Biology subjects

Li, Y.

Publications and source records attributed to Li, Y..

At least 253 records · Page 14Linked to original sources

bioRxiv2026

Spatiotemporal Cascade of AP1/CCA1-TOC1 Module Gates Stem Development

Stem development is crucial in plant vertical architecture and overall crop improvement. The molecular mechanisms underlying the initiation and circadian growth of stem remain still enigmatic. Here, we demonstrate that APETALA1 (AP1) spatially initiates circadian stem growth through a noncell-autonomous role of TIMING OF CAB EXPRESSION1 (TOC1) emanating from the floral meristem to inflorescence meristem in Arabidopsis thaliana. Mechanistically, AP1 interacts with and recruits CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) to associate TOC1. Dynamic formation of the AP1-CCA1 complex is crucial for maintaining the circadian rhythmicity and expression of TOC1. Tissue-specific expression of TOC1 in floral meristems rescues the developmental defects of toc1 mutants at both functional and transcriptional levels. Furthermore, TOC1 directly activates the circadian expression of pectin methylesterase gene family, which is critical for its role in stem development. AP1 homologs regulate circadian stem elongation and plant height in wheat and rice, underscoring the conserved mechanism across flowering plants. Our findings uncovered a spatiotemporal regulatory cascade gating stem development and identified candidate genes for crop improvement.

plant biology↗

bioRxiv2026

(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both {micro}- and {delta}-opioid receptors in astrocytes. Chronic stress reduces {micro}-{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased {micro}-{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the {micro}-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic {micro}-{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.

neuroscience↗

bioRxiv2026

Discovery of BilV reveals a multienzymatic basis for bilirubin reduction across vertebrate gut microbiomes

Gut bacteria reduce bilirubin to urobilinogen, allowing it to be excreted through feces and urine, but studies have long noted a heterogeneous mixture of partially reduced bilirubin-derived intermediates, suggesting that multiple enzymes are involved. Here we identify bilirubin vinyl reductase (BilV), a novel Old Yellow Enzyme family reductase encoded in the genomic neighborhood of the known bilirubin reductase (bilR). Using heterologous expression and LC-MS/MS, we show that BilR acts on the methine bridges in the bilirubin reduction pathway; co-expression with BilV enables vinyl-group reduction and complete conversion to urobilinogen. In bacterial genomes, bilV co-occurs primarily with the bilR-insertion subtype and is largely absent alongside bilR-short. Analysis of 1,197 gut metagenomes across 14 vertebrate species reveals that this differential co-occurrence shapes pathway availability across hosts: carnivores and omnivores carry balanced bilR and bilV, whereas avian microbiomes, dominated by bilR-short, are depleted for bilV. These findings establish that bilirubin reduction to urobilinogen involves two enzymes with complementary regioselectivity, and that their distribution across vertebrate gut microbiomes varies in concert with host bile pigment chemistry.

microbiology↗

bioRxiv2026

Stochastic Differential Equations (SDEs) in NONMEM for Probing Population Pharmacokinetic Model Misspecification: Diagnostic Utility, Practical Considerations, and Future Directions

Population pharmacokinetic (popPK) models are commonly developed using ordinary differential equations (ODEs) to describe deterministic concentration-time profiles, with unexplained variability typically attributed to interindividual variability or residual error. When model misspecification is present, system-level deviations may be absorbed into these conventional variability terms, making the source and magnitude of model inadequacy difficult to assess quantitatively. Stochastic differential equations (SDEs) provide an alternative framework by introducing an explicit system-noise component into the structural model, allowing model-data mismatch to be evaluated more directly. However, historical implementation of SDE-based models in NONMEM has been technically challenging. The availability of the Fortran plug-in subroutine SDE.f90 substantially lowers this barrier and enables more practical implementation of SDE-based models in NONMEM. In this work, SDE-based nonlinear mixed-effects models were evaluated as a quantitative diagnostic framework for probing popPK model misspecification. The SDE.f90 implementation was first verified using simulated one-compartment intravenous bolus datasets with stochastic process noise. Additional simulation-estimation scenarios were then conducted under intentionally misspecified structural or stochastic assumptions, including time-varying elimination, compartmental misspecification, and residual error misspecification. Across these scenarios, the estimated system-noise parameter was generally sensitive to misspecification, with larger values usually associated with greater structural or stochastic mismatch. SDE-based modeling also helped partially separate system-level variability from residual variability and, in selected settings, supported localization of misspecification to specific model components, thereby helping guide model refinement. Overall, SDE-based popPK modeling is a useful addition to the pharmacometric diagnostic toolbox, with system-noise estimates best interpreted together with structural model evaluation, residual diagnostics, parameter behavior, and pharmacologic plausibility.

pharmacology and toxicology↗

bioRxiv2026

Differential Transcript Usage Reveals Isoform-Level Remodeling of Tumor Biology in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by transcriptional reprogramming driven by hypoxia signaling, metabolic rewiring, and immune modulation. While gene-level analyses have defined key features of ccRCC biology, they do not capture isoform-level variation arising from alternative splicing. Differential transcript usage (DTU) represents an additional regulatory layer that may influence protein function, pathway activity, and clinical outcomes, yet its role in ccRCC biology and prognosis remains incompletely understood. We assessed differential expression in 127 ccRCC tumors and 33 normal-adjacent tissues from the Dartmouth Cancer Center cohort, with external validation in 94 CPTAC tumors, adjusting for cell-type proportions. DTU was identified using DRIMSeq/stageR, followed by limmavoom modeling with clinical and tumor microenvironment covariates. Transcript-based consensus clustering defined tumor subgroups, and Cox proportional hazards modeling integrated transcript-level features with clinical variables. In tumor versus normal comparisons, 1,170 transcripts exhibited significant differential usage, mapping to canonical ccRCC pathways with distinct patterns across functional and non-functional transcript classes. Consensus clustering based on transcript us-age identified two subgroups with distinct angiogenic profiles and significant survival differences. Cluster-level analysis revealed DTU in genes involved in cytoskeletal organization (ACTB), immune processes (B2M), extracellular matrix organization (FN1, APLP2), and iron metabolism (FTH1) with protein domain alterations, including the loss of actin-associated domains in ACTB and immunoglobulin-like domains in B2M. Prognostic modeling identified twelve transcripts consistently retained across bootstraps, improving risk stratification over clinical variables alone. External validation confirmed overlapping prognostic transcripts, including FGFR1 and NUCB1. Isoform-level features may serve as biomarkers and therapeutic targets in ccRCC. Statement of significanceTranscript-level analysis uncovers potential regulatory pathways in ccRCC missed by gene-level approaches, revealing isoform-specific alterations that define survival sub-groups and offer potential biomarkers and therapeutic targets.

cancer biology↗

bioRxiv2026

A Sandwich-Structured Silk Fibroin Mesh with ROS-Responsive and Immunoregulatory Functions for Pelvic Floor Repair

Current biodegradable meshes for pelvic floor repair are constrained by a limited ability to actively modulate the hostile immune microenvironment following implantation. To address these challenges, we developed a functionalized degradable silk fibroin mesh (SFM) integrated with a reactive oxygen species (ROS)-responsive nanocomposite hydrogel. The resulting composite mesh, SFM@Gel-NP, features a "hydrogel-mesh-hydrogel" sandwich structure, wherein the hydrogel layers are loaded with self-assembled nanoparticles (NP-H-CRFP) for the co-delivery of the STING inhibitor H-151 and the ROS-scavenging agent catechin. This design provides immediate mechanical reinforcement while enabling microenvironment-triggered drug release. In vitro, NP-H-CRFP demonstrated efficient cellular uptake, significant ROS clearance, and effective attenuation of macrophage inflammation and apoptosis. In vivo, SFM@Gel-NP remodeled the local immune milieu by inhibiting the ROS/cGAS-STING/NF-{kappa}B axis, thereby promoting a shift from pro-inflammatory M1 toward pro-regenerative M2 macrophage polarization. This immunomodulatory effect, coupled with enhanced and well-organized collagen deposition--particularly of early type III collagen--resulted in improved tissue integration and repair. This work presents a novel strategy that combines structural reinforcement with active immune regulation, offering a promising next-generation solution for durable and functional pelvic floor reconstruction.

bioengineering↗

bioRxiv2026

Molecular grammar of RNA m6A modification in ribonucleoprotein granules

Diverse RNA chemical modifications collectively regulate nearly all aspects of RNA metabolism. Among these, N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNAs. Recent studies have implicated m6A in the formation and regulation of ribonucleoprotein (RNP) granules--biomolecular condensates that organize RNA metabolism in space and time. However, the underlying biophysical mechanisms remain to be elucidated. Here, building on SMART, a single-molecule platform for quantitatively measuring RNP granule assembly across nanometer-to-mesoscale regimes, we develop SMART-epi to enable precise control of the m6A modification ratio. Using this approach, we show that physiological m6A levels inhibit YTHDF2 RNP granule assembly while directing specific RNA-RNA interaction architectures. Moreover, YTHDF1/2/3 exhibit distinct assembly kinetics, suggesting functional divergence. Together, these findings reveal a molecular grammar by which m6A modulates condensate dynamics and suggest that RNA modifications can encode regulatory information to tune RNP granule behavior, with potential implications for therapeutic intervention.

biophysics↗

bioRxiv2026

Exclusive liquid repellency isolation (ELRi) microliter scale isolation technique unmasks T-cell migration defects to CCL21 in pediatric asthma

Exclusive Liquid Repellency Isolation (ELRi) is a novel, chip-free platform designed for efficient microscale immune cell isolation. Leveraging the inherent exclusive liquid repellency (ELR) properties of polypropylene tubes with an oil overlay, ELRi ensures that small sample volumes, as low as 8 L, have no contact with container walls, preventing cell loss. Here we describe ELRi and demonstrate magnetic bead-based isolation of diverse immune cells, including T cells, and monocytes, from whole blood. The platforms utility is highlighted in its application to pediatric asthma research, where sample volume is highly restricted. It has been reported that the T cell homing receptor CCR7 is downregulated in cells from asthmatic patients, but a direct functional link to impaired cell migration remains unconfirmed (1, 2). Using ELRi-isolated cells, we provide the first functional evidence that T cells from asthmatic children exhibit significantly impaired chemotaxis toward the CCR7 ligand, CCL21. By simplifying RBC depletion and enabling such functional assays alongside RNA sequencing from the same tiny sample, ELRi overcomes the limitations of large-volume flow cytometry or cell-specific sorting methods. Easily integrated into lab workflows and scalable for various needs, ELRi facilitates more frequent, minimally invasive, and functionally informative immune profiling of restricted volume samples.

immunology↗

bioRxiv2026

Human hindbrain organoids with segment-specific 5-HT neurons for motor modulation

The serotonergic system regulates human mood, reward, and motor control, and its impairment contributes to debilitating psychiatric disorders. Serotonergic neurons (SNs) arise predominantly in the hindbrain and acquire segment-specific identities and functions; however, the lack of human models remains a challenge to understanding the human serotonergic system. Here, we generate human serotonergic-enriched rostral and caudal hindbrain organoids (hsrHOs and hscHOs) that produce segment-specific SNs with regional identities corresponding to rhombomeres r2-r3 and r5-r8, respectively. hsrHOs and hscHOs produce SNs that recapitulate their in vivo counterparts in transcriptomic profiles, function, and ascending or descending projection preferences. Assembly with human neuromusculoskeletal organoids enables modeling of serotonergic modulation of motor control. This system further reveals that deficiency of the schizophrenia risk gene DISC1 disrupts human serotonergic development and impairs motor modulation. Together, our study establishes a human organoid platform for modeling development, circuit function and disease-associated dysfunction of the serotonergic modulatory system.

neuroscience↗

bioRxiv2026

HESTA: a curated and reusable database for the human early organogenesis spatiotemporal transcriptome atlas

BackgroundHuman organogenesis is orchestrated by precise spatiotemporal gene expression. Mapping these dynamic processes requires transcriptomic data that preserve native anatomical context across continuous developmental stages. FindingsWe present a spatiotemporal transcriptome database of human embryogenesis, profiling 77 sagittal sections from 13 euploid embryos (CS12-CS23) using Stereo-seq, yielding 14,708,858 bin50 spots. The atlas annotates 50 organs and maps 198 molecularly distinct substructures, complemented by 607,093 snRNA-seq cells. The database features a Spatial Exploration module for locating sections and visualizing spatial distributions of organs and substructures, and an Organ Atlas module for visualizing gene expression, regulon activities, and pathway enrichment at the single-organ level across stages. ConclusionsThis database provides an interactive resource to access spatial gene expression, substructures, and regulatory networks across 50 developing human organs, supporting further research into the mechanisms of human organogenesis.

bioinformatics↗

bioRxiv2026

UcTCRp: a TCRβ-based framework for quantitative MAIT- and iNKT-associated repertoire-state profiling

MAIT and iNKT cells are conventionally identified using invariant or semi-invariant TCR chains, antigen-loaded tetramers, or transcriptomic phenotypes. These requirements limit their detection in public and clinical immune-repertoire datasets that contain only TCR{beta} sequences. Here we present UcTCRp, a TCR{beta}-only framework for profiling MAIT- and iNKT-associated repertoire states in bulk immune repertoires. UcTCRp integrates V-gene context and CDR3{beta} sequence features using a transformer-based representation pretrained on more than one million TCR{beta} sequences and supervised with curated cross-species MAIT, iNKT and conventional T cell references. The framework defines conserved model-informative TCR{beta} features, uses V-matched negative sampling to reduce germline-segment shortcuts, and generalizes across independent human and mouse datasets. In paired scRNA-seq/scTCR-seq datasets, UcTCRp recovered transcriptome-defined MAIT and iNKT cells and identified additional MAIT-like candidates supported by receptor evidence but missed by expression-only annotation. Bulk calibration against paired single-cell references and synthetic spike-in experiments established operating characteristics for repertoire-level abundance estimation. These results establish unpaired TCR{beta} repertoires as an actionable substrate for reconstructing unconventional T cell-associated immune states, enabling archived repertoire resources to be repurposed for systems-level studies of tissue immunity, disease and therapeutic response.

bioinformatics↗

bioRxiv2026

SOX8-USP7-PGC-1α axis enhances thermogenesis in brown adipocytes

Obesity is one of the most prevalent diseases worldwide. Increasing thermogenesis to enhance energy expenditure has emerged as a promising therapeutic strategy. In an effort to identify new regulatory targets in thermogenic adipocytes, we found that SOX8 is correlated with obesity and serves as a novel marker of classical brown adipocytes in both humans and mice, upregulating during acute cold exposure. Functional studies further demonstrated that adipocyte-specific knockdown of SOX8 leads to obesity and metabolic dysfunction in mice. Mechanistically, SOX8 directly interacts with USP7 and stabilizes PGC-1 by reducing its K48-linked polyubiquitination. AAV-Rec2-mediated SOX8 overexpression initially enhanced energy expenditure, improved insulin sensitivity, and alleviated metabolic dysfunction in HFD-fed mice. However, prolonged SOX8 overexpression induced compensatory metabolic maladaptation, characterized by reduced energy expenditure, impaired glucose homeostasis, and mitochondrial structural disruption. These findings reveal a novel SOX8-USP7-PGC-1 regulatory axis in brown adipocytes, and reveal a previously unrecognized time-dependent effect of sustained thermogenic activation, highlighting SOX8 as a promising therapeutic target for obesity and metabolic syndrome.

cell biology↗

bioRxiv2026

ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity

B cell activation and differentiation into antibody-secreting cells require extensive metabolic and epigenetic remodeling, yet the molecular mechanisms that integrate these programs remain incompletely understood. ATP-citrate lyase (ACLY) links glucose metabolism to acetyl-CoA production, supporting lipid biosynthesis and protein acetylation. However, its role in humoral immunity has not been fully defined. Here, using genetic and integrated multi-omics approaches, we show that B cell activation is accompanied by coordinated metabolic, transcriptional, and epigenetic reprograming. Although ACLY is dispensable for B cell development and homeostasis, it is required to establish chromatin accessibility programs in activated B cells, with a more pronounced impact on the epigenetic landscape than on transcriptional output. ACLY-deficient B cells exhibit profound defects in TLR and BCR elicited activation, survival and metabolic fitness ex vivo. In vivo, B cell-intrinsic loss of ACLY results in impaired antigen-specific antibody production, associated with reduced germinal center and plasmablast formation, but normal homeostatic proliferation. Deletion of ACLY after B cell activation reduces plasmablast generation in vivo, indicating a continued requirement for ACLY beyond the initial activation phase. Together, these findings identify ACLY as a central regulator that links metabolism to epigenetic programing that supports B cell activation and humoral immunity.

immunology↗

bioRxiv2026

Distinct effects of hypomorphic IFT and dynein-2 skeletal ciliopathy disease alleles on chondrogenic differentiation, ECM composition and wnt signalling in ATDC5 derived cartilage-like organoids

Dysfunction of ciliary intraflagellar transport (IFT) and dynein-2 genes causes severe developmental defects, including skeletal phenotypes characterized by shortened ribs and long bones and polydactyly. Specific gene-phenotype associations suggest individual functions of the different IFT/dynein-2 proteins in development. Since null models disrupt ciliogenesis and hence are not suitable to study individual protein functions, we recreated human hypomorphic disease alleles in IFT-A (IFT43 p.M1V), IFT-B (IFT74 deletion of exon 2), and dynein-2 (WDR60 p.A911V), alongside a WDR60 null model in ATDC5 chondrocyte precursor cells. Hypomorphic mutants did not show alterations in ciliation efficiency or cilia length but displayed distinct defects in IFT88 localization, indicating impaired intraflagellar transport. Despite altered IFT, Hedgehog signalling responses were variably affected across the different genotypes. Transcriptomic analysis revealed concurrent increases in canonical Wnt signalling and expression of genes related to late skeletal development in WDR60 A911V and IFT74 del ex 2 mutants, but not in IFT43 M1V or WDR60 loss-of-function mutants. These changes were accompanied by alterations in ECM composition. In addition, all hypomorphic mutants showed reduced levels of the non-canonical Wnt ligand WNT5A in ECM proteomic analyses. Interestingly, loss of cilia in WDR60 loss-of-function mutants had only modest effects on chondrogenic differentiation and ECM composition. Overall, our data provide new evidence of genotype-dependent altered ECM composition as well as dysregulation of canonical and non-canonical Wnt signalling and accelerated chondrocyte differentiation in skeletal ciliopathies. Furthermore, our findings suggest a modulatory rather than essential role of the primary cilium for ATDC5 cell differentiation.

cell biology↗

bioRxiv2026

Ferrous Iron Accumulation Is a Hallmark and Therapeutic Vulnerability of Therapy-Induced Senescence

Chemotherapy and radiation reduce tumor burden but leave behind residual cells that survive via therapy-induced senescence (TIS). These cells constitute a latent reservoir fueling recurrence, yet strategies for their selective elimination are lacking. Here, we identify lysosomal ferrous iron accumulation as a conserved hallmark and actionable vulnerability of TIS tumor cells. Across diverse models, senescent tumor cells exhibit marked hypersensitivity to ferroptosis induction. In breast cancer PDX models, sequential ferroptosis induction following chemotherapy significantly delays recurrence, while dual inhibition of GPX4 and FSP1 produces durable, often complete, eradication of residual tumors without overt toxicity. Mechanistically, activation of the TFEB-HO-1 axis in TIS tumor cells drives ferrous iron accumulation, thereby priming cells for ferroptosis. Together, these findings establish ferrous iron accumulation as a defining feature of TIS and position ferroptosis induction as a potent senolytic strategy to eliminate therapy-refractory residual disease. Statement of significanceSenescent tumor cells remaining after treatment can drive cancer recurrence yet remain poorly understood and therapeutically intractable. Here, we identify lysosomal ferrous iron accumulation as a universal hallmark of therapy-induced senescence and demonstrate that ferroptosis induction functions as an effective senolytic strategy. Our findings provide mechanistic and translational support for the "one-two punch" therapeutic paradigm.

cancer biology↗

bioRxiv2026

Probabilistic spike propagation shapes sympathetic output in mouse preganglionic neurons

Sympathetic preganglionic neurons (SPNs) provide the final pathway through which the central nervous system regulates autonomic function. SPN axons projecting to paravertebral sympathetic chain ganglia branch extensively and diverge across multiple segments, enabling amplification of central sympathetic commands through extensive postganglionic neuronal populations. Spike propagation along these projections has generally been assumed to occur reliably. However, most SPN axons are extremely small unmyelinated fibers, a structural feature predicted to reduce the safety factor for spike propagation. Using an isolated mouse thoracic sympathetic chain preparation, we combined anatomical tracing with multi-site compound action potential recordings to assess conduction across SPN axons. Neurobiotin labeling revealed widespread rostrocaudal divergence through interganglionic nerves, while axon measurements confirmed that most SPN axons are small unmyelinated fibers. Across preparations, supramaximal recruitment of SPNs revealed substantial intertrial variability in compound responses, indicating frequent conduction failures. Failures were most prominent in slow-conducting axons and occurred in both branching interganglionic pathways and the unbranching axons within the splanchnic nerve. During repetitive activation, frequency dependent depression was observed at 1, 5 and 10Hz, but only slow-conducting branching axons exhibited pronounced depression. Overall, these findings indicate that spike propagation in SPN axons may operate probabilistically rather than deterministically, with reliability strongly dependent on axonal subtype and recent activity history. We conclude that axonal conduction variability constitutes an intrinsic and dynamically regulated mechanism that shapes sympathetic output. By varying the recruitment of postganglionic populations, unreliable spike propagation in SPN axons introduces a previously unrecognized presynaptic gain-control mechanism, operating independently of central spike generation to modulate sympathetic output. SIGNIFICANCESympathetic preganglionic neurons provide the final pathway through which the central nervous system controls end-organs. These neurons project through the sympathetic chain where their axons branch extensively to recruit more numerous paravertebral postganglionic neurons. Spike propagation along these projections has generally been assumed to occur reliably. Here we show that this assumption is incorrect. Using anatomical tracing and electrophysiological recordings in mouse sympathetic chain preparations, we demonstrate that spike conduction in sympathetic preganglionic axons is frequently variable and prone to failure, particularly in the slowest-conducting unmyelinated fibers. Conduction variability was preferentially enhanced in branching axonal pathways during repetitive activation. These findings reveal that axonal conduction reliability represents an important presynaptic mechanism regulating the magnitude and variability of sympathetic output.

neuroscience↗

bioRxiv2026

Disease-specific differences in particulate matter handling drive pathogenic responses in human derived nasal epithelial cells

BackgroundParticulate matter (PM) exposure is associated with increased risk and exacerbation of chronic rhinosinusitis (CRS), yet underlying mechanisms remain poorly understood. ObjectiveTo define the epithelial mechanisms by which PM exposure promotes and exacerbates CRS, with a focus on epithelial remodeling, inflammation, barrier dysfunction, and cellular uptake of PM. MethodsHuman nasal epithelial cells obtained from ethmoid tissue of CRS (n = 5) and control donors (n = 4) were cultured at an air-liquid interface and exposed to PM. Single-cell RNA sequencing was performed to characterize PM-induced cellular and transcriptional changes. Protein expression, epithelial barrier integrity, cell death, and intracellular PM uptake were evaluated using biochemical, imaging, and ultrastructural approaches. ResultsUnsupervised clustering identified seven epithelial cell populations. Gene set analysis revealed baseline enrichment of inflammatory and keratinization pathways and reduced ciliogenesis in CRS compared with controls. Although PM induced inflammation and squamous differentiation in controls, the pathogenic responses were significantly amplified in CRS, including uniquely enhanced IL-1 signaling. Transcriptional changes were validated by ELISA, transepithelial electrical resistance, and immunofluorescence, demonstrating increased inflammation, epithelial barrier disruption, and cell death following PM exposure. Transmission electron microscopy revealed increased intracellular PM within membrane-bound organelles. Pre-treatment with an endocytosis inhibitor rescued PM-induced epithelial barrier dysfunction and inflammation. ConclusionCRS epithelium exhibits baseline dysfunction that may predispose it to environmental injury. PM exposure both induces CRS-like epithelial changes in controls and exacerbates disease-associated phenotypes. Key MessagesO_LICompared to controls, CRS nasal epithelium exhibits baseline inflammatory, keratinization, and ciliogenesis abnormalities. C_LIO_LIParticulate matter induces inflammation and squamous differentiation, while amplifying epithelial injury that is more robust in CRS epithelium compared to controls. C_LIO_LIInhibition of dynamin-dependent endocytosis rescues PM-induced epithelial barrier leakiness and inflammation, implicating intracellular particulate matter uptake in disease pathogenesis. C_LI Capsule SummaryParticulate matter induces CRS-like epithelial remodeling in controls and exacerbates inflammation and epithelial barrier dysfunction in CRS nasal epithelium, which can be rescued with endocytosis inhibition. This suggests a mechanistic link between baseline CRS vulnerability, intracellular uptake of particulate matter, and disease pathogenesis.

cell biology↗

bioRxiv2026

Toward CT-based Tractography: Presurgical White Matter Tract Mapping in Intracerebral Hemorrhage

Presurgical mapping of key white matter (WM) fiber tracts is crucial for intracerebral hemorrhage (ICH) surgery, but it currently relies on tractography from diffusion MRI (dMRI), which has limited applicability in urgent or resource-constrained settings due to long scan times and limited MRI availability. To bridge this gap, we developed a deep learning approach designed to reconstruct critical fiber tracts directly from routinely acquired CT scans, focusing on the corticospinal tract (CST) due to its high clinical relevance. By training a novel network on a curated dataset of 150 paired CT-dMRI scans (101 ICH patients and 49 healthy subjects), we enabled the direct mapping of the CST from CT images alone, bypassing the traditional requirement for dMRI. Our results demonstrate that the CT-derived tracts achieve high anatomical plausibility, with neurosurgeon expert assessments yielding a Likert score of 3.64. Furthermore, the clinical relevance of these reconstructions was validated by a significant correlation between CT-derived tract integrity and patient motor scores (r = 0.726, p = 3.731x 10-7). These findings suggest that in complex clinical scenarios, particularly where dMRI signal quality is compromised by lesion-induced distortion, this CT-based mapping may serve as a useful anatomical reference. Overall, by enabling CT-based WM mapping, our method potentially offers a practical route to gain the key advantages of tractography in resource-limited or time-critical settings

neuroscience↗