Biology subjects

Zhou, T.

Publications and source records attributed to Zhou, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Building virtual cell dynamics that evolve with biological measurements

Virtual cell models built from single-cell measurements need to predict how cells change over time, but new biological measurements often reveal dynamical relationships that existing models cannot express. Translating such measurements into dynamics therefore requires deciding what biological relation should be modeled, where it should enter the formulation and how its recovery should be validated. Here we present CellCompass, an agentic AI system that couples a scientific agent with an extensible dynamical engine for modeling state transitions and population change, along with fate and molecular readout. CellCompass reuses existing formulations when sufficient and designs, implements and refines new ones when experimental measurements introduce additional constraints. To assess this capability, we developed DynBench100, a benchmark of 100 simulated single-cell time-course scenarios with hidden dynamical ground truth. CellCompass achieved the highest aggregate performance among the tested general-purpose and biomedical agents across six dynamical tasks. Across four real single-cell studies, it retained an existing velocity-growth model to reconstruct context-dependent epithelial-mesenchymal transition and developed three new dynamical formulations for distinct experimental measurements. In drug-response data, incorporating metabolic RNA labeling reduced pulse-control identifiability error by 31.1%, revealing staged response programs and generating testable predictions for perturbing a candidate adaptive program. In hematopoietic lineage tracing, incorporating clonal barcodes improved clone-fate agreement by 54% over the strongest dynamical baseline, identifying early lineage priming among transcriptionally similar progenitors. Finally, in time-resolved CITE-seq data, CellCompass reduced future surface-protein distribution error by 13.2% for RNA-initialized trajectories, uncovering lineage-specific temporal offsets between transcriptional and protein programs. Together, CellCompass provides a framework in which virtual-cell dynamics can expand with the biological measurements used to constrain them.

bioinformatics↗

bioRxiv2026

Cross-feeding reshapes interactions between antibiotic stressors through metabolic feedbacks

Stressors can combine to inhibit organismal growth or function more (synergy) or less (antagonism) strongly than expected from their individual effects, yet whether these interactions are intrinsic properties of cells or stressors, or emergent consequences of ecological interactions remains unclear. Antibiotic combinations provide a tractable model for studying stressor interactions, but have been characterized largely in bacterial monocultures. Here, we compared antibiotic stressor interactions in Escherichia coli growth in monoculture versus when cross-feeding with Salmonella enterica. Across 36 antibiotic pairs, cross-feeding frequently shifts interactions toward antagonism and away from synergy. In the sulfamethoxazole-trimethoprim pair, dual treatment increases carbon excretion by E. coli, promoting partner growth and attenuating stressor synergy through reciprocal metabolic feedback. Perturbing partner metabolite usage restores monoculture-like interaction outcomes across multiple drug pairs. Together, our results demonstrate that stressor interactions in microorganisms can emerge from ecological feedbacks mediated by metabolic excretion.

microbiology↗

bioRxiv2026

Timed binary WNT activity is sufficient to model the early human neural axis

The vertebrate nervous system develops into functionally distinct domains along the body axis[1]. Developmental studies implicate multiple signaling pathways in coordinating this process, but the order of specification events, sufficiency of individual signals, and molecular basis of competency remain unclear [2,3], leaving the field without a unified model of neuraxis patterning. Enteric nervous system (ENS) and midbrain dopaminergic (mDA) progenitors have reached clinical and preclinical testing [4-11], yet neither is produced at full purity, and yields vary markedly across human pluripotent stem cell (hPSC) lines, reflecting incomplete control of axial identity. Here we use single-cell genetic fate mapping to demonstrate that hPSCs can commit to anterior or posterior cranial fate within the first 24 hours of differentiation, before neural induction. Building on this finding, we show that the duration of a single saturating WNT pulse is sufficient to specify three 'first-order' domains: anterior cranial (0 h), posterior cranial (24 h) and trunk (48 h), each pre-neural and competent for CNS, neural crest and epidermal lineages. Nested 'second-order' domains are specified within first-order domains in response to WNT, FGF, and retinoic acid. Mechanistically, an anterior gene regulatory network repressing WNT targets is irreversibly shut down during the transition to posterior identities. Applying this binary WNT patterning logic, we generate mDA neurons and ENS progenitors robustly across hPSC lines and establish an assembloid model combining first-order progenitors to produce all major regions of the nervous system.

developmental biology↗

bioRxiv2026

Urban planning leaves an audible legacy in a megacity's bird soundscape

Cities are planned for people, yet planning also determines where wildlife persists and where residents hear it. How can this acoustic footprint guide planning and monitoring? We combined AI-powered passive acoustic monitoring at 31 stations with detection-corrected models and spatial validation to map Asian Koel activity across Shenzhen. Koel acoustic opportunity declined with tree and built cover and increased with starling and myna opportunity; host information improved prediction at unmonitored sites. Weekly opportunity expanded in spring and varied across the city; sampled-minute exposure concentrated around dawn. Supported predictions intersected planning-sensitive places, while 51.5% of the city grid remained a monitoring gap. We translated these boundaries into monitoring priorities for underrepresented environments and uncertain spring predictions. This reproducible workflow reveals the acoustic imprint of the present-day urban landscape and connects ecological diagnosis, prediction boundaries and adaptive monitoring to inform urban coexistence.

ecology↗

bioRxiv2026

NEIL2 regulates RNA polymerase II dynamics to suppress transcription replication conflicts in pancreatic cancer

Transcription replication conflicts (TRCs) arise from spatiotemporal interference between replication and transcription machinery and contribute to genome instability in cancer cells. In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic KRAS drives TRC formation, and base excision repair (BER) contributes to TRC resolution as an adaptive response. Here, we show that TRCs are enriched in pancreatic tumor sections from patients and are associated with malignant progression. We identify NEIL2, a bifunctional DNA glycosylase in the BER pathway, as a critical regulator of TRCs in PDAC cells. Mechanistically, NEIL2 loss causes aberrant RNA polymerase II (RNAPII) occupancy at transcription start sites and downstream of transcription end sites. Dysregulated RNAPII dynamics promote R-loop-dependent and -independent TRCs contributing to replication stress, DNA damage, and impaired cancer cell proliferation. Notably, the DNA-binding motif of NEIL2 necessary for canonical BER function is dispensable for TRC regulation. Together, these findings reveal an unrecognized role for NEIL2 in regulating RNAPII dynamics and mitigating TRCs in pancreatic cancer cells.

molecular biology↗

bioRxiv2026

SubcellPert: Benchmarking Subcellular Perturbation Prediction

Perturbations change both RNA abundance and intracellular organization, but gene-count predictors omit the positions needed to model spatial responses. To address this limitation, we introduce \textbf{\textit{SubcellPert}}, a benchmark for perturbation-response prediction at single-RNA-molecule resolution. It comprises 14 imaging datasets with 13.88 million cells and 3.65 billion RNA molecules. Given source observations and a directed condition change, models generate target RNA populations in normalized two-dimensional coordinates. Two independently trained tasks separate abundance from localization: \textit{Oracle} predicts coordinates given exact target counts; \textit{Joint} predicts both. Eight baselines span source resampling, classical transport, and frozen foundation-model adapters. Fixed perturbation and cellular-context holdouts evaluate abundance error, target-gene coverage, and conditional spatial error. Through within-dataset analyses, we find context-dependent gains from spatial features in condition decoding. Interpreting spatial responses requires distinguishing changes within spatial clusters from population composition, and RNA fractions from enrichment relative to compartment geometry. Through comprehensive experiments, we find that Gaussian transport achieves the lowest Oracle spatial error on eight of eleven cellular-context OOD datasets. Audits show that better centroid accuracy can accompany worse radial distributions, and that 19 of 190 Joint adapter fits retain source counts after validation. SubcellPert opens a spatial frontier for virtual cell research, laying the groundwork for predictive models that capture both the molecular composition and intracellular organization of cellular responses. The code is available at \url{https://github.com/king159/SubcellPert}.

bioinformatics↗

bioRxiv2026

Flexible 3D multimodal organoid interface reveals functional subnetworks and coordinated circuit activity in cortical organoids

The balance between excitatory and inhibitory (E/I) neurons is fundamental to cortical function, and its disruption underlies a wide range of neurological disorders, including epilepsy, Alzheimers disease and autism spectrum disorder. Cortical organoids offer a promising model to study this balance, as they recapitulate key features of brain development, including the emergence of E/I circuitry. However, no existing technology can simultaneously resolve neuronal identity, spatial organization, and dynamic network activity within intact organoids, limiting precise interrogation of E/I circuit function. Here, we report INFORM, an INtegrated Flexible Organoid Recording Multimodal neural interface that conformally wraps organoids of any size and shape, enabling long-term recordings over 371 days with above 90% of channels detecting spikes. INFORM interface combines four distinct modalities; electrophysiology, two-photon calcium imaging, targeted electrical microstimulation, and chemical intervention to monitor and modulate neural activity across multiple spatial and temporal scales spanning from action potentials from single neurons to synchronized bursts from large-scale populations. Such high-resolution interrogation enables probing of emergence of functional connectivity in fusing assembloids and resolves spatially discrete functional subnetworks that can be selectively recruited and modulated by INFORM. Neurotransmission blockade confirms that stimulus-evoked suppression of neuronal spiking is mediated by GABAergic inputs providing direct functional evidence of the presence of inhibitory signaling in organoids. This work allows single-cell dissection of functional networks in brain organoids, providing a powerful platform for modelling and studying cortical development, neurological diseases, and the E/I imbalances underlying circuit dysfunction.

neuroscience↗

bioRxiv2026

Increased stress in early life epigenetically rewires pathways related to aging and longevity

Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RRBS-based blood DNA methylation profiles, we show that experimental lifespan-reducing early-life stress rapidly accelerates epigenetic age in zebra finch chicks (Taeniopygia guttata). Corticosterone-treated 29-day-old chicks share differentially methylated loci with non-treated aged birds and cluster with 6-month-old birds. The transcriptional repressor ZBTB16 emerges as an epigenetically top age-correlated gene and is strongest affected by corticosterone. Elevated developmental corticosterone causes rapid epigenetic remodelling of metabolic pathways well-established in aging and longevity. Our results demonstrate epigenetic rewiring of the aging trajectory through conserved stress-survival mechanisms immediately following elevated early-life stress exposure.

developmental biology↗

bioRxiv2026

A FIT2-BLTP1 module sustains lipid droplet phosphatidic acid and restrains overgrowth

Lipid droplets (LDs) are assembled at discrete endoplasmic reticulum (ER) subdomains whose local phospholipid composition, rather than their protein content alone, determines whether a LD nucleates and how large it grows. Phosphatidic acid (PA) is the pivotal lipid of this environment, yet how PA reaches a forming LD has remained unknown. Here we show that the bridge-like lipid transfer protein BLTP1 is required to maintain PA in LD-associated membranes. BLTP1 depletion impaired LD formation and produced fewer but enlarged LDs across mammalian cell types, and lowered LD accumulation during adipogenic differentiation. At the ER, BLTP1 engaged the LD emergence factor FIT2 through its N-terminal transmembrane segment, an interaction that strengthened upon induction of LD formation and was strongly reduced by the disease-associated FIT2 G232R substitution. Co-depletion of FIT2 relieved the LD overgrowth caused by loss of BLTP1. Wild-type BLTP1, but neither a FIT2-binding-defective chimera nor a lipid-transfer-groove mutant, rescued LD formation in BLTP1-depleted cells. Lipidomics of purified LDs showed that BLTP1 loss most strongly lowered PA, most prominently the species PA 36:2, whereas PA and the major phospholipid classes of bulk ER membranes were unchanged. Collectively, we propose that local PA supply by BLTP1 coordinates LD assembly and growth.

cell biology↗

bioRxiv2026

Unraveling APA dynamics during quiescence transitions reveals Pabp modulation of sod2 expression via APA to regulate cellular quiescence

Quiescence is a reversible proliferation arrest enabling cells to adapt to environmental changes, yet the post-transcriptional mechanisms governing its transitions remain poorly understood. Here, we map genome-wide alternative polyadenylation (APA) dynamics across 15 time points of quiescence transitions in fission yeast using 3'-end RNA sequencing. We reveal that APA undergoes extensive remodeling: driving global 3'UTR lengthening during early quiescence entry, 3' UTR shortening upon quiescence establishment, and progressive reversal to proliferative-state lengths during quiescence exit. Integrating 3' UTR dynamics with differential expression analysis, we identify candidate genes potentially regulated through APA-mediated 3' UTR mechanisms. We demonstrate that sod2, encoding mitochondrial superoxide dismutase, autoregulates its mRNA and protein levels via APA-dependent 3' UTR changes. Disrupting proximal APA site of sod2 in a mitophagy-deficient (atg43{Delta}) background exacerbates quiescence maintenance defects and mitochondrial dysfunction. We further identify Pabp as an upstream regulator of sod2 APA. This study establishes the temporal APA remodeling during quiescence transitions and reveals a Pabp-APA-sod2 regulatory axis governing post-transcriptional control of cellular quiescence.

cell biology↗

bioRxiv2026

Decoding subtype development and function in human pluripotent stem cell-derived midbrain dopaminergic neurons

Midbrain dopaminergic (mDA) neurons comprise molecularly and functionally distinct subtypes with differential vulnerability in neurodegenerative and psychiatric disorders. However, the mechanisms specifying subtype identity remain poorly understood, and protocols for the selective derivation of human mDA subtypes are lacking. Here we establish a strategy to derive substantia nigra (A9) and ventral tegmental area (A10) mDA neurons from human pluripotent stem cells (hPSCs). A9 identity is specified by dual-SMAD activation through Activin A and BMP7 at the midbrain floor-plate progenitor stage, whereas A10 identity is promoted by BMP inhibition. A9 mDA neurons are purified based on ALDH1A1 expression, and subtype identity is maintained by continued TGF-{beta} modulation and ESRRB activation in vitro and upon transplantation in vivo. Single-cell RNA sequencing and biochemical analyses demonstrate that hPSC-derived A9 neurons exhibit increased oxidative phosphorylation, neuromelanin-like pigmentation, elevated dopamine synthesis and release, and electrophysiological properties characteristic of A9 mDA neurons in vivo. Integration with human fetal midbrain datasets confirms strong transcriptional concordance between in vitro-derived and in vivo mDA subtypes. Neuromelanin-like structures produced by hPSC-derived A9 neurons trigger pro-inflammatory cytokine secretion from hPSC-derived microglia, and A9 neurons are primed to upregulate MHC-I genes in response to interferon-{gamma}, features which may contribute to the selective vulnerability of A9 neurons. Together, these results establish a robust in vitro platform to interrogate human mDA subtype development, function, and selective vulnerability, enabling mechanistic studies relevant to Parkinson's disease and the development of cell-based therapies.

developmental biology↗

bioRxiv2026

Modeling human embryonic adrenogenesis in pluripotentstem cell-derived corticomedullar-like assembloids

During embryogenesis, the cortical and medullary compartments of the adrenal gland emerge from two distinct sources: intermediate mesoderm-derived steroidogenic progenitors that comprise the cortex, and migratory neural crest-derived catecholaminergic progenitors that give rise to the medulla. The distinct cellular origins and paracrine signaling environments that foster induction, differentiation, and/or migration of cortical and medullary layers present challenges to recapitulating their co-emergence and incorporation in a human pluripotent stem cell (hPSC) based system. To address this, we developed an approach for modeling the adreno-gonadal primordium (AGP) in compound organoids that are organized along a gradient of NR5A1 expression and which unexpectedly incorporate SOX10-expressing Schwann cell precursors that ultimately generate chromaffin cells. Deconstruction of paracrine signaling within AGP-like organoids (AGPLOs) identified a fibroblast growth factor 9 (FGF9)-driven mechanism that expands bridge cell-like chromaffin progenitors and correlates to paracrine signaling cues encountered by physiological correlates along their migration corridor to the cortex in vivo. Combination of NR5A1-expressing cells with chromaffin cell clusters generated corticomedullar-like assembloids (CMLAs) that generated steroids and catecholamines and were responsive to adrenocorticotropic hormone. This work establishes a platform for modeling the reciprocal signaling relationships that drive adrenal gland development and function in health and disease and provides an approach for generating hPSC-derived adrenal cells/tissues that can be applied therapeutically.

developmental biology↗

bioRxiv2026

BRIDGE-AD reveals Alzheimer's disease effectors through interpretable large-scale omics integration

The growing landscape of Alzheimer's disease (AD) datasets creates opportunities to integrate heterogeneous evidence and systematically discover disease effectors. We present BRIDGE-AD, an interpretable network medicine framework that transforms multimodal data into a unified, disease-specific gene representation for AD effector prioritisation. We integrated more than 30 datasets and curated resources spanning omics, functional, genetic and prior disease knowledge layers. BRIDGE-AD outperformed recently published pretrained and modality-specific gene embeddings in recovering AD-associated genes and produced a genome-wide resource of candidate AD effectors. Established and newly prioritised effectors formed 19 functional clusters, revealing a global molecular landscape of AD biology. BRIDGE-AD supported an SPP1-centred cross-compartment hypothesis and nominated SCARB2, a poorly characterised candidate, for functional validation. SCARB2 rewired lysosomal, lipid-handling and autophagic programmes in microglia, whereas disrupted SCARB2 glycosylation in AD implicated altered SCARB2 processing and function. The accompanying website, https://explore-bridgead.com, enables users to trace the curated evidence and generate mechanistic hypotheses.

bioinformatics↗

bioRxiv2026

Additive genes contribute to yield heterosis in rice

The molecular mechanisms underlying heterosis remain unresolved, largely owing to the scarcity of accurately identified heterosis-associated genes. Here, we systematically investigate the inheritance patterns of three yield heterosis-related genes in rice, analyzing their effects in both homozygous and heterozygous genetic backgrounds. We find that heterozygosity at individual loci predominantly produces additive, rather than overdominant, effects. Nevertheless, heterozygous states of these genes generate yield heterosis in heterozygous genetic backgrounds, supporting the overdominance model. Our findings confirm that heterozygous additive genes are key contributors to yield heterosis in rice.

genetics↗

bioRxiv2026

Intranasal Fritillaria taipaiensis nanovesicles alleviate acute lung injury via the lung-brain axis

Acute lung injury (ALI) is a severe inflammatory syndrome frequently complicated by brain injury, which worsens outcomes. Here, we explored whether regulation of the lung-brain axis represents a therapeutic strategy for the management of ALI. We show that intranasal administration of Fritillaria taipaiensis-derived exosome-like nanovesicles (Ft-ELNs) ameliorates LPS-induced ALI and ALI-associated hypothalamic inflammation in mice. Ft-ELNs preferentially accumulate in the lungs, inhibiting TRPV1 in both the lungs and the hypothalamus to establish the lung-brain axis. In parallel, Ft-ELNs primarily regulate systemic humoral immunity by inhibiting the VEGFR1/PI3K/AKT/NF?B signaling pathway. In vitro experiments further confirmed that Ft-ELNs are efficiently internalized by alveolar epithelial MLE-12 cells, exerting protective effects by suppressing VEGFR1 expression. Mechanistically, we identified Ft-miR1 of Ft-ELNs as the key functional effector that directly targets the Flt1 3'UTR to inhibit VEGFR1 expression. These data suggest that Ft-ELNs attenuate lung-brain axis inflammation by targeting VEGFR1 and may hold potential as novel therapeutic agents for the treatment of severe ALI.

immunology↗

bioRxiv2026

Vaccine imprinting drives increased SARS-CoV-2 variant infection in children

Virus exposure history, particularly first exposure, is believed to shape vaccine efficacy and infection susceptibility; however, evidence for mechanistic links between immune responses in individuals and epidemiological outcome in populations is scarce. Recent co-circulation of SARS-CoV-2 variants XFG and BA.3.2 has revealed a striking enrichment in BA.3.2 cases among children. By combining epidemiological modeling, serology and monoclonal antibody analysis in children and adults, we show the dependence of effective variant-specific antibodies on vaccination history which may explain birth-year influence on differential susceptibility to these co-circulating variants. Ancestral cross-reactive site I antibodies frequently neutralize BA.3.2, but not XFG. By contrast, Omicron type-specific site I/III and III antibodies frequently neutralize XFG but not BA.3.2, revealing a tradeoff in the ability to neutralize these two co-circulating strains. These findings mechanistically link immune history, variant neutralization, antibody repertoire and variant infection risk, and suggest that vaccination regimens in children should prioritize neutralization breadth.

immunology↗

bioRxiv2026

Phagocytic activity of perivascular cell promotes CNS injury pathology

Injury, stroke, and neurological diseases cause persistent accumulation of cellular debris that deteriorates lesion microenvironment and impedes central nervous system (CNS) repair. Debris clearance in the injured CNS has long been attributed primarily to microglia and infiltrating macrophages. Here, we identify perivascular cells as previously unrecognized phagocytes that expand after injury and exhibit robust phagocytic activity. Perivascular cell phagocytosis is conserved across multiple mouse models of CNS injury and human stroke lesions. These cells exhibit key hallmarks of phagocytosis, including LC3-associated phagocytosis for efficient lysosomal degradation. Mechanistically, phosphatidylserine serves as the eat-me signal and Axl mediates myelin debris uptake. Myelin phagocytosis drives perivascular cell proliferation, fibrosis and lesion progression. Genetic deletion of Axl in perivascular cells or pharmacological inhibition with the FDA-approved Axl inhibitor Gilteritinib reduces pathology and improves functional recovery after spinal cord injury. Together, these findings establish Axl-dependent perivascular cell phagocytosis as a therapeutic target for CNS repair.

neuroscience↗

bioRxiv2026

Rapid and efficient oligodendrocyte differentiation from human pluripotent stem cells via dual inhibition of BMP and Notch signaling

The protracted timing required for oligodendrocyte differentiation from human pluripotent stem cells (hPSCs) has limited their use in disease modeling, drug screening, and cell therapy. In particular, the signals that drive oligodendrocyte specification and maturation after neural induction and ventral patterning remain poorly understood. Here, we present a protocol to derive human oligodendrocytes from hPSCs that is based solely on extrinsic cues, and we identify dual inhibition of BMP and Notch signaling as critical drivers of oligodendrocyte commitment and maturation. By day 42 of differentiation, up to 70% of the cells are positive for the oligodendrocyte marker O4, with minimal astrocyte contamination, and show robust expression of mature myelin markers including MBP, MOG, and MAG. These hPSC-derived oligodendrocytes closely match the molecular identity of primary fetal human oligodendrocytes as assessed by single-cell RNA sequencing and are functional as shown by in vitro myelination assays. In addition to the rapid generation of myelinating oligodendrocytes, the new protocol can be modularly adapted for the efficient production of PDGFR+ oligodendrocyte precursors or mixed glial populations containing AQP4+ astrocytes, thereby providing a cellular toolbox for the study of human glial lineages in translational applications.

developmental biology↗