that the novel use of immersive VR experiences with interactive discussions can raise awareness of DDB consequences and is a promising method to enhance driving safety education. The widespread accessibility of VR technology allows for scalable integration into driver training programs, warranting a larger, prospective, randomized study.
Sodium butyrate prevents cytokine‐induced β‐cell dysfunction through restoration of stromal interaction molecule 1 expression and activation of store‐operated calcium entry
(Wiley, 2024) Lee, Chih-Chun; Kono, Tatsuyoshi; Syed, Farooq; Weaver, Staci A.; Sohn, Paul; Wu, Wenting; Chang, Garrick; Liu, Jing; Slak Rupnik, Marjan; Evans-Molina, Carmella; Pediatrics, School of Medicine
Sodium butyrate (NaB) improves β-cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been fully elucidated. In this study, we investigated the impact of NaB on β-cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 β cells. Consistently, NaB improved glucose-stimulated Ca2+ oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+ in the β cell is governed by changes in endoplasmic reticulum (ER) Ca2+ levels, we explored the relationship between NaB and store-operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+ levels through STIM1-mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+ levels and restored SOCE in IL-1β-treated INS-1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine-treated INS-1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent β-cell death in response to IL-1β treatment. Mechanistic experiments revealed that NaB mediated these beneficial effects in the β-cell through histone deacetylase (HDAC) inhibition, iNOS suppression, and modulation of AKT-GSK-3 signaling. Taken together, these data support a model whereby NaB treatment promotes β-cell function and Ca2+ homeostasis under proinflammatory conditions through pleiotropic effects that are linked with maintenance of SOCE. These results also suggest a relationship between β-cell SOCE and gut microbiome-derived butyrate that may be relevant in the treatment and prevention of diabetes.
RAD51 regulates eukaryotic chromatin motions in the absence of DNA damage
(American Society for Cell Biology, 2024) Maarouf, Amine; Iqbal, Fadil; Sanaullah, Sarvath; Locatelli, Maëlle; Atanasiu, Andrew T.; Kolbin, Daniel; Hommais, Chloé; Mühlemann, Joëlle K.; Bonin, Keith; Bloom, Kerry; Liu, Jing; Vidi, Pierre-Alexandre; Physics, School of Science
In yeasts and higher eukaryotes, chromatin motions may be tuned to genomic functions, with transcriptional activation and the DNA damage response both leading to profound changes in chromatin dynamics. The RAD51 recombinase is a key mediator of chromatin mobility following DNA damage. As functions of RAD51 beyond DNA repair are being discovered, we asked whether RAD51 modulates chromatin dynamics in the absence of DNA damage and found that inhibition or depletion of RAD51 alters chromatin motions in undamaged cells. Inhibition of RAD51 increased nucleosome clustering. Predictions from polymer models are that chromatin clusters reduce chain mobility and, indeed, we measured reduced motion of individual chromatin loci in cells treated with a RAD51 inhibitor. This effect was conserved in mammalian cells, yeasts, and plant cells. In contrast, RAD51 depletion or inhibition increased global chromatin motions at the microscale. The results uncover a role for RAD51 in regulating local and global chromatin dynamics independently from DNA damage and highlight the importance of considering different physical scales when studying chromatin dynamics.
Words Matter: The Use of Generic “You” in Expressive Writing in an Oncology Setting
(Sage, 2024) Snyder, Stella; Milbury, Kathrin; Wagner, Richard; Cohen, Lorenzo; Psychology, School of Science
The use of generic "you" (GY) in writing samples fosters psychological distancing and functions as a linguistic mechanism to facilitate emotion regulation. This method of creating psychological distance from the traumatic experience of cancer may be used by patients processing emotions. We used behavioral coding to analyze expressive writing samples collected from 138 cancer patients to examine the association between the use of "you" and cancer-related symptoms and psychological outcomes. Occurrences of GY were low, but our qualitative results showed how the use of GY could create a universal experience of cancer. The use of GY was not associated with cancer-related symptoms and depressive symptoms, but longitudinal analyses revealed that those using GY had fewer intrusive thoughts and avoidance behaviors across the follow-up period of 1, 4, and 10 months after the intervention. The development of psychological self-distancing prompts to use in writing interventions or as a clinical tool for cancer patients should be explored.
Characterization of the Ocular Phenotype in a Col4a3 Knockout Mouse Model of Alport Syndrome
(Association for Research in Vision and Ophthalmology, 2024) Belamkar, Ameya; Luo, Qianyi; Mahajan, Neha; Abhyankar, Surabhi; Jones, Bryce A.; Sodhi, Rupinder Kaur; Pattabiraman, Padmanabhan P.; Levi, Moshe; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
Purpose: Alport syndrome (AS) is a genetic condition caused by a dysfunctional collagen (IV) α3α4α5 heterotrimer, leading to basement membrane instability and, ultimately, abnormalities in the kidney, inner ear, and eyes. This study aimed to characterize ocular pathology of AS by focusing on inflammatory and fibrotic markers. Methods: Col4a3tm1Dec knockout (KO) mice eyes were evaluated for the localization of collagen (IV) α3 and collagen (IV) α4, then stained for transforming growth factor-β1 (TGF-β1), TGF-β2, connective tissue growth factor (CTGF), and β-catenin. mRNA levels of the profibrotic genes S100a4, Acta2, Col1a1, Snai1, Snai2, and Twist1 were assessed using real-time reverse transcription quantitative PCR (RT-qPCR). Results: Collagen (IV) α3 and collagen (IV) α4 were co-expressed in Descemet's and Bruch's membrane but not in the retina, lens, or other corneal substructures. Immunofluorescence quantitation revealed upregulation of TGF-β1 in the anterior lens and TGF-β2 in the retina of KO eyes. Conversely, CTGF and β-catenin were shown to be elevated in the corneal epithelium but not the retina or lens. RT-qPCR showed an increase in the transcription of Acta2, Col1a1, and Snai2 in the retinas and Snai2 in anterior segments of KO mice. Conclusions: Col4a3 KO mice exhibited a differential inflammatory and profibrotic response in the cornea, retina, and lens, which may play a role in the ocular pathology of AS.
Development and validation of the DHIS2 platform for integrating sociomedical data to study wound care outcomes
(Public Library of Science, 2024-12-04) Paddo, Atika Rahman; Kodela, Snigdha; Timsina, Lava; Mathew-Steiner, Shomita S.; Purkayastha, Saptarshi; Sen, Chandan K.; Surgery, School of Medicine
Wound trajectory and outcomes research has applications in different aspects of wound healing: forecasting wound healing time, access and utilization of wound care services, factors associated with disparities in wound care services, and its quality and outcomes. Wound care research benefits from a well-maintained record management system. In this article, we demonstrate the customization of the District Health Information Software (DHIS2) platform to integrate wound care clinical data with social determinants of health from several Comprehensive Wound Centers (CWC) in Indiana. We describe the modules and features of our platform, such as tracker capture, visualization, and maps. DHIS2 is used in more than 60 countries to monitor and evaluate health programs. However, to the best of our knowledge, this is the first attempt to use DHIS2 as a wound care data warehouse, a platform to perform wound care research for academic researchers and clinical practitioners. Clinicians can use the platform as one of the key tools to make an informed decision in determining the treatment for favorable healing trajectory and wound outcomes. We conducted a usability and acceptance survey among researchers at the Indiana Center for Regenerative Medicine and Engineering and found that DHIS2 can be a suitable infrastructure to manage metadata to import and analyze combined data from disparate sources, including Electronic Medical Records, WoundExpert, and clinical trials management software like REDCap.
Autologous Testicle Construction With Buried Metoidioplasty Correction
(Wolters Kluwer, 2024-12-06) Sparks, Payton J.; Moit, Harley L.; Tom, Alan; Roth, Joshua; Hadad, Ivan; Surgery, School of Medicine
Gender-affirming surgery is essential for transgender individuals seeking alignment between their physical appearance and gender identity. Metoidioplasty is a masculinizing option for those assigned female at birth and often includes vaginectomy, urethral lengthening, scrotoplasty, creation of a neophallus, and testicular prostheses, typically implanted during a second-stage procedure. We describe a 39-year-old transgender man who initially underwent a laparoscopic hysterectomy, metoidioplasty, and tubularized plate urethral lengthening 19 months earlier. Although the patient could achieve an erection and orgasm, he struggled with standing urination due to the penis being buried by the mons pubis and upper labia majora. In addition, he feared superior migration of the testicular prostheses, which could diminish the prominence of the neophallus. We elected to perform a monsplasty with resection and rearrangement of excess upper labial tissue to mimic testicles. This approach helps avoid the risks associated with prostheses, using the patient's own tissues instead. This second-stage operation enhances the appearance of the neophallus and creates the cosmetic appearance of testicles using the patient's own tissues, offering a safe and effective surgical option. Although metoidioplasty offers significant benefits in terms of appearance and sensation, it has limitations, including the challenge of achieving standing urination due to the typically shorter length of the neophallus. We aimed to present the effectiveness and associated patient satisfaction with this innovative approach, showing its viability as a safe surgical option.
Inhibition of pterygium cell fibrosis by the Rho kinase inhibitor
(Springer Nature, 2024-12-28) Dai, Jiannong; Rayana, Naga Pradeep; Peng, Michael; Sugali, Chenna Kesavulu; Harvey, Devon H.; Dhamodaran, Kamesh; Yu, Eric; Dalloul, Joseph M.; Liu, Shaohui; Mao, Weiming; Ophthalmology, School of Medicine
Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinase inhibitors are a potential post-surgical treatment to prevent pterygium recurrence.
Disruption of FBN1 by an Alu element insertion: A novel genetic cause of Marfan syndrome
(Elsevier, 2023) Helm, Benjamin M.; Smith, Amanda M.; Schmit, Kelly; Landis, Benjamin J.; Vatta, Matteo; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
Alu elements are retrotransposons with ubiquitous presence in the human genome that have contributed to human genomic diversity and health. These approximately 300-bp sequences can cause or mediate disease by disrupting coding/splicing regions in the germline, by insertional mutagenesis in somatic cells, and in promoting formation of copy-number variants. Alu elements may also disrupt epigenetic regulation by affecting non-coding regulatory regions. There are increasing reports of apparently sporadic and inherited genetic disorders caused by Alu-related gene disruption, but Marfan syndrome resulting from Alu element insertion has not been previously described. We report a family with classic features of Marfan syndrome whose previous FBN1 genetic testing was inconclusive. Using contemporary next-generation sequencing and bioinformatics analysis, a pathogenic/disruptive Alu insertion occurring in the coding region of the FBN1 gene was identified (c.6564_6565insAlu; p. Glu2189fs) and was confirmed and specified further with Sanger sequencing. This identified the molecular basis of disease in the family that was missed using previous genetic testing technologies and highlights a novel pathogenic mechanism for Marfan syndrome. This case adds to the growing literature of Mendelian diseases caused by Alu retrotransposition, and it also shows the growing capability of genomic technologies for detecting atypical mutation events.

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