Biology subjects

Bi, Q.

Publications and source records attributed to Bi, Q..

10 recordsLinked to original sources

bioRxiv2026

A multimodal interrogation of Broca's area in the pediatric and adult human brain

Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Brocas area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Brocas and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Brocas area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language- related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD/ADHD. Finally, evolutionary analysis of differentially accessible regions between Brocas area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Brocas area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

A Selective Multivalent NET-Associated Chromatin Neutralizer Resolves Infection-Associated Inflammation in Severe Sepsis

Targeting the overwhelming inflammation driven by neutrophil extracellular traps (NETs) during infection provides an opportunity to manage severe sepsis. This potential needs to be realized by exploring selective NET-neutralization materials, which remains a challenge. Herein, we report a multivalent macromolecular strategy that targets NET-associated DNA-histone chromatin complexes while preserving antibacterial activity of aminoglycoside. We identify 8-arm PEG-conjugated netilmicin (8-arm Netil) as a lead NETs-neutralizer from a library of multivalent aminoglycoside-displayed materials. When compared with 2- and 4-arm counterparts, 8-arm Netil exhibits potent antibacterial activity and high-affinity binding to DNA-histone chromatin complexes through stable multivalent noncovalent interactions, thereby suppressing NET-induced TLR4/TLR9 activation and macrophage inflammatory responses. In severe septic mice, intravenously administered 8-arm Netil preferentially accumulates in inflamed tissues, leading to improved survival protection, owing to the reduction of bacterial dissemination, NET accumulation, systemic cytokine production, and multiple-organ injury. These findings establish NET-associated DNA-histone chromatin complexes as actionable extracellular targets and demonstrate multivalent chromatin targeting as a rational material design strategy for selective NET neutralization and inflammation control in severe sepsis.

bioengineering↗

bioRxiv2026

Urban green space exposure reduces subjective stress and physiological arousal

Stress is a major risk factor for mental disorders, and urban living is a key environmental contributor. Nature exposure may promote stress recovery and mental health, but how physiological arousal and subjective stress change across green versus gray space during naturalistic urban mobility is poorly understood. This preregistered study (https://doi.org/10.17605/OSF.IO/HF4RW) employed geolocation-based ambulatory assessment to examine psychophysiological arousal and subjective stress during transitions between urban green and gray environments. Thirty-six healthy urban residents completed a counterbalanced circular walking route in Cologne, Germany, with continuous GPS, cardiovascular, and electrodermal recording alongside ecological momentary assessment of subjective stress, affect, and exertion. Green compared to gray spaces were associated with lower subjective stress and higher affective well-being, with cardiac indices reflecting reduced autonomic arousal during green space exposure. Autonomic changes surrounding environmental transitions persisted beyond the immediate transition window, suggesting that physiological benefits of green space exposure extend into subsequent gray environments. These findings underscore the public health potential of urban green infrastructure for preventing stress-related mental health conditions.

physiology↗

bioRxiv2026

Progenitor Diversity and Architecture of the Human Ganglionic Eminences Shaping the Basal Ganglia

The embryonic medial and lateral ganglionic eminences (MGE, LGE) are the principal sources of most neurons and glia for the basal ganglia. In primates, the MGE has a distinctive cytoarchitecture characterized by doublecortin enriched cellular nests (DENs), yet the architectonic organization underlying DEN formation, the molecular heterogeneity of ganglionic eminence progenitors and their lineage relationships, remain poorly understood. Here, using paired single-nucleus transcriptomics and chromatin accessibility profiling of the three GEs, we identify distinct progenitor populations, delineate their gene regulatory networks, and reconstruct their lineage trajectories. Live imaging reveals a unipolar outer radial glia-like population (GE-oRG) that undergoes mitotic somal translocation. Spatial transcriptomics identifies a distinct CRABP1+/ANGPT2+ domain within the MGE. Integrated spatial and electron microscopy demonstrates a periphery-to-center gradient of differentiation in the MGE. Leveraging DEN-forming MGE organoids derived from PCDH19 knockout human pluripotent stem cell lines, we identify the protocadherin, PCDH19, as a key regulator of DEN formation.

neuroscience↗

bioRxiv2025

A multivariate pattern metric of individualized hemispheric functional asymmetry

Functional asymmetry is a fundamental feature of human brain organization, yet existing measures of functional connectivity asymmetry rely mainly on univariate indices that miss distributed pattern structure. We introduce the Pattern Dissimilarity of Hemispheric Functional Connectivity (PDHC), a multivariate metric that quantifies the pattern-level distance between each individuals left- and right-hemisphere connectivity architecture. In over one thousand adults, PDHC showed high test-retest reliability, cross-atlas robustness, and strong individual specificity. Network analyses indicated that hemispheric similarity is anchored in conserved sensorimotor and subcortical systems, whereas higher-order networks drive divergence. Developmental data from infancy through early adulthood revealed a characteristic trajectory: dissimilarity declines sharply early in life and increases modestly thereafter. Twin and Turner syndrome samples further demonstrated moderate heritability and sensitivity to X-chromosome dosage. PDHC thus provides a reliable and individualized metric of hemispheric functional architecture, offering a scalable tool for probing lateralization across development, genetics, cognition, and clinical conditions.

neuroscience↗

bioRxiv2025

Vitamin D regulates olfactory function via dual transcriptional and mTOR-dependent translational control of synaptic proteins

Vitamin D (VitD) deficiency, affecting over 1 billion people worldwide, is associated with neurological dysfunction, but its cell-type-specific neural mechanisms remain unclear. Using a dietary mouse model, we show that VitD bidirectionally regulates olfactory acuity: deficiency impairs odor discrimination, while supplementation enhances sensitivity. Single-nucleus and spatial transcriptomics pinpoint selective vitamin D receptor (VDR) expression in olfactory bulb (OB) tufted cells, where it drives synaptic protein expression. Genetic VDR knockdown replicates deficiency-associated olfactory deficits, establishing VDR as essential for synaptic and translational regulation. Notably, we identify mTOR-mediated protein synthesis as a critical convergence point--pharmacological mTOR inhibition (rapamycin) rescues synaptic protein deficits and behavioral impairments in VitD-deficient mice. These findings delineate a noncanonical VDR-mTOR-translational axis--complementing conventional transcriptional regulation--through which VitD serves as a nutrient-sensitive neuromodulator that integrates dietary status with synaptic functions and sensory processing. Our study expands the physiological role of VitD beyond traditional endocrine signaling and reveals mechanistic insights that may inform novel therapeutic strategies for neurological and psychiatric conditions associated with VitD deficiency.

neuroscience↗

bioRxiv2025

α7 nicotinic acetylcholine receptors regulate radial glia fate in the developing human cortex

Prenatal nicotine exposure impairs fetal cortical grey matter volume, but the precise cellular mechanisms remain poorly understood. This study elucidates the role of nicotinic acetylcholine receptors (nAChRs) in progenitor cells and radial glia (RG) during human cortical development. We identify two nAChR subunits--CHRNA7 and the human-specific CHRFAM7A--expressed in SOX2+ progenitors and neurons, with CHRFAM7A particularly enriched along RG endfeet. nAChR activation in organotypic slices and dissociated cultures increases RG proliferation while decreasing neuronal differentiation, whereas nAChR knockdown reduces RG and increases neurons. Single-cell RNA sequencing reveals that nicotine exposure downregulates key genes in excitatory neurons (ENs), with CHRNA7 or CHRFAM7A selectively modulating these changes, suggesting an evolutionary divergence in regulatory pathways. Furthermore, we identify YAP1 as a critical downstream effector of nAChR signaling, and inhibiting YAP1 reverses nicotine-induced phenotypic alterations in oRG cells, highlighting its role in nicotine-induced neurodevelopmental pathophysiology.

neuroscience↗

bioRxiv2024

Molecular and cellular dynamics of the developing human neocortex at single-cell resolution

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation1. Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalog cell type-, age-, and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification, and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the transition from neurogenesis to gliogenesis in the human neocortex. We identified a tripotential intermediate progenitor subtype, termed Tri-IPC, responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells, and astrocytes. Remarkably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale GWAS data, we created a disease-risk map highlighting enriched ASD risk in second-trimester intratelencephalic projection neurons. Our study sheds light on the gene regulatory landscape and cellular dynamics of the developing human neocortex.

neuroscience↗

bioRxiv2023

PVN microglia via P2Y12 transmit hemodynamic signal to promote sympathetic excitation in hypertension

Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Furthermore, either pharmacological blockade or genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated insults, which is mediated by microglia.

neuroscience↗

bioRxiv2022

A cross-species proteomic map of synapse development reveals neoteny during human postsynaptic density maturation

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here, we generated a cross-species proteomic map of synapse development in the human, macaque, and mouse neocortex. By tracking the changes of >1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we found that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that the human PSD matures about two to three times slower than other species and contains higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of the RhoGEF signaling in human neurons delays the morphological maturation of dendritic spines and the functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Together, our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

neuroscience↗