Biology subjects

O'Connell, R. M.

Publications and source records attributed to O'Connell, R. M..

5 recordsLinked to original sources

bioRxiv2026

Disrupted FAP-satellite cell communication contribute to maladaptive muscle remodeling in older women

Aged skeletal muscle has decreased ability to rebound from physiological stressors such as disuse atrophy. We previously observed that older adults during recovery following muscle disuse were characterized by rapid skeletal muscle immune cell expansion, cellular senescence and collagen deposition, responses that were biased toward older women. Here we used single-nucleus RNA sequencing and complementary in vitro muscle primary cell experiments in young (YF; 22[plusmn]3y; n=8) and older females (OF; 66[plusmn]5y; n=9) to investigate age-mediated cellular function and intercellular communication during recovery from disuse atrophy. Compared with YF, OF exhibited a markedly greater transcriptional response at 7d-recovery (YF: 1,548 DEGs, OF: 7,999 DEGs), driven primarily by slow- (YF: 96 DEGs, OF: 984 DEGs) and fast-twitch myonuclei (YF: 194 DEGs, OF: 1,234 DEGs), satellite cells (YF: 548 DEGs, OF: 2,784 DEGs) and FAPs (YF: 326 DEGs, OF: 2,102 DEGs). Satellite cells from OF demonstrated collagen signatures including elevated THBS1 expression and enrichment of TGF-[beta] signaling. Concurrently, OF FAPs exhibited increased expression of fibroblast activation marker ADAMTS14. Furthermore, NicheNet analyses unmasked altered FAP-satellite cell communication in OF. Complementary In vitro experiments revealed that myogenic progenitor cells collected at 7d-recovery from OF (vs YF) donors displayed impaired myogenic differentiation and a cellular senescence-associated phenotype, while fibroblasts exhibited greater myofibroblast-like activation. Conditioned media derived from OF fibroblasts at 7d-recovery further increased cellular senescence and impaired myogenic potential (vs YF fibroblast conditioned media). Collectively, these findings suggest that recovery from disuse atrophy in older females is characterized by altered FAP-satellite cell communication and intrinsic function which may contribute to poor muscle remodeling.

cell biology↗

bioRxiv2025

microRNA-21 promotes dysregulated lipid metabolism and hepatocellular carcinoma

Backgrounds and AimsThe prevalence of hepatocellular carcinoma (HCC) is rising in parallel with increasing obesity and metabolic dysfunction-associated steatohepatitis (MASH). MicroRNAs are key post-transcriptional regulators of gene expression and are attractive targets for HCC therapy. Here we sought to identify and characterize dysregulated microRNAs in MASH-driven HCC (MASH-HCC). Approach and ResultsWe profiled microRNA expression in liver tissue from patients with MASH and/or MASH-HCC and in zebrafish HCC driven by activated {beta}-catenin (ABC), one of the most commonly mutated oncogenes in MASH-HCC. We found significant overlap between dysregulated human and zebrafish miRNAs, including miR-21, which was increasingly upregulated from normal liver to MASH to MASH-HCC. We generated transgenic zebrafish that overexpress or sponge (downregulate) miR-21. We found that miR-21 overexpression caused larval liver overgrowth and increased HCC while miR-21 sponge suppressed {beta}-catenin-driven larval liver overgrowth. By performing histologic and lipidomic analysis, we found that overexpression of miR-21, like ABC, suppressed lipid accumulation in response to a high cholesterol diet and increased accumulation of acylcarnitines. ConclusionsHere we characterize microRNA dysregulation in MASH and MASH-HCC in patients, identify miR-21 as increasingly dysregulated from MASH to MASH-HCC, and delineate the impacts of miR-21 overexpression on lipid metabolism and hepatocarcinogenesis in zebrafish {beta}-catenin-driven HCC. This study shows that miR-21, which is similarly dysregulated in human and zebrafish HCC, promotes lipid metabolic changes that may help drive hepatocarcinogenesis.

cancer biology↗

bioRxiv2023

TCGEx: A visual interface for multifaceted analyses of The Cancer Genome Atlas gene expression data

The Cancer Genome Atlas (TCGA) initiative has been essential for revealing key mechanisms in human cancer leading to the development of novel therapeutics. Analysis of the cancer transcriptomics data in the TCGA and other public repositories require coding skills that are associated with a steep learning curve for most non-specialists. To enable a wider utilization of these data, we introduce The Cancer Genome Explorer (TCGEx), a web-based visual data analysis interface that can perform a number of sophisticated analyses ranging from survival modeling and gene set enrichment analysis to unsupervised clustering and linear regression-based machine learning. In addition to providing access to preprocessed data from TCGA and immune checkpoint inhibition studies on cBioportal and CRI-iAtlas, the TCGEx platform allows users to upload and investigate their own data. Using this tool, we investigated the molecular subsets of human melanoma and identified microRNAs associated with intratumoral interferon signaling. We validated these findings using independent data from clinical trials involving immune check-point inhibitors for melanoma and other cancers. Moreover, our analyses unveiled a subset of cytokines predictive of positive responses to diverse immune checkpoint inhibitors prior to treatment initiation. Built on the R/Shiny framework, TCGEx modules offer customizable features to tailor the analysis to different study contexts and help generate publication-ready plots. TCGEx is freely available at https://tcgex.iyte.edu.tr, and it provides an interactive solution to extract meaningful insights from cancer transcriptomics data and guide scientific inquiry.

bioinformatics↗

bioRxiv2022

Estrogen receptor alpha mutations regulate gene expression and cell growth in breast cancer through microRNAs

Estrogen receptor (ER) mutations occur in up to 30% of metastatic ER-positive breast cancers. Recent data has shown that ER mutations impact the expression of thousands of genes not typically regulated by wildtype ER. While the majority of these altered genes can be explained by constant activity of mutant ER or genomic changes such as altered ER binding and chromatin accessibility, as much as 33% remain unexplained, indicating the potential for post-transcriptional effects. Here we explored the role of microRNAs in mutant ER-driven gene regulation and identified several microRNAs that are dysregulated in ER mutant cells. These differentially regulated microRNAs target a significant portion of mutant-specific genes involved in key cellular processes. When the activity of microRNAs is altered using mimics or inhibitors, significant changes are observed in gene expression and cellular proliferation related to mutant ER. An in-depth evaluation of miR-301b led us to discover an important role for PRKD3 in the proliferation of ER mutant cells. Our findings show that microRNAs contribute to mutant ER gene regulation and cellular effects in breast cancer cells.

cancer biology↗

bioRxiv2020

Nef enhances HIV-1 replication and infectivity independently of SERINC3 and SERINC5 in CEM T cells

The lentiviral nef gene encodes several discrete activities aimed at co-opting or antagonizing cellular proteins and pathways to defeat host defenses and maintain persistent infection. Primary functions of Nef include downregulation of CD4 and MHC class-I from the cell surface, disruption or mimicry of T-cell receptor signaling, and enhancement of viral infectivity by counteraction of the host antiretroviral proteins SERINC3 and SERINC5. In the absence of Nef, SERINC5 incorporates into virions and inhibits viral fusion with target cells, decreasing infectivity. However, whether Nefs counteraction of SERINC5 is the cause of its positive influence on viral growth-rate in CD4-positive T cells is unclear. Here, we utilized CRISPR/Cas9 to knockout SERINC3 and SERINC5 in a leukemic CD4-positive T cell line (CEM) that displays relatively robust nef-related infectivity and growth-rate phenotypes. As previously reported, viral replication was attenuated in CEM cells infected with HIV-1 lacking Nef (HIV-1{Delta}Nef). This attenuated growth-rate phenotype was observed regardless of whether the coding regions of the serinc3 or serinc5 genes were intact. Moreover, knockout of serinc3 or serinc5 failed to restore the infectivity of HIV1{Delta}Nef virions produced from infected CEM cells. Taken together, our results corroborate a similar study using another T-lymphoid cell line (MOLT-3) and indicate that the antagonism of SERINC3 and SERINC5 cannot fully explain the virology of HIV-1 lacking Nef.

microbiology↗