Biology subjects

Gopal, J.

Publications and source records attributed to Gopal, J..

4 recordsLinked to original sources

bioRxiv2026

Small molecules targeting BRCA1-deficient cancer cells

BRCA1 mutation-carriers frequently develop triple-negative breast cancers that are resistant to cancer therapies. We used our established luciferase-expressing BRCA1-deficient human mammary epithelial-derived cell line series with stable shRNA-mediated BRCA1-knockdown, H-RasG12V-mediated transformation, and TP53-deficiency (PMID: 20038817) to perform a high-throughput-screen using the National Cancer Institute (NCI) chemical library Diversity Set II of 1,440 small molecules and noninvasive bioluminescence imaging. We selected five (NSC667251, NSC636948, NSC21683, NSC281383, and NSC136513) compounds that reproducibly induced cell death in engineered BRCA1-knockdown cells and in BRCA1-deficient human cancer cell lines. In p53-mutant MDA-MB-231 and SKBr3 lines, the compounds induced apoptosis and PARP cleavage by 12 hours. Sub-G1 flow cytometric analysis demonstrated maximal apoptosis induction by 48 hours of drug exposure. p53 protein stabilization and phosphorylation were observed with the selected compounds in BRCA1-deficient wild-type TP53-expressing cells. Drug-treated BRCA1-knockdown MCF10A cells and BRCA1-mutant HCC-1937 breast cancer cells showed gamma-H2AX foci and phospho-H2AX by immunoblotting indicating genotoxicity and DNA damage as contributing factors for apoptosis. NSC636948 was previously characterized as an inhibitory ligand of peroxisome proliferator-activated beta, delta; (PPAR beta, delta) and both NSC636948 and NSC667251 act as inverse agonists of PPAR beta, delta. Kaplan Meier survival analysis of a combined breast cancer cohort (n = 1,959) derived from the METABRIC, demonstrated that patients with high PPARD expression exhibited significantly worse overall survival compared with those with low PPARD expression (log-rank p = 0.008). The selected compounds provide candidate therapeutic leads as well as insights into molecular targets for further evaluation in BRCA1-deficient tumor models and for assessment in combination therapy strategies.

cancer biology↗

bioRxiv2025

Distinct neural temporal architectures encode rapid social expressions and sustained internal mood states

Affective processing operates across multiple temporal scales, from rapid social signaling through facial expressions to sustained internal mood states, yet the neural computational principles governing these different timescales remain unclear. Understanding how the brain implements distinct temporal architectures for momentary versus persistent affective phenomena is important to comprehending emotional processing and developing objective biomarkers for psychiatric conditions. Here, we introduced a multimodal approach combining automated facial expression monitoring and continuous intracranial electroencephalography in 2,037 electrode contacts across 16 epilepsy patients, over multiple days. Of these, 15 and 12 patients met criteria for facial expression and for mood analysis, respectively. Among patients meeting criteria, we captured 1,396 naturalistic smiles, and 3,746 neutral expressions - separated by at least 10 seconds, alongside 336 periodic mood assessments. This paradigm revealed distinct behavioral and neural computational architectures. Aperiodic neural activity in the lateral temporal cortex (79.5% accuracy) encoded facial expressions with high cross-participant generalizability. Mood states, however, showed different encoding patterns. Facial expressions provided no consistent mood indicators across participants. Critically, low-gamma power dynamics in limbic regions encoded mood states in only a subset of individuals (5 of 12 participants) with expression-mood behavioral correlations, suggesting a distinct encoding phenotype. Cross-domain analysis confirmed computational independence: neural features optimized for facial expression decoding failed to predict sustained mood states, and vice versa. These findings suggest that multiple neural mechanisms may influence underlying affective processing, with variations in their contributions between individuals. The results provide a framework for understanding individual differences in neural mood representation and establish methodological approaches for objective measurement of naturalistic affective behaviors.

neuroscience↗

bioRxiv2024

Naturalistic acute pain states decoded from neural and facial dynamics

Pain is a complex experience that remains largely unexplored in naturalistic contexts, hindering our understanding of its neurobehavioral representation in ecologically valid settings. To address this, we employed a multimodal, data-driven approach integrating intracranial electroencephalography, pain self-reports, and facial expression quantification to characterize the neural and behavioral correlates of naturalistic acute pain in twelve epilepsy patients undergoing continuous monitoring with neural and audiovisual recordings. High self-reported pain states were associated with elevated blood pressure, increased pain medication use, and distinct facial muscle activations. Using machine learning, we successfully decoded individual participants high versus low self-reported pain states from distributed neural activity patterns (mean AUC = 0.70), involving mesolimbic regions, striatum, and temporoparietal cortex. High self-reported pain states exhibited increased low-frequency activity in temporoparietal areas and decreased high-frequency activity in mesolimbic regions (hippocampus, cingulate, and orbitofrontal cortex) compared to low pain states. This neural pain representation remained stable for hours and was modulated by pain onset and relief. Objective facial expression changes also classified self-reported pain states, with results concordant with electrophysiological predictions. Importantly, we identified transient periods of momentary pain as a distinct naturalistic acute pain measure, which could be reliably differentiated from affect-neutral periods using intracranial and facial features, albeit with neural and facial patterns distinct from self-reported pain. These findings reveal reliable neurobehavioral markers of naturalistic acute pain across contexts and timescales, underscoring the potential for developing personalized pain interventions in real-world settings.

neuroscience↗

bioRxiv2020

Altered kinetics of circulating progenitor cells in cardiopulmonary bypass (CPB) associated vasoplegic patients: An observational study

Vasoplegia observed post cardiopulmonary bypass (CPB) is associated with substantial morbidity, multiple organ failure and mortality. Circulating counts of hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPC) are potential markers of neo-vascularization and vascular repair. However, the significance of changes in the circulating levels of these progenitors in perioperative CPB, and their association with post-CPB vasoplegia, are currently unexplored. We enumerated HSC and EPC counts, via flow cytometry, at different time-points during CPB in 19 individuals who underwent elective cardiac surgery. These 19 individuals were categorized into two groups based on severity of post-operative vasoplegia, a clinically insignificant vasoplegic Group 1 (G1) and a clinically significant vasoplegic Group 2 (G2). Differential changes in progenitor cell counts during different stages of surgery were compared across these two groups. Machine-learning classifiers (logistic regression and gradient boosting) were employed to determine if differential changes in progenitor counts could aid the classification of individuals into these groups. Enumerating progenitor cells revealed an early and significant increase in the circulating counts of CD34+ and CD34+CD133+ hematopoietic stem cells (HSC) in G1 individuals, while these counts were attenuated in G2 individuals. Additionally, EPCs (CD34+VEGFR2+) were lower in G2 individuals compared to G1. Gradient boosting outperformed logistic regression in assessing the vasoplegia grouping based on the fold change in circulating CD 34+ levels. Our findings indicate that a lack of early response of CD34+ cells and CD34+CD133+ HSCs might serve as an early marker for development of clinically significant vasoplegia after CPB.

physiology↗