Biology subjects

George, U. Z.

Publications and source records attributed to George, U. Z..

4 recordsLinked to original sources

bioRxiv2026

Mutant Isocitrate Dehydrogenase 1 Alters Extracellular Vesicle Secretion and Cargo Composition in Cellular Models

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) define major subtypes of adult diffuse gliomas and occur across a broad spectrum of cancers. These mutations ablate the conventional turnover of isocitrate to alpha-ketoglutarate and confer the neomorphic production of D-2-hydroxyglutarate (D2HG), which drives epigenetic remodeling. Growing evidence suggests this neomorphic activity may also affect how tumor cells communicate; small extracellular vesicles (sEVs) are elevated in gliomas, though how mutant IDH1 shapes sEV production and cargo remains poorly understood. Using glioblastoma and chondrosarcoma cell models, we show expression of mutant IDH1 correlates with a trend of increased sEV secretion, and that D2HG is packaged into sEVs that are taken up by cells. Cell-permeable D2HG treatment dose-dependently increased sEV release from IDH1 wild type cells. Untargeted proteomics showed that mutant IDH1 expression remodeled sEV cargo in a cell type-specific fashion, with mutant chondrosarcoma sEVs enriched in one-carbon metabolism enzymes, and mutant glioma sEVs in lysosomal luminal proteins and endoplasmic reticulum (ER) chaperones. Mutant IDH1 glioma cell transcriptomics suggested expanded ER folding capacity and reduced ribosomal pathways, and sEVs from these cells decreased nascent protein synthesis in IDH1 wild type recipient cells. Together, this suggests sEVs can serve as carriers of mutant IDH1 phenotypes.

cancer biology↗

bioRxiv2024

Uniaxial force modifies the length of the mammary ductal network and the orientation of ducts during pubertal development: Findings from computational modeling and laboratory experiments

The orientation of the epithelium ducts determines the overall shape of the ductal network in the mammary gland, which in turn impacts the efficiency of the delivery of milk through the ducts to breastfeeding infants. However, how the orientations of the ducts are specified is not well understood. Cell-cell and cell-extracellular matrix (ECM) interactions perturb the tissue mechanical environment and influence mechanical signaling, which in turn regulates cell migration, tissue organization, and morphogenesis. This study examined if an applied force that perturbs the tissue mechanical environment can regulate the orientation of the epithelium ducts during puberty, in vivo. Uniaxial forces were applied continuously to the right abdominal number four mouse mammary glands (n=10; TEN) at 5-7 weeks of age, that is, during pubertal formation of the epithelial ductal network. The uniaxial force was applied by pulling and adhering the skin around the nipple of the right abdominal number four mammary gland. This pulling force on the right gland made the left abdominal number four gland also experience a contralateral (CONTRA) force. Mammary glands from litter mates were dissected at 3 weeks, 5 weeks, and 7 weeks of unmanipulated mice to serve as controls. Following dissection, whole mounts were prepared by carmine alum staining and panoramic images were captured under light microscopy. The ductal network in the images were skeletonized and straighten along the longitudinal midline to accurately capture the length of the ductal network without bias from its curvature. Findings from using the Measure tool in ImageJ version 1.54j indicated that the length of the ductal network was increased in the TEN and CONTRA mammary glands compared to control (P < 0.05). Analysis of the images using OrientationJ version 16.01.2018, an ImageJ plug-in, indicated that the orientation of ducts in the TEN and CONTRA mammary glands where altered compared to control (P < 0.05). Although the ductal network was longer in the TEN and CONTRA glands compared to control, there was no significant difference in the total cross-sectional area. In-silico simulations of the ductal network formation using a branching and annihilating random walk model predicted that the increased length of the ductal network may have resulted from changes in the orientation of the epithelium ducts. Thus it is likely that mechanical forces regulate the orientation of ductal branches in vivo.

developmental biology↗

bioRxiv2024

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces D-2-hydroxyglutarate (D2HG), which can inhibit DNA demethylases to drive tumorigenesis. Mutations affect residue R132 and display distinct catalytic profiles for D2HG production. We show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of R132Q in cellular and xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H. Though expression of IDH1 R132Q leads to hypermethylation in DNA damage pathways, DNA hypomethylation is more notable when compared to R132H expression. Transcriptome analysis shows increased expression of many pro-tumor pathways upon expression of IDH1 R132Q versus R132H, including transcripts of EGFR and PI3K signaling pathways. Thus, IDH1 mutants appear to modulate D2HG levels via altered catalysis, resulting in distinct epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

genomics↗

bioRxiv2020

Title: Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection

ABSTRACTInflammatory control is critical to recovery from respiratory viral infection. Acetylcholine (ACh) secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation. This study was designed to explore the role of ACh in acute viral infection and recovery. Using the murine model of influenza A, cholinergic status in the lungs and airway was examined over the course of infection and recovery. The results showed that airway ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the airway and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers at the same frequency as their conventional (i.e., non-cholinergic) counterparts. In addition, they were retained in the lungs throughout the recovery phase and could still be detected in the resident memory regions of the lung up to two months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. When ACh production was inhibited, mice exhibited increased tissue inflammation, altered lung architecture, and delayed recovery. Together, these findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.View Full Text

immunology↗