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High-throughput Amplicon Sequencing Optimization for Downstream Prediction Purposes
No full textIUPUIAlongside short tandem repeat (STR) typing, forensic DNA phenotyping (FDP) can enhance forensic DNA analysis by inferring externally visible characteristics and biogeographical ancestry from single-nucleotide polymorphisms (SNPs). This project involves the optimization of a high-throughput amplicon sequencing assay targeting ~2,000 SNPs associated with pigmentation, facial morphology, and ancestry. Over 400 samples were processed through a genotyping pipeline involving DNA extraction, library preparation with a modified version of a commerical FDP assay, MiSeq FGx sequencing, genotype calling, and quality and ancestry inference assessments. The substantial dataset produced with this project will supply downstream applications in pigmentation and facial morphology prediction modeling. This work also advances FDP toward wide-scale integration into forensic laboratories and demonstrates how SNP-based genotyping can extend investigative leads when traditional STR matching is insufficient
IEPA, a novel radiation countermeasure, alleviates Acute Radiation Syndrome in rodents
No full textRepurposing therapeutic agents with existing clinical data is a common strategy for developing radiation countermeasures. IEPA (imidazolyl ethanamide pentandioic acid) is an orally bioavailable small molecule pseudopeptide with myeloprotective properties, a good clinical safety profile, and stable chemical characteristics facilitating stockpiling. Here, we evaluated IEPA's radiomitigative efficacy in the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) using total-body irradiation (TBI) models in C57BL/6J mice and WAG/RijCmcr rats, applying various posology schemes and introducing syringe feeding of the IEPA formulation in the pudding. Additionally, we assessed IEPA in the delayed effects of acute radiation exposure (DEARE) model after partial-body irradiation (PBI) in WAG/RijCmcr rats. Endpoints included survival, body weight, hematology, and pulmonary parameters, depending on the model. Results from mouse and rat TBI models demonstrated survival improvements with repeated IEPA dosing at 10 mg/kg, with the largest benefits observed in the bi-daily (BID) treatment over the 30-day ARS phase in female rats. Survival across PBI-DEARE subsyndromes was comparable between IEPA and vehicle groups, though IEPA improved pulmonary parameters in female rats during the lung-DEARE phase. Sex-related differences in response to irradiation and IEPA were noted, with females showing a survival advantage. IEPA treatment is compatible with Neulasta® (Pegfilgrastim; PEG-G-CSF); adequately powered studies are needed to confirm the trend toward improved survival over standard care alone. IEPA is a promising development candidate as a medical countermeasure against the effects of acute radiation syndrome. Further confirmatory studies in small and large animal models should validate the robustness and translatability of preliminary rodent data on IEPA's radiomitigative efficacy
Rectal Location and Postcolonoscopy Colorectal Cancer Outcomes
No full textThis cohort study examines whether there are survival differences among patients with postcolonoscopy colorectal cancer based on cancer location
Prostaglandin I2 signaling restrains Treg cell ST2 expression by repressing β-catenin in allergic airway inflammation
No full textBackground: T regulatory (Treg) cells dampen immune activation. Treg cells downregulate the type 2 response to innocuous environmental antigens that produce allergic airway inflammation; however, ST2-positive Treg cells promote allergic airway inflammation. Prostaglandin I2 (PGI2), which signals through the G protein-coupled receptor IP, promotes Treg cell function in an ovalbumin-based model of allergic airway inflammation, suggesting a role for PGI2 signaling through the IP receptor augmenting β-catenin activity in Treg cells.
Objective: We sought to define the mechanisms responsible for PGI2's promotion of Treg cell function in the context of an environmental allergen.
Methods: Treg cell-specific IP-deficient mice, Treg cell fate-tracking IP-deficient mice, and Treg cell-specific IP- and β-catenin-deficient mice were exposed to an Alternaria alternata extract sensitization and challenge model. Bronchoalveolar lavage fluid was evaluated for cell number, cell differential, and cytokines by ELISA. Lungs were evaluated by flow cytometry and histopathology.
Results: Utilizing Treg cell-specific IP-deficient mice, we found that loss of PGI2 signaling impaired Treg cell-suppressive function in response to A alternata; specifically, we found enhanced type 2 cytokine production, eosinophil infiltration, vascular remodeling, and numbers of ST2-positive Treg cells compared to controls. We found that dual IP and β-catenin deficiency in Treg cells prevented the enhanced type 2 response and the further increase in ST2-positive Treg cells via prevention of an increase in GATA3 expression in response to A alternata.
Conclusions: Together, these data further support the importance of PGI2 signaling within Treg cells to their support functionality and demonstrate that PGI2 prevents Treg cell dysfunction through downregulation of β-catenin
Exploring Alzheimer's Disease Progression Through a Graph-based Retrieval System
No full textBackground and Objective:
The cognitive decline spectrum includes cognitively normal (CN), mild cognitive impairment (MCI), and dementia stages. Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that predominantly causes dementia. Thus, identifying patients likely to progress to AD is clinically pertinent. The Alzheimer Disease Neuroimaging Initiative (ADNI) dataset features chronological imaging, biomarker levels, and cognitive scores for over 2,500 individuals across the cognitive decline spectrum. A current challenge in AD research is comprehensively utilizing the volume and variety of information in databases like ADNI. Knowledge graphs (KG) simplify information using points (nodes) and connections (edges). Retrieval systems extract information from a source. In this work, we developed a graph-based retrieval system that utilized ADNI data to classify patients progressing from CN to MCI or AD.
Methods:
The ADNI KG, containing 2,513 patient nodes, 15,497 visit nodes, and 1,135,912 measurement nodes, was processed using NetworkX. Our retrieval system was coded in python and performed Amyloid-Tau-Neurodegeneration (ATN) scoring for each patient in the KG using conventional criteria. Patient progression was determined by comparing diagnoses from the first 25% of visits with the last 25% of visits. The system’s ability to make predictions using cognitive, biomarker, and imaging data was validated on 200 randomly selected patients from the KG.
Results:
The system processed a KG with 1,153,922 nodes and 1,164,395 edges. For N=200 validation, the system removed 6 outliers, found 19 progressors (10 CN→MCI, 9 CN→AD), and achieved 76.7% accuracy when provided adequate biomarker data.
Conclusion and Potential Impact:
We present a graph-based retrieval system that can analyze large quantities of patient data, identify potential AD database errors, output patient-specific insights, and predict cognitive decline progression with reasonable accuracy. Future work will integrate this system with graph neural networks (GNN) and large language models (LLMs) to further improve its accuracy and clinical utility
Getting Started With OERs
No full textLearn how Open Educational Resources (OERs) can reduce textbook costs, boost student success, and how to find or create free, high-quality teaching materials in just 5 minutes
Establishment of sex-specific liver transcriptomes and H3K9me3 profiles during sexual maturity: the impact of maternal obesity
No full textBackground: The escalating prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to rising obesity rates. Maternal obesity (MO) is associated with increased susceptibility to metabolic disorders, including MASLD, in the offspring. This elevated risk could be a consequence of epigenetic modifications established during fetal development, a period highly sensitive to the maternal diet. H3K9me3, a hallmark of heterochromatin, plays a vital role in development by silencing gene programs dispensable for differentiated cell types. This study investigated how MO influences gene expression and chromatin architecture in male and female offspring liver, in early postnatal live and upon sexual maturity.
Methods: Female mice were fed a Western-style diet or a control diet before and throughout pregnancy and lactation. The offspring were weaned at 3 weeks and subsequently transitioned to a standard chow diet for 5 weeks.
Results: At 3 weeks, the liver transcriptomes of control offspring were similar between sexes. However, MO disrupted hepatic gene expression in both sexes, leading to the dysregulation of hundreds of genes and alterations in H3K9me3 binding patterns. By 8 weeks, as the mice reached sexual maturity, control offspring showed considerable sex-based gene expression divergence, with over 1,800 genes showing differential expression. These genes were predominantly involved in immune response regulation, cell adhesion and extracellular matrix organization, xenobiotic and glutathione-mediated detoxification, cholesterol metabolism, and lipid partitioning. Furthermore, thousands of differentially bound H3K9me3 peaks were observed between the 3- and 8-week time points. A significant fraction of these peaks were located on the X chromosome in females, suggesting a role in X inactivation. Remarkably, MO offspring displayed incomplete normalization of gene expression, H3K9me3 profiles, and hepatic lipid classes by week 8, underscoring the long-term impact of maternal diet on the genomic and metabolic landscape.
Conclusions: Collectively, this study highlights inherent sex differences in liver gene expression, and suggests that H3K9me3 plays a role in establishing sex-specific liver function during sexual maturation. Moreover, MO disrupts these patterns, which are not fully corrected by 5 weeks of postnatal dietary normalization
Heterogeneous endocrine cell composition defines human islet functional phenotypes
No full textPhenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers, enabling the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes, analyzed using this pipeline, highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While α and β cell composition influenced insulin and glucagon secretory traits, the abundance of δ cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and β cell replacement therapy