Biology subjects

Yasar, E.

Publications and source records attributed to Yasar, E..

4 recordsLinked to original sources

bioRxiv2026

A pan-cancer benchmark of integrated ferroptosis, cuproptosis and disulfidptosis prognostic signatures

Integrated prognostic signatures combining ferroptosis, cuproptosis, and disulfidptosis are increasingly reported in oncology as advances in risk stratification, yet their added value over simpler pathway-specific or proliferation-related models remains unclear. Here, we developed an integrated regulated cell-death signature and evaluated it through an adversarial pan-cancer benchmark. Using the TCGA pan-cancer cohort comprising 9,808 tumours across 33 cancer types, we curated 118 genes associated with the three cell-death programmes, characterised inter-pathway crosstalk, and derived a 26-gene LASSO-Cox risk signature. The model showed reproducible prognostic performance across cancers, with a pan-cancer concordance index of 0.573 (95% CI, 0.552-0.594), and was independently validated in METABRIC and CGGA cohorts, remaining significant after adjustment for standard clinical variables. However, benchmarking revealed that the integrated signature, although superior to size-matched random gene sets (empirical p < 0.001), did not outperform a ferroptosis-only model (DeLong p = 0.81), indicating no measurable gain from pathway integration. Moreover, much of the prognostic signal reflected tumour proliferation rather than regulated cell death. After adjustment for the proliferation meta-signature (meta-PCNA), ferroptosis performance declined from 0.573 to 0.504, while the integrated model decreased to 0.554. High-risk tumours were more sensitive to anti-proliferative drugs, and the risk score was most strongly associated with E2F, MYC, and G2M target programmes. The signature stratified prognosis but did not predict immune-checkpoint blockade response in IMvigor210 (AUC {approx} 0.50). Importantly, the underlying biology was not merely a modelling artefact. Signature genes showed concordance with protein abundance in CPTAC cohorts, and the three cell-death programmes co-varied within individual malignant cells, with correlations ranging from {rho} = 0.46 to 0.66. Overall, our findings indicate that integrated multi-death signatures are reproducible and biologically grounded, yet prognostically redundant and substantially confounded by proliferation. This study provides a cautionary benchmark for the rapidly expanding use of composite regulated cell-death signatures in cancer prognosis.

bioinformatics↗

bioRxiv2026

A Sonification Framework for GPCR Molecular Dynamics: Auditory Signatures of β2-Adrenergic Receptor

Sonification, the systematic mapping of data to non-speech sound, has been applied with quantitative success in astronomy, seismology, and most recently materials chemistry, but has seen limited use in the analysis of biomolecular dynamics. Earlier protein-music studies have focused largely on the static amino-acid sequence, and G-protein-coupled receptor (GPCR) molecular dynamics (MD) trajectories have not previously been the subject of an auditory display framework. Here we present an end-to-end open-source sonification framework for GPCR molecular dynamics together with a quantitative cross-modal validation procedure, and we apply the framework as a proof of concept to three reference {beta}2-adrenergic receptor ({beta}2AR) trajectories from the GPCRMD repository spanning the activation continuum (inactive, active apo, active + orthosteric agonist). The framework extracts activation-related geometric features per MD frame, maps them under a single rule onto pitch, note duration, velocity, harmonic intensity, and percussive accents, and renders the result with three timbres (piano, violin, flute). The mapping was tested on two designed pairwise contrasts (activation pair; ligand pair) using Mann-Whitney U tests, Random Forest cross-modal classification with leave-one-instrument-out generalisation, and canonical correlation analysis between the MD and audio feature spaces. All four informative MD features differed between paired states at q < 1 x 10-20. A Random Forest classifier trained on audio features alone recovered the MD state with balanced accuracy 0.995 {+/-} 0.003 (activation pair) and 1.000 {+/-} 0.000 (ligand pair), corresponding to information-retention ratios of 1.006 and 1.000 relative to the MD-feature baseline. First canonical correlations between MD and audio spaces reached r1 = 0.926 (activation) and r1 = 0.995 (ligand). The sonification framework therefore provides a quantitatively faithful auditory representation of GPCR activation dynamics, with potential applications in exploratory MD analysis, accessibility, and education. The framework is system-agnostic and transfers to other GPCRs and allosteric MD systems without code changes beyond residue selection.

biophysics↗

bioRxiv2026

The Cytochrome b m.14849T>C (S35P) Variant Induces Structural and Dynamic Alterations in the Heme bL Microenvironment in Multisystem Disease

Mitochondrial Complex III dysfunction is frequently associated with pathogenic variants in the MT-CYB gene, yet the functional consequences of many missense substitutions remain unresolved because they are classified as variants of uncertain significance (VUS). One such variant, m.14849T>C (p.Ser35Pro), has been reported in patients with multisystem mitochondrial phenotypes, including septo-optic dysplasia, cardiomyopathy, and exercise intolerance, although its structural impact on Cytochrome b function remains unclear. In this study, we employed 300 ns all-atom molecular dynamics simulations to assess structural and energetic consequences of the S35P substitution in the Cytochrome b subunit of human mitochondrial Complex III. The S35P variant did not induce global destabilization of the protein scaffold but instead promoted localized perturbations within the heme bL microenvironment. The mutation was associated with loss of a heme-proximal hydrogen-bonding network involving Ser35 and a decrease in electrostatic interaction energy between the protein matrix and the heme bL cofactor. Radial distribution function analysis further supported loosening of local packing around the prosthetic group. Consistent with these local changes, dynamics analyses indicated increased flexibility in distal transmembrane helices that form the heme-pocket scaffold and greater variability in the inter-heme Fe(bL)-Fe(bH) distance. Together, our findings suggest that S35P may exert functional effects by reorganizing the heme bL microenvironment rather than by inducing large-scale structural destabilization, underscoring the value of structure- and dynamics-based evaluation for mitochondrial VUS and suggesting a plausible mechanistic link to the pathophysiology of multisystem mitochondrial diseases.

biophysics↗

bioRxiv2025

Angiotensin 1-7 Modulates the Dynamics and Activation of the Proto-oncogene Mas Receptor

The proto-oncogene Mas receptor (MasR, UniProt ID: P04201) is a class-A (orphan-type) G protein-coupled receptor (GPCR) that mediates the protective effects of Angiotensin 1-7 (Ang 1-7) within the renin-angiotensin system (RAS). Despite its therapeutic relevance, the molecular mechanisms underlying MasR activation by Ang 1-7 remain elusive due to the lack of experimental structural data. In this study, we performed 1-microsecond all-atom molecular dynamics (MD) simulations of AlphaFold-modeled active and inactive MasR conformations, with and without Ang 1-7, to characterize ligand-induced conformational dynamics. Ang 1-7 binding led to increased interaction stability in the active state, reflected by higher occupancy of hydrogen bonds, salt bridges, and hydrophobic contacts. Structural analyses revealed reduced RMSD/RMSF values and stabilization of key transmembrane (TM) helices and the NPxxY micro-switch. TM distance and dihedral analyses indicated partial TM6 displacement and time-dependent NPxxY reorganization. Network-based metrics including betweenness centrality and shortest path length highlighted the emergence of state-specific communication hubs, while PCA, correlation and communication propensity analyses revealed enhanced conformational diversity and selective inter-residue signaling in the ligand-bound state. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations showed favorable binding energetics in the active state ({Delta}GBind = -13.99 kcal/mol). These results demonstrate that Ang 1-7 acts as a partial agonist of MasR by stabilizing the inactive conformation while inducing limited activation features in the active state through non-canonical micro-switch dynamics. This work advances structural insights into MasR regulation and provides a foundation for therapeutic targeting of the ACE2/Ang 1-7/MasR axis.

biophysics↗