Biology subjects

Wei, X.

Publications and source records attributed to Wei, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Multiscale transcriptomic organization of the human brain with DigitalBrain

The human brain varies across anatomical regions, cell types, development, aging and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, highlighted dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate that DigitalBrain is a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.

bioinformatics↗

bioRxiv2026

Strong inhibition of insulin/IGF-1 signaling in early-mid adulthood compresses morbidity, but in later life accelerates aging

Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans. However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover, life-extension by IIS reduction is particularly inter-individually variable within populations, confounding efforts to understand the intra-individual biology of such interventions. Here, we performed a longitudinal investigation at individual nematode resolution, of IIS reduction on aging-related health and lifespan, through temporally-controlled auxin-induced degradation (AID) of the DAF-2 insulin/IGF-1 receptor. Our results show how inter-individual variation in aging rate within control populations explains the complex demographic effects of age-specific DAF-2 AID on population lifespan. Strikingly, adult-limited IIS reduction causes an inter-individually homogeneous increase in lifespan (reducing Gompertz rather than {beta}) that is driven by healthspan expansion and compression of morbidity. Unexpectedly, cessation of DAF-2 AID in decrepit elderly individuals rejuvenates locomotory capacity and extends lifespan, showing that higher levels of IIS are optimal for health and survival towards the end of life. We also document a memory effect of transient IIS reduction during early adulthood, that is sufficient to fully extend lifespan (+189% median lifespan). Together, these findings demonstrate that both lifespan and healthspan can be maximized by appropriate temporal and directional modulation of IIS.

genetics↗

bioRxiv2026

General, orders-of-magnitude faster whole-genome analysis with genotype representation graphs

Whole-genome sequencing (WGS) of biobank-scale cohorts have generated datasets that traditional tabular genotype formats cannot efficiently store or analyze. Genotype Representation Graphs (GRGs) offer a compelling alternative: a biologically-motivated, hierarchical, graph-based representation that compactly and losslessly encodes the genotypes, and that supports computation directly on the graph rather than on a materialized genotype matrix. Here we introduce two advances that together make GRG a practical foundation for biobank-scale population and statistical genetics. First, we present GRG v2, a substantially improved format and construction algorithm that reduces construction time by 10-20x, halves the disk and RAM footprint of the resulting files, and improves load time by more than 20x. Applied to the recently phased UK Biobank WGS dataset (490,541 individuals, 706,556,181 variants), GRG v2 produces files 25 times smaller than .vcf.gz and more than 8 times smaller than PLINK2s PGEN format, while costing less than 90 GBP to construct. Second, we introduce grapp, a Python library and command-line tool that exploits the computational advantages of GRG for both routine analyses and new method development. grapp provides standard pipelines for variant and sample filtering, genome-wide association studies (GWAS) with covariates, principal component analysis (PCA), and data export, all implemented as graph-based operations. Moreover, it provides linear operators that integrate with the numpy and scipy sparse linear algebra ecosystem, enabling implicit matrix multiplication against the standardized genotype matrix, the linkage disequilibrium matrix, and the genetic relatedness matrix all via an underlying GRG. Using these operators, scipy-based PCA can be implemented in four lines of Python and runs 51-492x faster than existing methods while using less RAM. PCA on 89,988,512 variants in the UK Biobank runs in two to four hours. This scalability allows us to introduce a leave-one-chromosome-out (LOCO) approach to GWAS covariate construction that avoids LD artifacts without requiring LD pruning. Together, GRG v2 and grapp enable a level of scalability and methodological flexibility that is not achievable with traditional genotype formats.

genetics↗

bioRxiv2026

Quinone reductase 2 reads H3 serotonylation to support neuronal maturation

Histone H3 Gln5 serotonylation (H3Q5ser) is a recently described posttranslational modification1 that plays important roles in guiding transcriptional permissiveness in brain and peripheral systems2-5. H3Q5ser has been implicated in diverse physiological and pathological processes ranging from neural differentiation1 to sensory processing6, circadian rhythmicity7, stress responsivity8, placental gene regulation9, and tumorigenesis10-19. Since H3Q5ser can occur in combination with H3 Lys4 trimethylation (H3K4me3), most mechanistic studies to date have focused on H3Q5sers roles in modulating H3K4me3 reader interactions, where it has been shown to potentiate TAF3/TFIID binding to H3K4me31,20,21 and inhibit the recruitment of K4me3 demethylases21; however, whether H3 serotonylation functions as an autonomous chromatin signaling mark through dedicated reader proteins has remained unknown. Here, using a combination of proteomic-, structural-, molecular-, epigenomic-, and cellular-based approaches, we demonstrate that the Quinone reductase 2 (QR2) enzyme reads H3Q5ser independently of H3K4me3. CRISPR-Cas9-mediated disruption of H3 serotonylation or QR2s binding to the mark in human induced pluripotent stem cell-derived neurons impairs the establishment of neuronal transcriptional programs, alters synaptic connectivity, and disrupts electrophysiological maturation. These findings thus uncover an H3 serotonylation-dependent chromatin signaling axis that is essential for human neurodevelopment.

molecular biology↗

bioRxiv2026

Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease

Alzheimers disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2s function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology.

systems biology↗

bioRxiv2026

A conserved node degree-based backbone and flexible hub organization of brain connectome underlying naturalistic movie watching

How does the brain organize and transmit information during naturalistic conditions? Using large-scale movie-watching fMRI data spanning 14 diverse clips, validated in an independent dataset, we revealed a degree-based dual architecture of the functional connectome under naturalistic stimuli. During movie watching, the brain consistently expresses a conserved network backbone characterized by persistently high node degree in temporal and occipital sensory cortices and parietal association regions, whereas anterior higher-order cognitive regions show relatively lower node degree and substantially greater variability across different clips. We further found that this backbone links brain network organizational patterns to stimulus features of the clips, particularly audiovisual features capturing human presence and social communication. Within this backbone, subregions in superior temporal gyrus (STG), temporo-parieto-occipital junction (TPOJ), precuneus/posterior cingulate cortex, intraparietal sulcus (IPS), dorsal/ventral visual stream (DVS/VVS), and middle temporal visual and motion-sensitive areas (MT+) frequently emerge as connetome hubs, statistically mediating associations between multiple stimulus features and the integration of distinct large-scale functional systems. This study demonstrated a mechanistic framework in which movie watching relies on a conserved network backbone for stable large-scale integration, alongside stimulus-dependent rich-club hubs that flexibly mediate naturalistic information across distributed cortical systems.

neuroscience↗

bioRxiv2026

Exploiting HLA-II Promiscuity via Peptide Terminal Overhang Recognition for Pan-Allelic and Tumor-Selective AML Immunotherapy

Antibodies targeting peptides presented by human leukocyte antigen (HLA) molecules expand the therapeutic landscape by enabling recognition of intracellular antigens. While most efforts have focused on allele-restricted peptides presented by HLA class I (HLA-I), HLA class II (HLA-II) epitopes remain underexplored despite their potential for promiscuous presentation. Acute myeloid leukemia (AML) is characterized by high expression of both HLA-II and the myeloid lineage antigen myeloperoxidase (MPO). Here, we identified an MPO-derived epitope (MPO100-132) that is promiscuously presented by multiple HLA-II molecules. We generated a MPO100-132-specific antibody (146D5) that recognizes the N-terminal overhang of this peptide independent of specific HLA contacts, enabling pan-allelic recognition. Engineered into bispecific T cell engagers (BiTEs), this antibody mediated robust cytotoxicity against primary AML samples across diverse HLA-II backgrounds. Crucially, 146D5-based BiTEs selectively spared normal myeloid cells, indicating that the MPO100-132 peptide, derived from the MPO propeptide, was functionally undetectable in normal myeloid cells, providing a significant safety window. In vivo, the MPO-targeting BiTE demonstrated potent antitumor activity and prolonged survival in AML xenograft models. Our findings identify peptide terminal overhangs as an actionable class of antibody targets and introduce a strategy to exploit HLA-II promiscuity for broadly applicable HLA-dependent but allele-agnostic immunotherapies.

immunology↗

bioRxiv2026

Connectome lateralization in autism across the first 14 years: heterogeneity related to developmental stage, hemisphere, and pathophysiology

Hemispheric lateralization is fundamental feature to neurodevelopment, yet its dynamic evolution in autism across childhood and underlying molecular mechanisms remain unknown. Thus, using a large-scale resting-state fMRI dataset (n = 1553, ages 1-14), we investigated developmental heterogeneity in connectome lateralization. At the group level, abnormalities in dynamic connectome lateralization strength (DCLS) progressed from focal patterns in early childhood ([≤] 6 years) to widespread distributions by late childhood ([≤] 14 years), independent of symptom severity. The late-stage patterns were validated using the ABIDE dataset (n=153). Late childhood also showed marked increases in inter-individual heterogeneity. These alterations were significantly associated with clinical phenotypes, transcriptomic profiles, and multiple neurotransmitter systems, with distinct patterns across childhood groups. Our findings reveal a developmentally dynamic trajectory of connectome lateralization in autism and highlight late childhood as a critical window for stage- and individual-specific interventions tailored to substantial individual heterogeneity.

neuroscience↗

bioRxiv2026

Microhomology-Mediated Tandem Duplication Drives Tandem Repeat Formation Across Life

Tandem repeats (TR) are common genomic elements that are highly variable and with major functional consequences. Yet, the evolutionary trajectory for their formation remains poorly understood. One proposed mechanism is microhomology-mediated tandem duplication (MTD), in which single-copy DNA segments flanked by microhomology undergo tandem duplication (TD) and can further expand into TRs. Although MTD was first identified in the fission yeast Schizosaccharomyces pombe, its universal occurrence and postulated role in TR evolution have not been established. Using whole-genome deep sequencing and new analytical tools, we show that MTDs occur de novo universally across bacteria, archaea, fungi, and viruses. Further analysis of 2,245 reference genomes and millions of isolate genomes from 103 prokaryotic and eukaryotic microbial species, combined with human population TD data, somatic-germline mutations, and disease-associated variants, reveals that MTDs are consistently the dominant TD-forming mechanism across domains of life. Evidence suggests that MTDs have initiated the formation of the majority of existing TRs in genomes. Importantly, MTDs also prevail in human pathogenic TR mutations, including those linked to cancers. Mechanistically, deletion of the conserved mutator gene Rad27 specifically increased de novo MTD frequency in the budding yeast Saccharomyces cerevisiae, implicating Rad27-mediated Okazaki fragment maturation in MTD formation. These findings establish MTD as a universal and functionally significant mechanism for TR genesis. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/708716v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@db9ff1org.highwire.dtl.DTLVardef@e1a14corg.highwire.dtl.DTLVardef@124be79org.highwire.dtl.DTLVardef@15531ea_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementMicrohomology-mediated tandem duplications (MTDs) represent a universal mechanism driving tandem repeat formation across all domains of life--from viruses to humans. These duplications initiate genome evolution by expanding into functional tandem repeats and are the predominant form of pathogenic tandem duplications in human cancers and heritable disorders. Critically, disruption of the conserved Okazaki fragment processing pathway promotes MTD formation, establishing a fundamental link between DNA replication fidelity and genomic plasticity.

microbiology↗

bioRxiv2026

Cell Type Architecture and Positional Gene Gradients in an Adult Animal at Subcellular Resolution

The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3, ptpn11, pi4ka, upf3b, and cul1, revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

developmental biology↗

bioRxiv2026

4D Single-Cell Spatial Transcriptomics Reveals Dynamic Morphogenetic Gradients and Regenerative Domains in Planarians

Regeneration relies on precise spatiotemporal gene expression and cellular responses to establish tissue identity and body patterning. Using high-resolution Stereo-seq (715 nm) on 353 sections from 16 whole animals at 8 regeneration timepoints, we constructed a 4D spatiotemporal transcriptomic map of planarian regeneration. Our analysis captured 36 refined cell types from 3,508,004 segmented cells, enabling genome-wide transcriptional imputation of gene expression dynamics across body axes at cellular, tissue, and organismal scales. We identified dynamic positional gradients and distinct spatially distributed cell types during regeneration, including an injury-induced Anterior Regenerative Zone (ARZ). The ARZ exhibited enriched positional signals in epidermal, muscle, and neural cells and was regulated by Mediator 8, which is crucial for polarity remodeling and blastema formation. This study provides a comprehensive spatial molecular and cellular map of regenerative processes, highlighting injury-induced spatial domains and key regulatory factors in planarian regeneration. We also provide an interactive web portal, offering a valuable resource for exploring and analyzing regeneration mechanisms in a spatiotemporal context.

developmental biology↗

bioRxiv2026

On-target toxicity of GSPT1 molecular glue degraders in mice

Thalidomide is teratogenic in humans but not in rodents due to species-specific differences in the sequence of Cereblon (CRBN), an E3 ubiquitin ligase targeted by thalidomide and its derivative molecular glue degraders (MGDs). This species divergence has hindered the accurate prediction of MGD-induced toxicities in standard laboratory animals. GSPT1 MGDs, such as CC-90009, have shown potent anticancer activities in preclinical models and leukemia patients; however, their clinical development was challenging due to severe adverse effects. This highlights the critical need to characterize on-target toxicities in relevant animal models to exploit the therapeutic safety of this class of MGDs. Here, we generated humanized CrbnV380E and CrbnV380E/I391V knock-in mouse strains, in combination with a degradation-resistant Gspt1G574N strain, to interrogate the in vivo on-target effects of CC-90009 and its analog CC-885. We found that targeted GSPT1 depletion in mice led to rapid mortality, preceded by multiple dysfunctions including intestinal obstruction, liver damage, splenic atrophy, and hematological abnormalities. Remarkably, these toxicities, along with the underlying transcriptional perturbations, were completely rescued by the undegradable Gspt1G574N mutant, establishing a definitive causal link between GSPT1 degradation and systemic injury. Induced proximity and degradation proteomic analyses revealed that GSPT1 loss triggered a secondary downregulation of many proteins, including MYC, PLK1 and CDK4, which were not directly recruited by these MGDs to CRBN. Collectively, our data define the in vivo on-target toxicities associated with endogenous GSPT1 degradation and provide a genetic framework to guide the preclinical safety evaluation of CRBN-based MGD therapeutics.

molecular biology↗

bioRxiv2026

The genetic repertoire of the deep sea: from sequence to structure and function

The deep sea as the largest and maybe most hostile environment on Earth is still underexplored especially regarding its genetic repertoire. Yet, previous work has revealed significant habitat-specific deep-sea biodiversity. Here, we present an integrated deep-sea genetic dataset comprising 502 million nonredundant genes from 2,138 samples and 2.4 million predicted structures, and used it to link specific protein structures with genetic variants associated with life in the deep sea and to assess their biotechnology potential. Combining global sequence analysis with biophysical and biochemical measurements revealed unprecedented sequence diversity, yet substantial structural conservation of proteins. Especially proteins involved in replication, recombination, and repair were identified to be under rapid evolution and with specialized properties. Among these, a structurally divergent helicase exhibited advantages in controlling nanopore sequencing speed. Thus, our work positions the deep sea as a unique evolutionary engine that generates and hosts genetic diversity and bridges genetic knowledge with biotechnology.

bioinformatics↗

bioRxiv2026

An immune-poised state of human bronchial epithelial cells mediates RSV resistance in adults

Respiratory syncytial virus (RSV) impairs STAT3 activation in infected ciliated cells in infants, but not adults, causing apoptosis to facilitate virus spread. How age regulates the STAT3 response to RSV in human bronchial epithelial cells (BEpiCs) is unknown. Here, we identify an age-associated immune-poised physiological state in human bronchial basal stem cells (BSCs) and progeny BEpiCs, rendering robust RIG-I to guard against the inactivation of RIG-I-STAT3 signaling by RSV nonstructural protein 2. In contrast, infant BEpiCs are vulnerable to such inactivation by RSV due to lower RIG-I levels. We show that acute respiratory viral infection in specific pathogen-free mice, rather than physical age, triggered sustained epigenetic and transcriptomic remodeling in BEpiCs that resembled age-associated changes in human BEpiCs. In addition, cytokine pretreatment of human neonatal BSCs induced an adult-like immune-poised state that was maintained in progeny BEpiCs to protect against RSV. Therefore, respiratory infection and inflammation during a lifetime imparts the effect of age to BSCs, which fortifies RIG-I in progeny cells to mediate RSV resistance.

microbiology↗

bioRxiv2026

Ultra-flexible PINE arrays for month-long, continuous intracellular ion flux monitoring in plants with nanomolar accuracy

High-precision in vivo monitoring of ion fluxes is essential yet challenging studying plant electrophysiology such as growth regulation, signal transduction and stress responses. Existing methods for probing ion dynamics are limited by low sensitivity, high invasiveness that interferes physiological processes, and the inability to accurately resolve ion homeostasis with required spatial and temporal resolution. Here, we introduce ultraflexible, plant implantable nanoelectrode (PINE) arrays manufactured on 1.2-m-thick polymer substrates, which enable ultrasensitive and selective measurement of ionic current for month-long via scalable nanofabrication techniques. The fabricated PINE arrays have a smaller dimension than typical plant cells as well as less stiffness, facilitating minimally invasive integration with living plant cells. This subcellular-scale plant-electronic interface allows for reliable, selective detection of K+ flux with a detection limit of [~]10- M, and thus allows continuous, stable monitoring of tomato stem cells over six weeks, capturing dynamic potassium fluctuations during all key growth stages. More importantly, the method permits long-term, real-time tracking of ion-specific dynamics without disrupting plant cellular structure or altering endogenous ion concentrations. Therefore, PINE provides unprecedented access to ion homeostasis and signaling networks, making it an excellent platform for precision agriculture and a foundational tool for future digital plant engineering.

plant biology↗

bioRxiv2026

Endothelial MRG15 Is a Mechanosensitive Suppressor of Atherosclerosis

Disturbed blood flow induces early endothelial inflammation in atherosclerosis, yet the precise mechanisms of endothelial sensing of disturbed flow remain incompletely understood. In this study, we integrated proteomic profiling of human endothelial cells (ECs) subjected to disturbed flow with coronary artery disease risk related genes from large-scale genome-wide association studies (GWAS). We identified mortality factor 4-like protein 1 (MORF4L1, also called MRG15) as a critical modulator in the pathogenesis of atherosclerosis induced by disturbed flow. We show that the expression of MRG15 is markedly reduced in ECs of human aortic atherosclerotic plaques, as well as in ECs exposed to disturbed flow in mouse carotid artery and in cultured human umbilical vein endothelial cells (HUVECs). Endothelial-specific deletion of Mrg15 significantly worsened, while its overexpression attenuated endothelial inflammation and atherosclerotic lesions in turbulent blood flow- or Western diet-induced mouse atherosclerosis model. Single-cell transcriptomics showed that Mrg15 deficiency increased endothelial inflammation and intercellular adhesion molecule 1 (Icam1) expression, and enhanced integrin-mediated adhesion pathways. Mechanistically, MRG15 facilitated the recruitment of enhancer of zeste homolog 2 (EZH2) to maintain repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on the promoters of ICAM1 and integrin subunit alpha 5 (ITGA5). Disturbed blood flow rapidly led to an elevation of protein neddylation, which subsequently induced neddylation-dependent degradation of MRG15 within endothelial cells. This degradation of MRG15 alleviated the transcriptional repression of ICAM1 and ITGA5, thereby enhancing monocyte adhesion to ECs. These findings highlight endothelial MRG15 as a mechanosensitive suppressor of atherosclerosis induced by disturbed flow. Consequently, MRG15 emerges as a promising novel therapeutic target for atherosclerosis.

molecular biology↗

bioRxiv2026

Hidden causal inference delineates dynamic lncRNA regulation in autism spectrum disorder

Long non-coding RNAs (lncRNAs) are increasingly implicated in autism spectrum disorder (ASD), yet their causal regulatory mechanisms remain poorly characterized. Conventional static causal inference methods fail to capture the dynamic interplay of lncRNAs across diverse brain biological contexts. Here, we develop a hidden causality-based method Clean to infer dynamic lncRNA causal regulation in ASD. Our analysis reveals that dark causality, representing a hybrid form of positive and negative interdependencies, dominates lncRNA-mediated regulation in ASD. Moreover, dynamic lncRNA causal regulation emerges in diverse brain biological contexts, and 14 ASD risk lncRNAs significantly contribute to disease pathogenesis through disrupted gene regulatory programs. We also illustrate that lncRNA expression signatures enable robust classification of sex and cell type, offering potential diagnostic lncRNA biomarkers. Notably, 20 immune-related lncRNAs are prominently involved in the immune, suggesting a potential role for neuroimmune regulation. Additionally, cell-cell interaction networks diverge substantially between ASD and Normal cohorts. This study establishes a paradigm for delineating the dynamic causal regulation of lncRNAs, underscoring their diagnostic and therapeutic potential in ASD.

bioinformatics↗

bioRxiv2026

IL-1α drives a tumor-stroma-neutrophil axis through inflammatory fibroblast activation in head and neck cancer

In head and neck squamous cell carcinoma (HNSCC), high tumor-associated neutrophil (TAN) density is a robust biomarker of poor prognosis. TANs predominantly localize to the stroma and their intratumoral density strongly correlates with adverse outcome. Here, we investigated how tumor-stroma communication regulates TAN recruitment, activation, and spatial organization. We identified interleukin-1 (IL-1), released by viable or necrotic tumor cells, as an upstream signal that induces an inflammatory cancer associated fibroblast (iCAF)-like transcriptional program in patient-derived mesenchymal stromal cells (MSCs) of the oral cavity. IL-1-stimulated MSCs secrete factors associated with neutrophil recruitment, survival, and function, together with mediators of extracellular matrix remodeling and angiogenesis. Notably, the IL-1-induced iCAF-like transcriptional program closely resembles CAF subsets in HNSCC that are associated with poor clinical outcome. Functionally, conditioned media from IL-1-stimulated MSCs promoted tumor growth and enhanced polymorphonuclear neutrophil survival, activation, trans-well migration and infiltration into spheroids, in vitro. In zebrafish xenografts, co-injection of IL-1-overexpressing tumor cells and MSCs markedly amplified neutrophil infiltration. TCGA analysis demonstrated robust correlations between the IL-1-induced MSC gene signature and neutrophil signatures across multiple TAN subsets in human HNSCC. Spatial analysis of HNSCC tissues showed that stromal regions adjacent to IL1A-positive tumor islets were enriched for CXCL8/CSF3 double-positive cells and exhibited increased TAN density, including higher frequencies of NE- and MPO-positive neutrophils. Collectively, these findings define an IL-1-dependent tumor-stroma signaling circuit that links tumor inflammation to stromal remodeling and neutrophil infiltration in HNSCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/700440v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@f8d282org.highwire.dtl.DTLVardef@1c4575aorg.highwire.dtl.DTLVardef@1430cfcorg.highwire.dtl.DTLVardef@1098887_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: IL-1 drives tumor-stroma communication and neutrophil recruitment in HNSCC. Here, we describe a mechanism in HNSCC that promotes high tumor-associated neutrophil (TAN) density, a biomarker associated with poor prognosis. Tumor-derived IL-1 activates stromal cells to adopt an inflammatory phenotype, resulting in the release of CXCL8, GM-CSF, and G-CSF to enhance neutrophil recruitment, activation, and survival. IL1A-positive tumor islets are surrounded by CXCL8/CSF3-rich stroma with elevated TAN densities in both tumor and stromal compartments. These TANs exhibit increased frequencies of MPO- and NE-positive cells, revealing a spatially organized inflammatory tumor microenvironment. Figure was created using BioRender. C_FIG

cancer biology↗