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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Now showing 1 - 10 of 28279

Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival
(American Association for Cancer Research, 2025) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia G.; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of Medicine
High-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation.
Endoscopic Ultrasound-Guided Drainage of Intra-Abdominal Abscess Using 15-mm vs. 10-mm Lumen-Apposing Metal Stents: An International Case-Matched Study
(Elsevier, 2025) Ichkhanian, Yervant; Chaudhary, Ammad J.; Veracruz, Nicolette; Faisal, Muhammad Salman; Peller, Matthew; Kushnir, Vladimir; Daugherty, T. Tyler; Genere, Juan Reyes; Pawa, Rishi; Pawa, Swati; Ahmed, Wafaa; Huggett, Matthew T.; Paranandi, Bharat; Aparicio, José Ramón; Martínez-Moreno, Belén; Nimri, Faisal; Ashraf, Taha; Alluri, Spandana; Obri, Mark; Dang, Duyen; Singla, Sumit; Piraka, Cyrus; Zuchelli, Tobias; Medicine, School of Medicine
Background and Aims Efficacy and safety of EUS-guided placement of lumen-apposing metal stents (LAMS) has been reported yet advantage of using 15-mm LAMS over 10-mm LAMS yet to be explored. Methods International, retrospective, case-matched study of patients with intra-abdominal abscess who underwent EUS-guided drainage with 15-mm (case) and 10-mm (control) LAMS between 03/2019 and 09/2022. Results 51 patients underwent EUS-guided drainage using LAMS [15-mm 29 (57%), 10-mm 22 (43%)]. The most common location of the abscess was peri-pancreatic 43%. Technical success rate was achieved in 97% of cases and 100 % of controls (p=0.412), while clinical success was achieved in 98% and 96%, respectively, (OR 1.3; p=0.089). AE occurred in 7.8% of the cases. Patients with 15-mm LAMS underwent fewer total endoscopic procedures (mean 2.5 vs.3.6; P < 0.023). Conclusion Both sizes showed comparable clinical success and safety profiles, with a significant trend of the need for fewer endoscopic procedures with the 15-mm LAMS.
LOAD1 and LOAD2: Longitudinal characterization of mouse models carrying human‐relevant risk factors for late‐onset Alzheimer’s disease
(Wiley, 2025-01-03) Bernabe, Cristian S.; Kotredes, Kevin P.; Pandey, Ravi S.; Carter, Gregory W.; Sasner, Michael; Oblak, Adrian L.; Howell, Gareth R.; Lamb, Bruce T.; Territo, Paul R.; MODEL-AD consortium; Medicine, School of Medicine
Background: Alzheimer’s disease (AD) is the most common form of dementia, yet the effectiveness of disease‐modifying interventions is inconclusive. Although exceptional progress in our understanding of AD neuropathology has been made via transgenic mouse models bearing familial mutations, they often fail to recapitulate the disease progression of late‐onset AD (LOAD). To address this, MODEL‐AD has developed LOAD1 and LOAD2 mouse models which carry the most common human‐relevant risk factors for AD. In‐depth, longitudinal characterization through aging will reveal useful insights to develop novel treatments for LOAD. Method: APOEε4 and Trem2*R47H, two risk factors for LOAD, were incorporated into C57BL/6J mice to produce the double homozygous LOAD1 model, whereas LOAD2 also contains humanized amyloid‐beta (Aβ) yielding a triple homozygous model. Cohorts of LOAD1 and LOAD2 mice were aged on multiple sites to 4‐, 12‐, 18‐, and 24‐month timepoints and both sexes were characterized using behavior, PET/CT, cytokines/Aβ40‐42 immunoassays, and astrocyte and microglia immunohistochemistry. Result: Although aging LOAD1 and LOAD2 mice did not display significant cognitive deficits, there was a genotype‐dependent increase of plasma levels of Ab40‐Ab42. Both sexes across genotypes showed significant region‐dependent increases in brain glycolysis and tissue perfusion between 4 and 24 months. Consistent with the increased brain metabolism and perfusion neurovascular coupling phenotypes, immunopathology analyses revealed an age‐dependent increased number of astrocytes across genotypes that was restricted to cortical regions. Similarly, the total number of activated microglia was slightly elevated in cortical regions of aging mice, even though the results were only marginally significant. Lastly, aged LOAD1 mice displayed increased brain levels of the pro‐inflammatory cytokine IL‐12p70 when compared to LOAD2. Longitudinal analyses of brain and plasma cytokines are still in progress. Conclusion: LOAD1 and LOAD2 PET/CT analyses revealed phenotypes which are in line with imaging profiles of patients at prodromal stages of AD. Combined with the astrogliosis, these strains are promising venues that can be used to test early disease‐modifying therapeutic targets and can also serve as platform to incorporate additional human‐relevant AD risk factors.
Polygenic scores for Alzheimer’s disease risk and resilience predict age at onset of amyloid‐β
(Wiley, 2025-01-03) O’Brien, Eleanor K.; Porter, Tenielle; Fernandez, Shane; Cox, Timothy; Dore, Vincent; Bourgeat, Pierrick; Goudey, Benjamin; Doecke, James D.; Masters, Colin L.; Rowe, Christopher C.; Villemagne, Victor L.; Cruchaga, Carlos; Saykin, Andrew J.; Laws, Simon M.; ADOPIC Consortium (AIBL, ADNI, OASIS); Radiology and Imaging Sciences, School of Medicine
Background: Genome‐wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer’s disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid‐β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 – 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ‐AAO trait‐specific PGS. Method: 1122 participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) study underwent genome‐wide SNP genotyping and assessment of brain Aβ using positron emission tomography (PET) imaging at two or more timepoints. AAO was the age at which participants were estimated to have crossed the 20 centiloid (CL) threshold for high Aβ. We utilised AD risk and resilience GWAS summary statistics and conducted a GWAS for AAO using a cross‐validation approach (10 test‐validation folds). We used PRSice to identify optimal PGSs for Aβ‐AAO for risk (PGSRisk), resilience (PGSResilience) and Aβ‐AAO (PGSAAO). Result: PGSRisk and PGSResilience were both significantly associated with Aβ‐AAO, such that higher PGSRisk and lower PGSResilience were associated with an earlier Aβ‐AAO. PGSRisk showed the strongest association and explained more variance in Aβ‐AAO than did PGSAAO. When stratified by APOE ε4 carriage, the strongest genetic risk factor for AD, the association of PGSRisk with Aβ‐AAO was stronger among ε4 non‐carriers, whilst PGSResilience, was more strongly associated with Aβ‐AAO in ε4 carriers. Conclusion: PGS based on genetic risk and resilience for AD are both significant predictors of the age at which people are estimated to cross the threshold for high brain Aβ burden. Predicting the age at which a person will pass this threshold would enable treatment at an earlier stage, when it may more effectively delay or prevent symptom onset.
Contributions of heavy metal exposure to late‐onset Alzheimer’s disease
(Wiley, 2025-01-03) Kotredes, Kevin P.; Minaeva, Olga; Pandey, Ravi S.; Moncaster, Juliet A.; Lamb, Bruce T.; Carter, Gregory W.; Goldstein, Lee E.; Howell, Gareth R.; Medical and Molecular Genetics, School of Medicine
Background: Late‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants‐LOAD association is known, the molecular mechanisms modulated by these gene‐environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD‐associated brain pathologies in next‐generation mouse models of LOAD. Examination of these gene‐environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis. Method: Young and aged mice from novel polygenic strains expressing LOAD risk alleles (APOE4, Trem2, APP, Mthfr, Abca7) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP‐mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human‐aligned, LOAD‐related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD‐relevant phenotypes, including amyloid burden, glial activity, and neuron loss. Result: Neurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD‐relevant genes in a toxicant‐specific manner, including a decrease in Vgf and an increase in App. Reduced VGF expression has been observed and reported in all four independent AMP‐AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated. Conclusion: Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.
Increased fibrin deposition in the brains of individuals with Down syndrome and Alzheimer’s disease
(Wiley, 2025-01-03) Du, Annie; Flores-Aguilar, Lisi; Edwards, Natalie C.; Lao, Patrick J.; Ryu, Jae Kyu; Akassoglou, Katerina; Wilcock, Donna M.; Kofler, Julia; Ikonomovic, Milos D.; Lai, Florence; Brickman, Adam M.; Head, Elizabeth; Neurology, School of Medicine
Background: Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood‐brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune‐mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD. Method: Fibrin immunoreactivity was assessed by free‐floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41‐65 years old) and DSAD (n = 12; 46‐66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope. Result: Individuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age‐matched neurotypical controls (p<0.0001). Conclusion: Neurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population.
Accuracy of Alternative PHQ-9 Scoring Algorithms to Screen for Depression in People Living With HIV in Sub-Saharan Africa
(Wolters Kluwer, 2025) Bernard, Charlotte; Font, Hélène; Zotova, Natalia; Wools-Kaloustian, Kara; Goodrich, Suzanne; Kamaru Kwobah, Edith; Rogers Awoh, Ajeh; Nko'o Mbongo'o, Guy Calvin; Nsonde, Dominique Mahambu; Gandou, Paul; Minga, Albert; Tine, Judicaël Malick; Ndiaye, Ibrahima; Dabis, François; Seydi, Moussa; de Rekeneire, Nathalie; Yotebieng, Marcel; Jaquet, Antoine; IeDEA Cohort Collaboration; Medicine, School of Medicine
Background: Screening for depression remains a priority for people living with HIV (PLWH) accessing care. The 9-item Patient Health Questionnaire (PHQ-9) is a widely used depression screening tool, but has limited accuracy when applied across various cultural contexts. We aimed to evaluate the performance of alternative PHQ-9 scoring algorithms in sub-Saharan African PLWH. Setting: Five HIV programs in Cameroon, Côte d'Ivoire, Kenya, Senegal, and the Republic of Congo. Methods: Adult PLWH were screened for depression during the 2018-2022 period. Diagnosis confirmation was done by psychiatrist blinded clinical evaluation (gold standard). Diagnostic performances, including sensitivity and area under the curve (AUC) of the traditional PHQ-9 scoring (positive screening - score ≥ 10), were compared to alternative scoring algorithms including (1) the presence of ≥1 mood symptom (PHQ-9 items 1 and 2) combined with ≥2 other symptoms listed in the PHQ-9, and (2) a simplified recoding of each 4-response item into 2 categories (absence/presence). Results: A total of 735 participants were included [54% women, median age 42 years (interquartile range 34-50)]. Depression was diagnosed by a psychiatrist in 95 (13%) participants. Alternative scoring sensitivities (0.59-0.74) were higher than that of the traditional score's (0.39). Compared to traditional scoring, AUC was significantly higher for PHQ-9 alternative scoring. Across settings, alternative scoring algorithms increased sensitivity and reduced variability. Conclusions: As a primary screening test, new scoring algorithms seemed to improve the PHQ-9 sensitivity in identifying depression and reducing heterogeneity across settings. This alternative might be considered to identify PLWH in need of referral for further diagnostic evaluations.
Korsgaard's Expanded Regress Argument
(SciELO, 2023-04) Kahn, Samuel; Philosophy, School of Liberal Arts
In this discussion note, I aim to reconstruct and assess Korsgaard's recent attempt to extend her regress argument. I begin, in section 1, with a brief recapitulation of the regress argument. Then, in section 2, I turn to the extension. I argue that the extension does not work because Korsgaard cannot rule out the possibility--a possibility for which there is both empirical evidence and argumentative pressure coming directly from the original regress--that we value animality in ourselves qua animality of rational beings.
Machine learning models to predict and benchmark PICU length of stay with application to children with critical bronchiolitis
(Wiley, 2023-06) Rogerson, Colin M.; Heneghan, Julia A.; Kohne, Joseph G.; Goodman, Denise M.; Slain, Katherine N.; Cecil, Cara A.; Kane, Jason M.; Hall, Matt; Pediatrics, School of Medicine
Objective To create models for prediction and benchmarking of pediatric intensive care unit (PICU) length of stay (LOS) for patients with critical bronchiolitis. Hypothesis We hypothesize that machine learning models applied to an administrative database will be able to accurately predict and benchmark the PICU LOS for critical bronchiolitis. Design Retrospective cohort study. Patients All patients less than 24-month-old admitted to the PICU with a diagnosis of bronchiolitis in the Pediatric Health Information Systems (PHIS) Database from 2016 to 2019. Methodology Two random forest models were developed to predict the PICU LOS. Model 1 was developed for benchmarking using all data available in the PHIS database for the hospitalization. Model 2 was developed for prediction using only data available on hospital admission. Models were evaluated using R2 values, mean standard error (MSE), and the observed to expected ratio (O/E), which is the total observed LOS divided by the total predicted LOS from the model. Results The models were trained on 13,838 patients admitted from 2016 to 2018 and validated on 5254 patients admitted in 2019. While Model 1 had superior R2 (0.51 vs. 0.10) and (MSE) (0.21 vs. 0.37) values compared to Model 2, the O/E ratios were similar (1.18 vs. 1.20). Institutional median O/E (LOS) ratio was 1.01 (IQR 0.90–1.09) with wide variability present between institutions. Conclusions Machine learning models developed using an administrative database were able to predict and benchmark the length of PICU stay for patients with critical bronchiolitis.
Longitudinal assessment of dental erosion-abrasion by cross-polarization optical coherence tomography in vitro
(SciELO, 2023) Romero, Maria Jacinta Rosario; Bezerra, Sávio José Cardoso; Fried, Daniel; Lippert, Frank; Eckert, George Joseph; Hara, Anderson Takeo; Biomedical and Applied Sciences, School of Dentistry
This study tested a novel in vitro dental erosion-abrasion model and the performance of cross-polarization optical coherence tomography (CP-OCT) in longitudinally monitoring the simulated lesions. Thirty human enamel specimens were prepared and randomized to receive three dental erosion-abrasion (EA) protocols: severe (s-EA, lemon juice/pH:2.5/4.25%w/v citric acid), moderate (m-EA, grapefruit juice/pH:3.5/1.03%w/v citric acid) and no-EA (water, control). EA challenge was performed by exposing the specimens to acidic solutions 4x/day and to brushing 2x/day with 1:3 fluoridated toothpaste slurry, for 14 days. Enamel thickness measurements were obtained using CP-OCT at baseline (D0), 7 (D7) and 14 days (D14) and micro-computed tomography (micro-CT) at D14. Enamel surface loss was measured with both CP-OCT and optical profilometry at D0, D7 and D14. Data was analyzed with repeated-measures ANOVA and Pearson's correlation (r) (α = 0.05). CP-OCT enamel thickness decreased over time in the s-EA group (D0 >D7 > D14, p < 0.001) and m-EA group (D0 > D14, p = 0.019) but did not change in the no-EA group (p = 0.30). Overall, CP-OCT and micro-CT results at D14 correlated moderately (r = 0.73). CP-OCT surface loss was highest for s-EA (p <0.001) but did not differ between moderate and no-EA (p = 0.25). Enamel surface loss with profilometry increased with severity (no-EA>m-EA>s-EA, p < 0.001). D14 surface loss was higher than D7 for both methods except for the no-EA group with profilometry. CP-OCT and profilometry had moderate overall correlation (r = 0.70). Our results revealed that the currently proposed in vitro dental erosion-abrasion model is valid and could simulate lesions of different severities over time. CP-OCT was a suitable method for monitoring the EA lesions.

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