Biology subjects

Pantula, A.

Publications and source records attributed to Pantula, A..

3 recordsLinked to original sources

bioRxiv2026

The Neural Impact Score benchmarks drugs in Multi-Region Brain Organoids

Only about 10 percent of drugs that clear animal testing succeed in humans, and central nervous system programs carry an even steeper translational gap. Human-relevant NAMs are gaining global regulatory and funding support, creating an urgent need for interpretable preclinical systems that can generate comparable, decision-ready evidence across assays, models, and species. Yet the multimodal treatment-response data produced by these systems are still evaluated assay by assay, with no unified metric showing whether a compound moves neural tissue toward a desirable or undesirable state. Here we present the Neural Impact Score (NIS), a framework that translates multimodal CNS drug-response data into a bidirectional score across four predefined biological categories: neurodevelopment, neuroinflammation, neurodegeneration, and longevity. A positive score indicates a desirable shift, whereas a negative score indicates the opposite, placing compounds on a single scale across assays, model systems, and species. To demonstrate NIS, we analyzed a vascularized human day-200 multi-region brain organoid (MRBO) composed of cortical, endothelial, and brainstem lineages and mimicking a mid-gestational cortical window (GW18-GW22). We tested five compounds with distinct mechanisms of action: a glucagon-like peptide-1 receptor agonist (GLP-1RA), a norepinephrine-dopamine reuptake inhibitor (NDRI), a selective serotonin reuptake inhibitor (SSRI), a sphingosine-1-phosphate receptor modulator, and an Akt activator. We profiled responses using single-nucleus RNA sequencing, bulk RNA sequencing, proteomics, and multi-electrode array electrophysiology. NIS integrated these readouts into category-specific and composite scores, separating beneficial from adverse effects for each compound and sorting compounds into interpretation tiers. Applying the same framework to independent human and rodent datasets without retraining, we recovered conserved human antidepressant responses despite near-chance gene-level agreement between human MRBO and rat brain, and identified an endothelial-dependent, human-specific GLP-1 response absent from the murine dorsal vagal complex. NIS therefore provides a human-relevant framework for drug evaluation and cross-species benchmarking, with a design extensible to other neural systems.

bioengineering↗

bioRxiv2026

Dual Transcriptomic and Epigenomic Signatures of THC Exposure in Human Prefrontal Cortex Development

Prenatal cannabis use is increasing globally, with estimates up to 35% in North America. Fetal exposure to {Delta}9-tetrahydrocannabinol (THC) has been linked to neurodevelopmental deficits. Yet mechanistic understanding remains limited because animal models incompletely recapitulate human fetal development, and human-relevant in vitro platforms are scarce. To address this gap, we generated human iPSC-derived prefrontal cortex organoids (PFCOs) and used an integrated multi-omics approach combining bulk RNA-seq, whole-genome bisulfite sequencing (WGBS), and electrophysiology to characterize early molecular and functional responses to acute THC exposure at a developmentally relevant stage. THC induced a rapid, transient shift toward excitatory and neurodevelopmental gene expression programs while simultaneously suppressing extracellular matrix and adhesion pathways critical for structural support. Concurrent epigenetic remodeling selectively targeted synaptic assembly, postsynaptic organization, and axonal guidance genes, creating a mismatch between early activation of neuronal programs and epigenetic repression of the scaffolding required for their proper integration. Functionally, these disruptions manifested as delayed but reversible increases in burst duration at 24 hours, indicating altered coordination of network activity. Transcriptional and epigenetic responses converged on autism spectrum disorder (ASD) associated gene networks, with strong enrichment among high-confidence and strong-candidate ASD risk genes, suggesting that THC preferentially perturbs neurodevelopmentally vulnerable pathways. Together, these findings define a mechanistic framework in which THC disrupts early human cortical development through a cycle of transient excitatory activation, compromised structural support, and persistent epigenetic alterations, which are features specifically revealed by human PFCOs.

genomics↗

bioRxiv2025

Computational modeling of necrosis in neural organoids

Neural organoids (NOs), also known as brain organoids, are derived from human-induced pluripotent stem cells and are Microphysiological Systems (MPS) of the brain that can recapitulate key aspects of neurodevelopment. They enable in vitro studies of brain development and disease mechanisms, providing disease models for various neurodegenerative or neurodevelopmental/degenerative disorders like Alzheimers disease, microcephaly, and autism. There are many protocols to generate NOs with different complexities and sizes, varying from 400 m to several mm in diameter, with a starvation-induced necrotic core eventually forming depending on the diameter and culture conditions. Thus, they can benefit from vascularization and more optimal culture conditions. There have been several attempts to decrease necrosis while growing larger NOs, such as by using orbital shaking or 2D/3D microfluidic chips, but only with limited success. In this study, we describe a 3D finite element model to simulate O2 starvation-induced necrosis in NOs using the Damkohler Number (Da) and the Michaelis-Menten kinetics. We measured the necrotic areas in NOs using fluorescent imaging and used them to calibrate the model with a specific Da. Using these calibrated values, we systematically compared simulations of different NO culture methods--static, orbital shaking, and microfluidic flow around organoids--highlighting their relative impacts on nutrient diffusion and necrosis. We observed that these culture strategies cannot prevent necrosis beyond a diameter of [~]800 m. Based on these findings, we propose that 3D spatial perfusion, achieved through uniformly distributed fluidic capillaries within the NO, could significantly reduce necrosis. We conducted parametric studies on capillary spacing, density, and layout. Our calibrated model offers insights for designing next-generation microfabricated bioreactors and culture devices, not just for NOs but also for all 3D tissue engineering and organoid research.

bioengineering↗