Biology subjects

Bidula, S.

Publications and source records attributed to Bidula, S..

4 recordsLinked to original sources

bioRxiv2026

A shared functional organisation underlies vascular disease remodelling

Cardiovascular disease involves coordinated remodelling across multiple biological processes. Gene-level signatures vary substantially between studies because different combinations of genes can support similar biological processes. Pathway-level analyses can provide more stable representations of these processes but typically consider pathways independently. We hypothesised that grouping related pathways into conserved biological functions and quantifying their relative weighting would reveal a higher-order, transferable property of vascular tissue that we term functional organisation. We quantified the relative weighting of six conserved biological functions across independent transcriptomic datasets spanning human vascular disease, experimental models and therapeutic interventions. Vascular tissues exhibited a reproducible functional organisation defined by the balance of these functions. A dominant remodelling trajectory captured coordinated, nonlinear rebalancing of structural, immune, signalling and metabolic programmes, while a second dimension distinguished contractile/ECM organisation from immune activity. This organisation was preserved across independently reconstructed reference cohorts and remained robust to analytical sensitivity testing. When independent datasets were projected into this fixed framework, biological and clinical phenotypes occupied coherent positions along the remodelling landscape. Plaque-derived vascular, stromal and immune cell populations also occupied ordered functional positions, linking cellular heterogeneity to tissue-level organisation. The same organisational structure generalised across atherosclerosis, peripheral vascular disease and abdominal aortic aneurysm and revealed continuous biological heterogeneity within conventional clinical classifications. Genetic, pharmacological and dietary perturbations reproducibly shifted functional organisation, demonstrating that organisational state is dynamic and biologically responsive. Together, these findings identify functional organisation as a reproducible tissue-level property of vascular remodelling and provide a framework for understanding cardiovascular disease as coordinated rebalancing of biological functions rather than alteration of individual pathways in isolation.

bioinformatics↗

bioRxiv2026

Epidermal Growth Factor/c-Met receptor signalling crosstalk drives tunneling nanotube formation in A549 lung adenocarcinoma cells

Tunneling nanotubes (TNTs) are actin-based cytoplasmic connections that can mediate intercellular transfer of various cellular cargo and have been implicated in cancer progression and chemoresistance. However, the signalling mechanisms driving their formation remain poorly understood. Given the frequent dysregulation of EGFR and c-Met signalling in non-small cell lung cancer (NSCLC), and prior evidence of TNTs in lung adenocarcinoma patient samples, we investigated the role of EGFR and c-Met receptor signalling crosstalk in TNT induction in A549 lung adenocarcinoma cells. Stimulation with EGF, HGF, or in combination induced a concentration dependent increase in the formation of TNTs. TNTs exhibited typical characteristics, including F-actin expression, non-adherence to the substratum and facilitated intercellular trafficking of lysosomes, mitochondria, and lipid vesicles. EGFR was identified as a novel component of TNTs, but had little co-localisation with the c-Met receptor. Co-stimulation with HGF and EGF did not produce consistent additive or synergistic effects on TNT formation, suggesting shared downstream signalling. Furthermore, although EGFR and c-Met inhibition blocked EGF- and HGF-induced TNTs respectively, inhibition of both receptors was required to suppress TNTs following dual HGF/EGF treatment. Interestingly, blocking the EGF receptor alongside c-Met resulted in a more potent inhibition of HGF-induced TNTs, indicating crosstalk. Furthermore, inhibition of downstream MEK and PI3K pathways reduced HGF- or EGF- induced TNT formation, but dual inhibition was required to completely block TNT formation in HGF+EGF co-stimulated cells. These findings reveal a novel convergence of EGFR and c-Met and their downstream MAPK/PI3K pathways in TNT regulation, which can have important clinical implications in combinatorial receptor and cell signalling pathway targeting in NSCLC.

cancer biology↗

bioRxiv2025

G-quadruplexes represent promising new targets to overcome multidrug-resistant fungal infections

The growing emergence of antifungal resistance has prompted the identification of novel antifungal targets. G-quadruplexes (G4s), four-stranded secondary structures that form in DNA and RNA, have arisen as a drug target to treat bacterial, viral, and parasitic infections. Here, we provide the first demonstration that G4s form in fungi and represent a promising new target for antifungal development. We found that PhenDC3 and pyridostatin (PDS), ligands that bind to and stabilise G4s, potently inhibited the metabolism of fungal pathogens in different ways. These pathogens included the pan azole-resistant Aspergillus fumigatus isolate TR34/L98H and Candida auris. Notably, PhenDC3 could synergise with amphotericin B, was protective in an in vivo model of fungal infection, and was well-tolerated by human cells. However, continuous exposure to PhenDC3 resulted in some cross-resistance to current antifungals and this needs to be explored further. PhenDC3 could also increase the number of RNA G4s in live A. fumigatus. Further, we demonstrated the structural flexibility of DNA sequences found in cyp51A and cyp51B, with these sequences capable of forming duplexes, hairpins, G4s and i-motifs. Finally, PhenDC3, but not PDS, caused duplex DNA structures in cyp51A to transition into antiparallel G4 structures potentially associated with PhenDC3s increased antifungal potency. Taken together, G4s represent an exciting antifungal target, but a more detailed understanding of their biological roles is essential.

microbiology↗

bioRxiv2020

Cross kingdom analysis of putative quadruplex-forming sequences in fungal genomes: novel antifungal targets to ameliorate fungal pathogenicity?

Fungi contribute to upwards of 1.5 million human deaths annually, are involved in the spoilage of up to a third of food crops, and have a devastating effect on plant and animal biodiversity. Moreover, this already significant issue is exacerbated by a rise in antifungal resistance and a critical requirement for novel drug targets. Quadruplexes are four-stranded secondary structures in nucleic acids which can regulate processes such as transcription, translation, replication, and recombination. They are also found in genes linked to virulence in microbes, and quadruplex-binding ligands have been demonstrated to eliminate drug resistant pathogens. Using a computational approach, we identified putative quadruplex-forming sequences (PQS) in 1362 genomes across the fungal kingdom and explored their potential involvement in virulence, drug resistance, and pathogenicity. Here we present the largest analysis of PQS in fungi and identified significant heterogeneity of these sequences throughout phyla, genera, and species. Moreover, PQS were genetically conserved. Notably, loss of PQS in cryptococci and aspergilli was associated with pathogenicity. PQS in the clinically important pathogens Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans were located within genes (particularly coding regions), mRNA, repeat regions, mobile elements, tRNA, ncRNA, rRNA, and the centromere. Genes containing PQS in these organisms were found to be primarily associated with metabolism, nucleic acid binding, transporter activity, and protein modification. Finally, PQS were found in over 100 genes associated with virulence, drug resistance, or key biological processes in these pathogenic fungi and were found in genes which were highly upregulated during germination, hypoxia, oxidative stress, iron limitation, and in biofilms. Taken together, quadruplexes in fungi could present interesting novel targets to ameliorate fungal virulence and overcome drug resistance.

microbiology↗