Biology subjects

Mahajan, S. S.

Publications and source records attributed to Mahajan, S. S..

3 recordsLinked to original sources

bioRxiv2026

Rapid and Interpretable AMR Diagnostics via Genomics and Cell Painting using Differential Geometry-based Directed-Simplicial Neural Networks on Multimodal Data

Antimicrobial resistance (AMR) remains a critical global health challenge, particularly in high-prevalence regions such as India, where rapid and interpretable diagnostic tools are urgently needed. To address this challenge, we present a computational framework for AMR prediction that integrates genomic and cellular phenotypic data using an in-house developed differential geometry-based Directed Simplicial Neural Network (Dg-Dir-SNNs) applied to multimodal datasets. Using this framework, we analyzed 384 clinically relevant AMR isolates, including Escherichia coli and Klebsiella pneumoniae, integrating 256 genomic k-mer features with 503 cellular morphology descriptors derived from high-content Cell Painting assays. The Dg-Dir-SNNs model constructs an inferred-causal network of top-ranked biomarker-driving features, predicting potential directional dependencies among genomic motifs and phenotypic features. Network analysis identified kmer_TATG as the top-ranked driver associated with predicted resistance, with a local neighborhood including other genomic motifs (kmer_TTTT, kmer_CGTG, kmer_TCAC, kmer_CGTA, kmer_GAAA, kmer_TAAA, kmer_TACA, kmer_TGTG, kmer_TGAG, kmer_AAAA) and a key morphological feature (Cells_correlation_ER_Brightfield). These relationships suggest potential mechanistic associations in which specific genomic motifs may influence cellular phenotypes linked to antimicrobial resistance. Although not yet clinically deployed, this approach demonstrates the potential of multimodal AI-driven modeling for rapid in silico AMR prediction. By providing interpretable, biologically grounded insights, the framework may support future diagnostic development, targeted surveillance strategies, and experimental validation in high-resistance healthcare settings.

microbiology↗

bioRxiv2025

EGR1 Mediates Riluzole-Induced Apoptosis in Osteosarcoma via the Yap/p73-Bax Signaling Axis

Osteosarcoma (OS), although rare, is the most common primary bone cancer, primarily affecting individuals aged 10-30 years. Despite therapeutic advances, survival rates have remained stagnant for decades. Recent studies show that Riluzole, a glutamate receptor antagonist, induces apoptosis in OS cells both in vitro and in vivo. Our previous work demonstrated that Riluzole increases reactive oxygen species (ROS), activating c-Abl kinase, which phosphorylates Yes-associated protein (Yap) at tyrosine 357. This modification promotes nuclear translocation of Yap and interaction with p73, enhancing Bax expression and inducing apoptosis. Early Growth Response 1 (EGR1), a zinc finger transcription factor often linked to apoptosis in other cancers, is significantly downregulated in OS. Here, we investigated the role of EGR1 in Riluzole-mediated apoptosis across OS cell lines and patient-derived xenografts (PDX). In this study, we show that Riluzole upregulates EGR1 expression in all OS cell lines. Chromatin immunoprecipitation followed by qPCR confirmed that EGR1 directly binds to the Bax promoter along with Yap/p73, enhancing Bax expression. Immunohistochemistry of in vivo xenograft tumors from Riluzole-treated mice revealed increased EGR1 and cleaved caspase-3 levels, indicating elevated apoptosis, while reduced NUMA expression suggested diminished tumor proliferation. Together, these findings reveal a novel mechanism where Riluzole promotes apoptosis through upregulation of EGR1, which then cooperates with YAP/p73 to activate Bax expression. These insights establish Riluzole as a promising therapeutic intervention for OS treatment through modulation of the EGR1/Yap/p73/Bax signaling axis.

cancer biology↗

bioRxiv2025

Riluzole as a Dual-Targeted Radiosensitizer for Osteosarcoma: Targeting Tumor Cells and Angiogenic Vasculature to Enhance Single High Dose Radiotherapy Efficacy

Osteosarcoma is a highly aggressive bone malignancy primarily affecting children and young adults. It presents significant treatment challenges due to its inherent resistance to conventional fractionated radiotherapy (CFRT). Single high dose radiation therapy (SDRT) has promise for the treatment of radioresistant sarcomas, especially those characterized with extensive vascularity. However, its clinical application is severely constrained by toxicity to adjacent critical tissues. Radiosensitizers can enhance tumor cell susceptibility to radiation-induced DNA damage, improving therapeutic efficacy and potentially reducing collateral toxicity. Monotherapies targeting tumor vasculature alone in solid tumors have shown limited success as radiosensitizers in clinical settings. This highlights the importance of compounds that can simultaneously target both tumor cells and its associated microvasculature to maximize the therapeutic outcome to SDRT. Riluzole, the FDA-approved drug for Amyotrophic Lateral Sclerosis, is currently under investigation as a therapeutic agent for osteosarcoma. Riluzole acts to inhibit glutamate release, reduce glutathione levels in cancer cells, and mitigate tumor angiogenesis, positioning it as a potent radiosensitizing agent for the treatment of osteosarcoma. We hypothesize that Riluzole enhances osteosarcoma radiosensitivity to SDRT by simultaneously targeting intrinsic tumor radioresistance and pro-angiogenic signaling. Our findings demonstrate that Riluzole radiosensitizes osteosarcoma cells in vitro by reducing clonogenic survival and enhancing apoptosis. Mechanistically, Riluzole potentiates irradiation-induced reactive oxygen species (ROS) production, induces G2/M phase cell cycle arrest, inhibits DNA repair, and thereby amplifies radiation-induced DNA damage. Additionally, Riluzole suppresses radiation-induced Vascular Endothelial growth factor A (VEGFA) expression indicating its ability to overcome endothelial cell mediated radioresistance. Collectively, these results establish Riluzole as a promising radiosensitizer for osteosarcoma, with the potential to improve SDRT efficacy by overcoming both tumor-intrinsic and microvasculature-mediated radioresistance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/681036v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1839ca2org.highwire.dtl.DTLVardef@1a05dcaorg.highwire.dtl.DTLVardef@16da8cborg.highwire.dtl.DTLVardef@64ce1d_HPS_FORMAT_FIGEXP M_FIG C_FIG This schematic illustrates the proposed mechanism by which Riluzole enhances SDRT efficacy in osteosarcoma by targeting both tumor cells and VEGFA-mediated pro-survival signaling in endothelial cells. Riluzole increases radiation-induced ROS levels, induces G2/M cell cycle arrest, and inhibits DNA repair in osteosarcoma cells, thereby overcoming intrinsic tumor radioresistance. It also suppresses tumor cell VEGFA expression, which may contribute to reduced pro-survival signaling in the angiogenic endothelial cells within the tumor microenvironment. Together, these effects sensitize osteosarcoma tumors to SDRT, improving therapeutic outcomes (Illustration created using BioRender (BioRender.com, 2025)).

cancer biology↗