Biology subjects

Fan, J.

Publications and source records attributed to Fan, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗

bioRxiv2026

Neuronal EphB2 signaling drives persistent neuropathic pain following spinal cord injury

Neuropathic pain after spinal cord injury reflects persistent hyperexcitability in the spinal cord dorsal horn, yet the molecular drivers sustaining this maladaptive state are unknown. Using an antibody microarray of dorsal horn tissue from mice six weeks after cervical contusion spinal cord injury, we found persistent upregulation of Eph-ephrin signaling, including increased EphB1, EphB2 and EphB3 expression and phosphorylation. Reversible chemogenetic inhibition of EphB kinase activity, using an EphB1/2/3 analog-sensitive knock-in mouse, selectively reversed established mechanical allodynia without affecting thermal hyperalgesia or motor function and also shifted dorsal horn signaling away from pain sensitization-associated pathways. Among EphB receptors, EphB2 showed the most consistent and robust injury-induced increase in expression within dorsal horn. Although EphB2 transcript levels increased in both dorsal horn neurons and astrocytes, conditional deletion of EphB2 only in dorsal horn neurons, but not in astrocytes, reversed established mechanical allodynia and reduced dorsal horn neuronal activation. These findings identify EphB signaling, and neuronal EphB2 in particular, as a mechanism that actively maintains pain hypersensitivity after spinal cord injury.

neuroscience↗

bioRxiv2026

Gallium induces cytotoxicity through disruption of DNA synthesis rather than ferroptosis

BackgroundGallium (Ga) is a promising anti-tumor agent; however, its precise molecular targets in osteosarcoma remain debated. While current paradigms largely attribute its toxicity to reactive oxygen species (ROS) and ferroptosis, understanding its true mechanism is essential for overcoming therapeutic resistance. This highlights the need for interdisciplinary approaches, such as metabolomics, to unveil novel vulnerabilities in cancer metabolism. MethodsWe employed an interdisciplinary strategy utilizing high-resolution liquid chromatography-mass spectrometry (LC-MS) metabolomics and 13C2-glutamine stable isotope tracing in osteosarcoma cells to elucidate the cytotoxic mechanisms of gallium nitrate. Scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS) was utilized for elemental mapping, and in silico modeling was applied to evaluated metal binding dynamics. Furthermore, synergistic effects were tested by combining gallium with the DNA-damaging agent cisplatin. ResultsOur metabolic profiling revealed a profound bifurcation characterized by the systemic depletion of glycolysis and pentose phosphate pathway intermediates, coupled with a novel ribonucleotide accumulation bottleneck. The observed distinct signature strongly implicated ribonucleotide reductase (RNR) as the primary enzymatic target. In silico modeling and SEM-EDS visually and thermodynamically confirmedthat gallium acts as a structural decoy for iron within the RNR active site. The co-localization induces functional iron starvation rather than canonical ferroptosis. Furthermore, isotope tracing confirmed that elevated ROS is a consequence of overall metabolic failure, not the primary driver of cell death. Crucially, gallium functioned as a metabolic DNA repair inhibitor, synergizing potently with cisplatin to prevent the repair of platinum-induced DNA lesions. ConclusionsGallium selectively sensitizes highly proliferative sarcoma cells by disrupting RNR-mediated DNA precursor synthesis, while sparing normal osteoblasts. Leveraging metabolomics to uncover this state of functional iron starvation provides a rational, interdisciplinary framework for developing gallium-based combination therapies designed to break platinum resistance in clinical oncology.

cancer biology↗

bioRxiv2026

Discovery of metabolites produced by reactions between central carbon metabolites and cysteine that mark inflammatory macrophages

Identifying metabolites and metabolic reactions specific to a cellular state, such as inflammatory state in immune cells, is of great interest, as it can provide important biomarkers and point to compounds and reactions of specific biological functions. However, many cell state-specific metabolites remain in the unannotated part of metabolome. Here we identified a series of sulfur-containing metabolites that are actively produced in macrophages upon classical activation, but not in resting state or alternative activation state. Isotopic tracing, in vitro assays and genetic perturbations further revealed that they are formed from reactions between free cysteine and several important intermediates in glycolysis and TCA cycle. Upon classical activation, macrophages specifically upregulate the import of cystine via Slc7a11, supporting the production of these adducts. Their production dynamically responds to changes in central metabolism, environmental nutrient levels, and is regulated by nitric oxide. Finally, we confirmed these newly identified compounds also present in human samples, and most of them are significantly elevated in inflammatory granuloma annulare lesions. This work elucidated a previously uncharted part of metabolic network that is associated with inflammation and metabolic stress condition, which has important implications and set foundation for many future discoveries.

biochemistry↗

bioRxiv2026

scRGCL: Neighbor-Aware Graph Contrastive Learning for Robust Single-Cell Clustering

Accurate cell type identification is a fundamental step in single-cell RNA sequencing (scRNA-seq) data analysis, providing critical insights into cellular heterogeneity at high resolution. However, the high dimensionality, zero-inflated, and long-tailed distribution of scRNA-seq data pose significant computational challenges for conventional clustering approaches. Although recent deep learning-based methods utilize contrastive learning to joint-learn representations and clustering assignments, they often overlook cluster-level information, leading to suboptimal feature extraction for downstream tasks. To address these limitations, we propose scRGCL, a single-cell clustering method that learns a regularized representation guided by contrastive learning. Specifically, scRGCL captures the cell-type-associated expression structure by clustering similar cells together while ensuring consistency. For each sample, the model performs negative sampling by selecting cells from distinct clusters, thereby ensuring semantic dissimilarity between the target cell and its negative pairs. Moreover, scRGCL introduces a neighbor-aware re-weighting strategy that increases the contribution of samples from clusters closely related to the target. This mechanism prevents cells from the same category from being mistakenly pushed apart, effectively preserving intra-cluster compactness. Extensive experiments on fourteen public datasets demonstrate that scRGCL consistently outperforms state-of-the-art methods, as evidenced by significant improvements in normalized mutual information (NMI) and adjusted rand index (ARI). Moreover, ablation studies confirm that the integration of cluster-aware negative sampling and the neighbor-aware re-weighting module is essential for achieving high-fidelity clustering. By harmonizing cell-level contrast with cluster-level guidance, scRGCL provides a robust and scalable framework that advances the precision of automated cell-type discovery in increasingly complex single-cell landscapes. Key MessagesO_LIscRGCL uses contrastive learning on a regularized representation for single-cell clustering. C_LIO_LIscRGCL outperforms four state-of-the-art methods on 15 datasets. C_LIO_LIscRGCLs cluster-aware negative sampling and the neighbor-aware re-weighting modules are essential for high-fidelity single cell clustering. C_LI

bioinformatics↗

bioRxiv2026

The pyruvate branch point controls lymphoid cancer cell dissemination

Cancer cell dissemination critically determines clinical prognosis, yet metabolic dependencies and corresponding therapeutic targets during spread of lymphoid malignancies remain poorly understood. Here we show that the pyruvate branch point operates as a metabolic checkpoint for lymphoid cancer cell migration and disease dissemination through mitochondrial ROS (mROS)/HIF-1a signaling. Isolation of highly migratory mROShi cells led us to identify selective metabolic requirements of malignant lymphocyte migration and disease dissemination. Highly migratory cells show a reprogrammed metabolic profile characterized by increased glucose uptake and reduced glucose-carbon entry into the TCA cycle. Reprogramming of the TCA cycle with downregulation of citrate synthase provide the mechanistic basis for decreased pyruvate oxidation leading to increased migration and disease dissemination through mROS/HIF-1a signaling. Our findings connect central carbon metabolism and migratory capacity of lymphoid cancer cells and identify the pyruvate branch point as a metabolic switch and potential therapeutic target in lymphoid cancer cell dissemination.

cancer biology↗

bioRxiv2026

An enzymatic metabolic sensing axis in taste cells detects glucose-yielding carbohydrates

Glucose is a potent reinforcer of intake, yet most foods contain complex saccharides that do not yield free glucose until after digestion. How the oral sensory system rapidly evaluates the potential metabolic value of food remains unclear. Here, we identify an oral enzymatic-metabolic sensing mechanism that enables detection of glucose-yielding carbohydrates independent of canonical sweet taste receptors. Using genetic, virogenetic, molecular, and behavioral approaches in mice, we show that glucokinase (GCK) in taste cells is necessary for the attraction to glucose-containing sugars. We further demonstrate that maltase glucoamylase (MGAM), a glycosidic enzyme expressed on and near taste cells, facilitates rapid oral sugar sensing. Disruption of either GCK or MGAM in the major taste fields selectively attenuates the attraction to maltose and a carbohydrate-rich mixed diet, establishing both as intermediaries in the initial transduction pathway for complex saccharides that ultimately give rise to nutrient reward. Molecular profiling of taste papillae further revealed that deficient sweet sensing was accompanied by a compensatory increase in lingual MGAM, highlighting an adaptive mechanism for maintaining oral carbohydrate sensitivity. Together, these findings reveal that the oral epithelium actively preprocesses and metabolically evaluates dietary carbohydrates, providing a mechanism for rapid estimation of energetic value prior to ingestion. Significance StatementCarbohydrates strongly motivate eating, yet most are consumed in complex forms that do not immediately release glucose. We show that the oral epithelium contains an adaptive enzymatic-metabolic sensing system that enables rapid evaluation of glucose-yielding carbohydrates before digestion. Two enzymes, maltase glucoamylase and glucokinase, act locally in taste fields to preprocess and metabolically assess complex sugars, biasing ingestive behavior toward energetically favorable foods. This mechanism operates independently of canonical sweet taste receptors and is dynamically regulated by dietary experience and receptor sensitivity. These findings reveal that the mouth actively estimates the energetic value of food prior to ingestion, reshaping our understanding of how nutrient sensing guides dietary choice.

neuroscience↗

bioRxiv2026

SenCat: Cataloging human cell senescence through multiomic profiling of multiple senescent primary cell types

There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize senotypes and senescent cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed SenCat. We found that, while senescent cells from all primary tissue types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Machine learning analysis of the SenCat transcriptomic and proteomic datasets successfully identified independent sets of senescent human cells, and senescent-like cells in mouse lung and kidney. In sum, SenCat represents a much-needed resource to identify senescent cells across tissues in the body. HIGHLIGHTSO_LIIdentifying senescent cells in organisms in vivo remains a challenge C_LIO_LIWe created SenCat: a catalog transcriptomes and proteomes of senescent primary cells C_LIO_LIMachine learning (ML) analysis of SenCat identified robust senescence scores C_LIO_LIML-derived senescence scores uncovered senescent-like cell dynamics in vivo C_LI

molecular biology↗

bioRxiv2026

Active Site Local Environment Allows Acidic and Basic Synergy in Enzymatic Ester Hydrolysis by PETase

Polyethylene terephthalate (PET) is a commonly used plastic worldwide and reducing its prevalence is crucial to improving environmental pollution. PETase that degrades PET plastic have received a lot of attention recently. This paper evaluates the ester hydrolysis process under both acidic and basic conditions, and shows that the local environment of the protein active site takes advantage of both. High pH in the protein buffer creates a better nucleophile to attack the ester through a proton shuttle channel in the protein, while local hydrogen bonds to the carbonyl of the ester stabilizes the intermediate/transition state of the hydrolysis reaction. With the understanding at the atomic level, we propose two engineering directions that can potentially improve the reactivity of the PETase: 1) increase the alkaline stability of the protein in general; 2) perturb the local hydrogen bond network to increase the partial charge on the PET carbonyl to be hydrolyzed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/703441v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@151b69borg.highwire.dtl.DTLVardef@1abb95dorg.highwire.dtl.DTLVardef@116a225org.highwire.dtl.DTLVardef@ef2bb1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies

B cell-targeted therapies represent a transformative frontier for systemic lupus erythematosus (SLE) intervention, yet clinical recommendation of specific treatment is hampered by the challenge to perform head-to-head comparisons of efficacy-toxicity trade-offs and tissue-specific impacts in patients. To address this gap, an advanced Toll-like receptor 7 (TLR7) agonist-induced SLE model is developed in a NCG-M (NOD-Prkdcem26Cd52Il2rgem26Cd22Rosa26em1Cin(hCSF2&IL3&KITLG)/Gpt) human immune system (HIS) mice. This model enables parallel evaluation of multiple B cell-directed therapies within a controlled cohort study. It recapitulates core SLE pathologies--including immune effector cell augmentation, autoantibody production and glomerulonephritis--within 2 months, demonstrating greater severity and clinical fidelity than conventional pristane-induced systems. Validated through replication of clinical responses to rituximab and belimumab, the platform directly compares two emerging modalities: universal chimeric antigen receptor-T cells (UCAR-T) elicits delayed but profound B-cell reset correlating with superior reduction in renal pathology and autoantibodies, while T cell engagers (TCEs) mediate rapid yet partial B-cell depletion and transient efficacy. UCAR-T concurrently induces greater acute inflammatory responses, aligning with its distinct toxicity profile. By resolving therapy-specific effects on human immune dynamics and symptom control, this study empowers context-specific therapeutic selection for SLE, advancing tailored management strategies.

immunology↗

bioRxiv2026

BRD8 Disruption Unlocks Retrotransposon-Driven Tumor-Intrinsic Immunogenicity via Redistribution of Histone Acetylation in Liver Cancer

Overall response rate for immune checkpoint blockade (ICB) therapy remains limited in advanced hepatocellular carcinoma (HCC). Epigenetic perturbation has been shown to enhance tumor-intrinsic immunogenicity and thus reverse resistance to immunotherapy in multiple cancer types. Here, through domain-focused CRISPR/Cas9 genetic screens targeting chromatin regulators, we identified the bromodomain-containing protein 8 (BRD8) as a novel epigenetic factor that functions to suppress tumor-intrinsic immunity through BRD8/EP400 chromatin remodeling complex in HCC. Depletion of BRD8 potently induces anti-tumor immune responses and sensitizes tumors to ICB therapy in mouse tumor models. Mechanistically, BRD8 knockout leads to partial redistribution of H3K27ac to repetitive elements, activating double-stranded RNA (dsRNA) accumulation and subsequent type I interferon (IFN) response, leading to tumor rejection via remodeling the tumor microenvironment. The first-in-class selective chemical probe DN02 targeting the bromodomain of BRD8 also exhibits immunomodulatory and anti-tumor effects. In line with these findings, low BRD8 expression correlated with enriched interferon signatures, elevated immune cell infiltration, and prolonged survival in HCC patients. Together, this study reveals BRD8 as a selective epigenetic vulnerability for promoting tumor immunogenicity, and its bromodomain as a druggable target to overcome immunotherapy resistance in liver cancer patients. SignificanceThe induction of viral mimicry by epigenetic interference could trigger tumor-intrinsic immune response and enhance immunotherapy efficacy. Here, through domain-focused CRISPR/Cas9 screening, we identify BRD8 complex as a regulator involved in the suppression of repetitive elements by controlling H3K27ac distribution and propose BRD8 as a novel target to enhance anti-tumor immunity.

cancer biology↗

bioRxiv2026

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1 and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

cell biology↗

bioRxiv2026

Selective class IIa HDAC inhibition reverses diastolic dysfunction in cardiometabolic HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent cardiometabolic syndrome with yet no effective therapies. Here, we report that selectively class IIa histone deacetylases (HDACs) but no other classes of HDACs are enzymatically activated in hearts from HFpEF patients and cardiometabolic HFpEF animal models. Cell type-specific and enzymatic activity-specific genetic loss-of-function models of the cardiomyocyte-enriched class IIa HDAC family member HDAC4 and the pharmacological class IIa HDAC-selective inhibitor TMP195 prevent and reverse diastolic dysfunction and exercise intolerance in cardiometabolic HFpEF in vivo. In contrast to pan-HDAC inhibition no adverse effects are observed. Despite its well-known non-enzymatic role as transcriptional repressor, we found that specifically enzymatic activation of HDAC4 has little direct effects on cardiomyocyte-intrinsic gene expression. Instead, non-epigenetic actions lead to endothelial activation via altered cardiocrine signaling. We discovered that selective enzymatic class IIa HDAC inhibition is a new therapeutic concept to combat cardiac HFpEF.

molecular biology↗

bioRxiv2026

Membrane proteins retain native architecture through native ESI and soft-landing

Native MS offers a clear picture of membrane protein stoichiometry and interactions, but it lacks direct structural insights at high resolution. Here, we examine the extent to which solution-phase structure and architecture can be retained after native, soft-landing electrospray ion beam deposition (ESIBD) by interrogating several membrane-protein complexes of diverse folds and oligomeric states by cryoEM. The overall protein architectures with secondary structure motifs can be observed after gas-phase transfer, soft landing, and embedding in amorphous ice. Notably, we determined the structure of the ammonium transporter AmtB at sub-3 [A] resolution. It is nearly identical to the structure of the plunge-frozen control and even shows an extended C-terminal segment of AmtB, a dynamic region absent in the solution-phase structure. Our analysis shows that detergent adducts preserve membrane protein structure in vacuum by minimising destabilization of solvent-exposed regions and stabilization through additional polar contacts in vacuo. Molecular dynamics (MD) simulations support these results, suggesting that a monolayer shell of surfactant adducts avoids destabilization driven by unshielded polar residues and disruption of hydrogen bond networks. Overall, our findings provide a structural framework for integrating native MS with cryo-EM showing that gas-phase transfer and surfactant stabilisation preserves key architectural features and high-resolution structure of membrane proteins.

biophysics↗

bioRxiv2026

Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1

Nitric oxide (NO*) is an important signaling molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-{gamma} (IFN{gamma}), macrophages generate NO* via inducible nitric oxide synthase (iNOS). To comprehensively define the effects of NO*, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFN{gamma}-activation, with or without iNOS expression or exogenous NO* donor treatment. The results revealed NO* has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO*-dependent manner, electron transport chain (ETC) is the most enriched. NO* drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Functionally, we found NO* is required, but not sufficient, for the strong suppression of cellular respiration upon macrophage activation. Among the most consistently upregulated proteins are many enzymes involved in redox defense. AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO* and LPS/IFN{gamma} stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO*-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO*-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO*-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO*-dependent regulation, revealed the crosstalk between NO* and immune signaling, and demonstrated mechanisms providing redox adaptation and precise control of NO*s effects.

immunology↗

bioRxiv2025

Spatial Transcriptomics As Rasterized Image Tensors (STARIT) characterizes cell states with subcellular molecular heterogeneity

Abstract Imaging-based spatially resolved transcriptomics (imSRT) technologies provide high-throughput molecular-resolution spatial characterization of genes within cells. Conventional analysis methods to identify cell-types and states in imSRT data rely on gene count matrices derived from tallying the number of mRNA molecules detected for each gene per segmented cell, thereby overlooking subcellular heterogeneity that can be useful in defining cell states. To take advantage of the molecular-resolution information in imSRT data and potentially identify cell-states based on subcellular heterogeneity, we developed STARIT (Spatial Transcriptomics As Rasterized Image Tensors). STARIT converts transcripts within segmented cells in imSRT data into an image-based tensor representation that can be combined with deep learning computer vision models for downstream analysis. Using simulated and real imSRT data, we demonstrate that STARIT distinguishes transcriptionally distinct cell-types and further separates cell states based on subcellular transcript localization, which conventional gene count analysis fails to capture. By providing a standardized framework to encode subcellular molecular information in imSRT data, STARIT will enable deeper insights into subcellular heterogeneity and enhance the identification and characterization of cell-types and states that are overlooked by gene count representations.

bioinformatics↗

bioRxiv2025

Distributed fMRI patterns coupled to low-frequency cardiorespiratory dynamics provide markers of aging

How aging affects brain-body connections can be investigated through changes in the coupling between functional magnetic resonance imaging (fMRI) signals and bodily autonomic processes across the adult lifespan. Recent studies using univariate approaches have identified age-related changes in the association between fMRI signals from multiple individual brain regions and low-frequency respiratory and cardiac activity. Here, we investigate if whole-brain spatial fMRI patterns associated with low-frequency physiological processes (heart rate and respiratory volume fluctuations) present generalizable changes with age. Data from human participants of both sexes are included in the analysis. We find that chronological age can be predicted statistically beyond chance from patterns of low-frequency fMRI-physiology coupling, even after accounting for individual differences in physiological signal characteristics and brain anatomy. Notably, brain areas implicated in central autonomic regulation, including nodes within salience and ventral attention networks (e.g., insula and middle cingulate cortex), are amongst the strongest contributors to age prediction. Further, we observe that after removing physiological effects from fMRI data, the residual blood oxygen level-dependent (BOLD) signal variability is still a reliable indicator of age. Together, these findings underscore the close integration between brain and body physiology, and highlight this interaction as a potential biomarker of the aging process. Significance StatementThe association between brain activity and respiratory or cardiac activity is often dismissed as "noise" in functional magnetic resonance imaging (fMRI) studies. However, emerging evidence suggests that coupling between fMRI and peripheral physiological signals can provide valuable insight into the brain-body connection. In this study, we show that whole brain patterns of coupling between fMRI signals and low-frequency respiratory and cardiac processes can reliably predict age across the adult lifespan. Brain regions involved in autonomic regulation, such as insula and cingulate cortex, were among the most informative predictors of age. These findings suggest that fMRI-physiology coupling may capture aging-related changes in brain vascular health and autonomic function and may have broader relevance for tracking disease-related disruptions in brain-body interaction.

neuroscience↗

bioRxiv2025

STcompare: comparative spatial transcriptomics data analysis of structurally matched tissues to characterize differentially spatially patterned genes

MotivationComparative analysis of spatial transcriptomics (ST) data is needed to identify genes that spatially change in their expression patterns between conditions, such as in diseased versus healthy tissues. Existing methods generally fail to distinguish changes in spatial patterning by focusing only on changes in gene expression magnitude for methods adapted from non-spatial data or on changes in significance of spatial variability for methods focusing on spatially-resolved data. ResultsTo address these limitations, we develop STcompare, a statistical framework for comparative analysis of ST data by testing for differences in spatial correlation and spatial fold-change across structurally matched locations. Using simulated data, we demonstrate how STcompare provides distinct insights from bulk differential gene expression analysis and spatially variable gene expression analysis as well as other spatial comparison methods. STcompare further robustly controls for false positives even in the presence of spatial autocorrelation common in ST data. We apply STcompare to real ST data of biological replicates of mouse brains to confirm high spatial correspondence of gene expression patterns across samples. We apply STcompare to identify genes that spatially change in mouse kidneys with acute kidney injury compared to a healthy control, revealing tissue compartment-specific molecular dysregulation. Overall, the application of this spatially-aware comparative analysis will enable the discovery of differential spatially patterned genes across various physiological and technological axes of interest. Availability and ImplementationSTcompare is implemented as an open-source R package at https://github.com/JEFworks-Lab/STcompare with additional documentation and tutorials available at https://jef.works/STcompare/.

bioinformatics↗