Biology subjects

Wang, G.

Publications and source records attributed to Wang, G..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Mediator Subunit MED16 Collaborates with UBP1-TFCP2 to Control Transcriptional Activation or Repression via Promoter Positional Specificity

The Mediator complex acts as a master transcriptional co-regulator, yet the mechanisms by which its individual subunits mediate gene-specific transcription remain incompletely defined. Here, we report that the Mediator subunit MED16 physically associates with the UBP1-TFCP2 heterodimer, which controls the context-dependent transcriptional activation or repression. Biochemical purification combined with mass spectrometry validated MED16 as a bona fide interactor of UBP1-TFCP2. Integrative transcriptomic analyses demonstrated that UBP1 recruits the Mediator complex through MED16 to activate a panel of silenced genes associated with lung homeostasis, angiogenesis and cell proliferation. By contrast, MED16-UBP1 co-occupancy at the HIV-1 transcription start site (TSS) represses viral transcription and sustains HIV latency by compromising pre-initiation complex assembly. Domain-mapping experiments revealed that MED16 must integrate into the intact Mediator complex to exert either activating or repressive function. Genomic analysis uncovered a positional regulatory logic: UBP1-TFCP2 binding motifs adjacent to the TSS promote transcription, while those overlapping the TSS elicit repression. Collectively, our work identifies an MED16-UBP1 regulatory module with dual transcriptional activity and highlights this signaling axis as a potential target for HIV-1 interventions.

biochemistry↗

bioRxiv2025

Visualising sub-second dynamics of nanoparticle extravasation in vivo

Altered vascular integrity is a hallmark for many diseases. Monitoring vascular permeability, including its extent and underlying transport pathways, is thus important for advancing our understanding of disease mechanisms towards innovative diagnosis and treatment. Here we show real-time fluorescence imaging using lanthanide-based upconversion nanoparticles as contrast agents to visualise subtle changes to vascular permeability in vivo. Based on simultaneous confocal imaging of the vasculature alongside single particle tracking in the wide-field at video rate, we performed high-throughput surveillance across live zebrafish larvae to pinpoint locations of potential nanoparticle extravasation, achieving superior sensitivity and specificity over conventional fluorescent dyes. Further analyses of the sub-second dynamics of individual nanoparticle extravasation events unveiled distinct characteristics to distinguish between transcellular and paracellular transport. We applied the technique to evaluate the blood-brain barrier (BBB) in zebrafish larvae at different developmental stages, and potential BBB perturbation strategy via nanoparticle functionalisation with polysorbates. Significantly increased BBB penetration by 36.5 folds was shown for the functionalised particles compared to phospholipid-coated particles, attributed to enhanced transcellular crossing. The technique is readily applicable to monitoring vascular integrity and investigating endothelial transport for improved understanding of vascular biology, facilitating advanced research in disease diagnostics and drug delivery towards translation.

biophysics↗

bioRxiv2025

Distinct goal location beta frequency dynamics in hippocampus and prefrontal cortex across learning

Neural activity at goal locations contributes to learning by providing feedback on the success of preceding actions. This period engages neocortical and hippocampal networks, which serve distinct functions in reward processing and in forming associations between experience and reward. A neocortical network signature for reward feedback processing is beta oscillations (15-30 Hz). Beta oscillations are thought to coordinate distributed neural processes across brain regions. However, it is unknown whether beta oscillations coordinate hippocampal-neocortical networks during the goal period, or how their dynamics relate to learning. Here, we show that beta oscillations occur in both hippocampal CA1 and the prefrontal cortex (PFC) when rats reach goal locations in spatial navigation tasks. Despite the presence of beta oscillations in both regions after goal entry, beta activity in each region differed in spectral and temporal properties. These differences suggest that the hippocampus and PFC are weakly coupled at the beta frequency. We found that across learning, the strengths of PFC and CA1 beta oscillations were inversely related: PFC beta power increased and CA1 beta power decreased. Beta burst properties in PFC also had an inverse relationship to those of hippocampal sharp wave-ripples (SWRs), a prominent hippocampal process required for learning. We found a subset of PFC neurons modulated by both beta and hippocampal SWRs, which had distinct task-related firing patterns. Our results suggest that during outcome processing at goal locations, the neocortex and hippocampus are locally modulated at the beta frequency and then become coordinated for memory-related processes during SWRs.

neuroscience↗

bioRxiv2025

Subtype-specific neutralizing antibodies promote antigenic shift during influenza virus co-infection

Reassortment between different influenza strains occurs when they co-infect the same host cell. The emergence of a reassortant virus depends on both its intrinsic fitness and extrinsic factors, including pre-existing humoral immunity. The generation of pandemic strains, such as H2N2 and H3N2, and zoonotic influenza A viruses, like H5N6, H5N8, and H7N9, in birds is suggested to be the result of extensive selection by pre-existing antibodies. To further explore the role of humoral immunity in reassortment, we generated two divergent fluorescent protein-expressing viruses and used strain-specific and cross-reactive monoclonal antibodies (mAbs) to assess the impact of cross-immunity on reassortment. Our results indicate that all mAbs altered the genotypic diversity and significantly reduced the release of progeny virions in co-infected cells both in vitro and in vivo. Moreover, antibody transfer studies in mice revealed protection from challenge with divergent pathogenicity profiles. Notably, selection driven by a strain-specific mAb depended on its neutralizing specificity, whereas the selection driven by broadly reactive mAbs was independent of neutralization specificity. Our findings demonstrate that pre-existing neutralizing antibodies shape reassortment and that strain-specific neutralizing antibodies promote antigenic shift during co-infection, which is not the case for broadly cross-reactive antibodies that recognize influenza viruses from different subtypes.

microbiology↗

bioRxiv2025

Improving polygenic risk prediction performance through integrating electronic health records by phenotype embedding

Large-scale biobanks provide comprehensive electronic health records (EHRs) that capture detailed clinical phenotypes, potentially enhancing disease risk prediction. However, traditional polygenic risk score (PRS) methods rely on simplified phenotype definitions or predefined trait sets, limiting their ability to represent the intricate phenotypic structures embedded within EHRs. To address this gap, we introduce a general framework, EEPRS, that leverages phenotype embeddings derived from EHRs to improve genetic risk prediction using only genome-wide association study (GWAS) summary statistics, enabling accurate, robust and interpretable risk prediction for a wide range of diseases. Employing embedding methods such as Word2Vec and GPT, we conducted EHR embedding-based GWAS and identified a distinct cardiovascular cluster via hierarchical clustering of genetic correlations. Across 41 clinical traits in the UK Biobank, our EEPRS framework consistently outperformed traditional single-trait PRS, particularly within this identified cluster. Validation using PRS-based phenome-wide association studies (PRS-PheWAS) further confirmed robust associations between EHR embedding-based PRS and circulatory system diseases. Furthermore, our data-adaptive method, EEPRS_optimal, employing cross-validation to select the best embedding method, leading to additional improvements in prediction. We further developed MTAG_EEPRS for multi-trait PRS, resulting in averaging 92.48% improvement in R2 for continuous traits and 24.06% in AUC for binary traits compared to single-trait PRS. Overall, EEPRS represents a robust and interpretable framework, enhancing genetic prediction accuracy through integrating EHR embeddings with single-trait and multi-trait PRS.

genetics↗

bioRxiv2025

Differential modulation of Interferon and Cell Death Responses defines Human vs Avian Influenza A Virus Strain-Specific Virulence and guides Combination Therapy.

Influenza A virus (IAV) poses a significant global health risk, with highly pathogenic strains like H5N1 (CFR [~]52%) causing severe disease compared to less lethal but more transmissible strains like H1N1 (CFR 0.01-0.03%). Although IAV primarily infects lung epithelial cells, causing cell death and tissue damage, the molecular basis of strain-specific pathogenesis remains poorly understood. Here we show that in cell culture, H5N1 induced more rapid and extensive cell death than H1N1. Since Interferon (IFN) signaling is key to innate immunity, we examined its role in virus-induced cell death using STAT1-knockout A549 cells and JAK/STAT pathway inhibitors like Baricitinib. Both approaches reduced cell death across various IAV strains, including H1N1, H5N1, H7N9, and H3N2. However, inhibition increased viral titers, raising concerns about its clinical use in isolation. To overcome this, we tested a combination of Oseltamivir (antiviral) and Baricitinib (anti-inflammatory). Post-infection treatment in a murine model reduced lung inflammation and improved survival. Given that both drugs are FDA-approved, this approach has strong translational potential for clinical IAV treatment.

microbiology↗

bioRxiv2025

SVPG: A pangenome-based structural variant detection approach and rapid augmentation of pangenome graphs with new samples

Breakthrough advances in long-read sequencing technologies have opened unprecedented opportunities to study genetic variations through comprehensive pangenome analysis. However, the availability of structural variant (SV) calling tools that can effectively leverage pangenome information is limited. In addition, efficient construction of pangenome graphs becomes increasingly challenging with acquisition of larger number of samples. In this study, we present SVPG, an approach that leverages haplotype-resolved pangenome reference for accurate SV detection and rapid pangenome graph augmentation from long-read sequencing data. Compared to state-of-the-art SV callers, SVPG maintained superior overall performance across different sequencing technologies and coverages. SVPG also achieved notable improvements in calling rare and individual-specific SVs on both simulated and real somatic datasets. Furthermore, in a benchmark involving 20 samples, SVPG accelerated pangenome graph augmentation by nearly 10-fold compared to traditional augmentation strategies. We believe that this novel SVPG method, has the potential to revolutionize SV detection and serve as an effective and essential tool, offering new possibilities for advancing pangenomic research.

bioinformatics↗

bioRxiv2025

An Unexpected Role of Molecular Chaperones in Regulating the Excited States and Activities of Folded Enzymes

Molecular chaperones are recognized for assisting protein folding. Emerging evidence suggests that chaperones also interact with natively folded proteins. Yet their functional impact on folded proteins remains unclear. Here, we show that chaperones can directly modulate the conformational dynamics and catalytic efficiency of enzymes in their native states. Spy and Hsp70 increased lysozyme activity by altering conformational exchanges, and this effect extended across other chaperones and enzymes. Hsp70, Spy, Hsp104, and Hsp20 enhanced the catalytic activities of multiple folded enzymes, including alkaline phosphatase, DNA polymerase Pfu, endonucleases Cas12a/Cas13a, and xylanase. These findings uncover an unanticipated function of chaperones in regulating enzyme function expanding their mechanistic scope beyond folding assistance and suggests opportunities in enzyme engineering, diagnostics, and cellular regulation.

molecular biology↗

bioRxiv2025

Molecular Basis for Asynchronous Chain Elongation During Rifamycin Antibiotic Biosynthesis

The rifamycin synthetase (RIFS) from the bacterium Amycolatopsis mediterranei is a large (3.5 MDa) multienzyme system that catalyzes over 40 chemical reactions to generate a complex precursor to the antibiotic rifamycin B. It is considered a hybrid enzymatic assembly line and consists of an N-terminal nonribosomal peptide synthetase loading module followed by a decamodular polyketide synthase (PKS). While the biosynthetic functions are known for each enzymatic domain of RIFS, structural and biochemical analyses of this system from purified components are relatively scarce. Here, we examine the biosynthetic mechanism of RIFS through complementary crosslinking, kinetic, and structural analyses of its first PKS module (M1). Thiol-selective crosslinking of M1 provided a plausible molecular basis for previously observed conformational asymmetry with respect to ketosynthase (KS)-substrate carrier protein (CP) interactions during polyketide chain elongation. Our data suggest that C-terminal dimeric interfaces--which are ubiquitous in bacterial PKSs--force their adjacent CP domains to co-migrate between two equivalent KS active site chambers. Cryogenic electron microscopy analysis of M1 further supported this observation while uncovering its unique architecture. Single-turnover kinetic analysis of M1 indicated that although removal of C-terminal dimeric interfaces supported 2-fold greater KS-CP interactions, it did not increase the partial product occupancy of the homodimeric protein. Our findings cast light on molecular details of natural antibiotic biosynthesis that will aid in the design of artificial megasynth(et)ases with untold product structures and bioactivities. Significance StatementBacteria use enzymatic assembly lines for the manufacture of complex and often medicinally active organic compounds. Their conserved modular design and biosynthetic logic suggest they evolved to be intrinsically reprogrammable. Yet, strategies to manipulate assembly-line product structures through protein engineering are still met with considerable challenges. This work investigates how a representative bacterial assembly line catalyzes an essential reaction during biosynthesis of the antibiotic rifamycin. Our data provide a molecular rationale for asynchronous C-C bond formation catalyzed by equivalent subunits of the homodimeric system while exposing new aspects of assembly line architecture. These findings represent a step closer towards the design of artificial assembly lines for sustainable production of user-defined chemicals.

biochemistry↗

bioRxiv2025

Downregulation of LATS1/2 Drives Endothelial Senescence-Associated Stemness (SAS) and Atherothrombotic Lesion Formation

BackgroundAtherothrombosis, the main event leading to acute coronary syndrome (ACS), is strongly linked to disturbed blood flow (d-flow) regions. Although the involvement of the Hippo pathway and its kinases Large Tumor Suppressor Kinase 1and 2 (LATS 1 and 2) in mechanical stress responses is known, the mechanisms by which d-flow simultaneously induces senescence, proliferation, and atherothrombosis remain unclear. MethodsThe role of endothelial cells (EC)-specific LATS1/2 was examined using EC specific knock-out (EKO) mice in a partial left carotid ligation (PLCL) model. Plaque spatial multi-omics analysis was performed by integrating imaging mass cytometry, sequential immunofluorescence (COMET), and spatial metabolomics at the single-cell level in human and mouse atherosclerotic plaques. ResultsIn tamoxifen-inducible Lats1homo(-/-) /Lats2 homo(-/-) EC-specific knockout (EKO) mice, deletion of LATS1/2 induced by tamoxifen led to fatal outcomes, characterized by severe systemic edema and markedly increased vascular permeability. In contrast, Lats1het(+/-)/Lats2 homo(-/-)-EKO mice survived and developed atherothrombotic plaques exhibiting neovascularization even without further additional dietary or genetic intervention. Spatial proteomics analysis revealed that LATS1/2 depletion in ECs triggered a senescence-associated stemness (SAS) phenotype, primarily driven by CD38 upregulation. Complementary spatial metabolomics profiling demonstrated a significant increase in sulfite and taurine within LATS1/2-deficient plaques, indicating lowered sulfite oxidase (SUOX) activity. Mechanistically, CD38 upregulation was found to suppress SUOX expression, induce the reverse mode of mitochondrial complex V, and increase succinate dehydrogenase (SDH) activity along with ATP consumption. Paradoxically, despite ATP depletion, this metabolic disturbance enhanced glutamate metabolism and the tricarboxylic acid (TCA) cycle, sustaining EC proliferation under energetically stressed conditions. The combined effect of LATS1/2 deletion and CD38 activation established a unique EC phenotype defined by increased SAS, leading to proliferation, senescence, and eventual cell death. These pathological processes culminated in the formation of atherothrombotic plaques, which were attenuated by inhibition of CD38. Notably, a similar phenotype--marked by metabolically active ECs--was observed in human atherothrombotic plaques, suggesting translational relevance. ConclusionLoss of LATS1/2 in ECs induces SAS state that promotes excessive EC proliferation, senescent cell accumulation, and the development of structurally fragile, leaky neo vessels--hallmarks of atherothrombotic lesions. CD38-mediated SUOX deficiency further amplifies this pathological process by inducing mitochondrial dysfunction, depleting ATP, and triggering compensatory upregulation of glutamate and TCA cycle metabolism. These findings identify a novel LATS1/2-CD38-SUOX axis in ECs that orchestrates SAS-driven atherothrombosis. Targeting CD38 may represent a promising therapeutic strategy to mitigate vascular dysfunction and plaque instability in high-risk ACS patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/660635v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@149d313org.highwire.dtl.DTLVardef@1c0988borg.highwire.dtl.DTLVardef@15efec9org.highwire.dtl.DTLVardef@1a96e03_HPS_FORMAT_FIGEXP M_FIG C_FIG Under normal physiological conditions, LATS1/2 and Lamin A work together to suppress CD38 expression. Lamin A binds directly to the CD38 promoter to repress transcription, and LATS1/2 interact with Lamin A to reinforce this suppression. This collaboration helps maintain low CD38 activity and preserves cellular NAD levels. However, under disturbed flow (d-flow), both LATS1/2 and Lamin A are downregulated. The loss of this dual repression leads to increased CD38 NADase expression. Elevated CD38 accelerates NAD consumption, causing NAD depletion--a hallmark of cellular senescence. Reduced NAD disrupts key metabolic and stress-response pathways, contributing to the onset of the senescent state. At the same time, CD38 suppresses sulfite oxidase (SUOX), leading to sulfite accumulation and mitochondrial redox imbalance. This shift activates the reverse mode of mitochondrial Complex V, which decreases ATP production and increases mitochondrial ROS, intensifying metabolic and oxidative stress in endothelial cells (ECs). In response, ECs compensate by upregulating succinate dehydrogenase (SDH), enhancing TCA cycle activity and glutamate metabolism. This metabolic adaptation provides the biosynthetic building blocks needed for cell growth and proliferation. As a result, ECs adopt a paradoxical phenotype: they show classical features of stress-induced senescence (such as NAD depletion, oxidative stress, and cell cycle arrest signals), while simultaneously undergoing metabolic activation and proliferation, also mediated by YAP. This defines a non-canonical endothelial program known as senescence-associated stemness (SAS), characterized by the formation of abnormal, proliferative, yet fragile neovessels. These dysfunctional vessels contribute to atherothrombosis, setting this process apart from the more stable lesions typical of conventional atherosclerosis.

molecular biology↗

bioRxiv2025

Deepening imaging-based spatial proteomics at high spatial resolution through controlled tissue resizing and in-situ bottom-up mass spectrometry

Understanding the spatial organization of proteins in tissues is essential for elucidating biological function, but current proteomic imaging methods face limitations in resolution, sensitivity, and multiplexing capability. Here, we present IMPACT (Imaging Mass Spectrometry for Proteome Analysis on Compressed Tissue), a hydrogel-based workflow that integrates controlled vertical tissue compression following expansion to enhance protein detection while improving spatial resolution in mass spectrometry imaging (MSI). Through a 6-fold lateral expansion and 100-fold thickness reduction, analytes were concentrated at the surface to improve detection and enable analysis of thick specimen. Coupled with optimized in-gel digestion using hybrid enzymes, IMPACT increased protein identifications 3-fold compared to conventional MSI while maintaining spatial fidelity. We demonstrate IMPACTs utility in mapping low-abundance proteins and resolving fine anatomical structures. Orthogonal validation with immunofluorescence and integration with spatial transcriptomics further reveal protein-RNA distribution discrepancies, highlighting the need for direct proteomic imaging. IMPACT bridges critical gaps in spatial proteomics by enabling high-resolution, high-sensitivity, and multiplexed untargeted protein imaging, opening new avenues for tissue biology and biomarker discovery.

biophysics↗

bioRxiv2025

The anaerobic WOR-3 Bacteria: Hydrogenotrophic metabolism and unique carbon fixation via Archaeal form III RuBisCO

The uncultured WOR-3 phylum is widely distributed in anaerobic environments, including hot springs, marine ecosystems, and hydrothermal vents, yet its ecological roles and metabolic capabilities remain poorly understood. In this study, we analyzed 180 medium- to high-quality metagenome-assembled genomes (MAGs), including 59 newly reconstructed from environmental samples and 121 retrieved from the Genome Taxonomy Database (GTDB). Phylogenetic analyses resolved the WOR-3 lineage into four subgroups (subgroup 1-4). Metabolic reconstruction revealed significant divergence of the carbon, sulfur, nitrogen and hydrogen metabolism pathways among the different subgroups. Subgroup 1 was characterized by fermentative metabolism involving formate and ethanol, and uniquely exhibited potential for carbon fixation via Calvin cycle, as indicated by the presence of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) gene. Notably, WOR-3 RuBisCO is phylogenetically affiliated with archaeal form III, although the carbon fixation pathway follows the canonical bacterial Calvin cycle--a feature of potential evolutionary significance. Subgroup 3 exhibits metabolic versatility, including genes for dissimilatory sulfate reduction, sulfur oxidation, partial denitrification, and fatty acid degradation. In addition, all subgroups harbored key components of hydrogen metabolism, including widespread NiFe hydrogenases and Rnf complexes, supporting H2-dependent electron transfer and energy conservation under anaerobic conditions. Featuring near-universal presence of complexes I and II and frequent occurrence of terminal oxidases (cydAB and coxABC)--suggests a facultative anaerobic lifestyle. Collectively, this study expands the genomic framework for the WOR-3 phylum and provides novel insights into the metabolic versatility and ecological functions of this previously uncharacterized lineage in biogeochemical cycles of carbon, nitrogen, and sulfur. IMPORTANCEThe WOR-3 phylum represents a widespread but poorly understood bacterial lineage inhabiting diverse anaerobic/microaerobic environments. By integrating 180 metagenome-assembled genomes, including 59 newly reconstructed, this study provides the most comprehensive genomic framework to date for WOR-3. Phylogenomic and metabolic analyses revealed four distinct subgroups with divergent capacities for carbon, sulfur, and nitrogen metabolism. Notably, subgroup 1 encodes a complete Calvin-Benson-Bassham (CBB) cycle featuring an archaeal-type form III RuBisCO, suggesting an unusual evolutionary trajectory for carbon fixation in this lineage. Subgroup 3 exhibits versatile metabolic potential, including dissimilatory sulfur metabolism, partial denitrification, and fatty acid degradation, highlighting its possible roles in multiple biogeochemical processes. The widespread presence of hydrogenases and respiratory complexes across all subgroups supports energy conservation under anaerobic or microaerobic conditions. These findings not only expand the taxonomic and functional landscape of the WOR-3 phylum but also offer key insights into its ecological roles in global element cycling.

microbiology↗

bioRxiv2025

Genome-wide CRISPR/Cas9 knockout screen identifies host factors essential for Bovine Parainfluenza Virus Type 3 replication

Bovine Parainfluenza Virus Type 3 (BPIV3) is a leading cause of respiratory illness in cattle and a primary component of Bovine Respiratory Disease Complex (BRDC), resulting in significant economic losses. Understanding the mechanisms of BPIV3 infection, particularly the entry process, is essential for developing effective control measures. Identifying specific host factors that viruses exploit during their life cycle can reveal critical vulnerabilities for potential antiviral targets. We established a genome-wide CRISPR/Cas9 knockout screen in bovine cells to identify host factors involved in viral infections. Our screen identified several key host factors required for BPIV3 infection, including the sialic acid transporter SLC35A1 and the protein LSM12. Further mechanistic analysis revealed that these factors play critical roles at distinct stages of the BPIV3 entry process. These findings not only advance our understanding of how BPIV3 infects host cells, but also identify potential host targets for inhibiting infection and developing novel antiviral strategies.

microbiology↗

bioRxiv2025

Spatial metabolomics reveals persistent localized niche-specific metabolic failure in kidneys following ischemia-reperfusion injury

After acute kidney injury (AKI), the persistence of failed repair proximal tubule (FR-PT) cells is postulated to hamper kidney regeneration and increase the risk of chronic kidney disease. This fibrotic shift likely depends on microenvironmental interactions, which remain largely unstudied. To investigate this, we mapped the spatial metabolic architecture of post-ischemic kidneys using an untargeted semi-quantitative spatial metabolomics (qMSI) approach, integrated with high-resolution spatial transcriptomics. Unsupervised neighborhood clustering of qMSI data revealed distinct microenvironments. Lipidome profiles identified diffusely spread areas with persistent injury markers surrounding FR-PT cells. These niches exhibited decreased linoleic acid and elevated succinic acid levels, even in epithelial cells that appeared otherwise healthy. Corresponding transcriptomic profiles confirmed downregulation of oxidative phosphorylation and fatty acid {beta}-oxidation in these regions. Together, these findings point towards niche-specific metabolic failure and persistent mitochondrial dysfunction in areas considered healthy, underscoring the need to prioritize metabolic resuscitation to prevent long-term consequences of AKI.

biochemistry↗

bioRxiv2025

Tactile and Visual Spatial Frequency Perception Follows Optimal Integration but Is Not Affected by Spatial Proximity

Spatial frequency is a fundamental feature in both visual and somatosensory perception, yet how these modalities integrate spatial frequency information remains unclear. This study investigates whether visuotactile spatial frequency perception follows the principles of Maximum Likelihood Estimation (MLE) and whether spatial proximity influences multisensory integration, using virtual reality (VR) and high-precision 3D-printed tactile stimuli. Experiment 1 found that the visuotactile integration of spatial frequency cues follows the MLE rule. However, Experiment 2 revealed that this integration is not affected by spatial proximity. These findings provide additional insights into the feature dependency of multisensory integration between vision and touch and highlight the potential for independent processing before integration, offering new perspectives on the mechanisms of spatial frequency processing in both visual and tactile modalities.

neuroscience↗

bioRxiv2025

The genomic and transcriptional landscape of the spinal cord H3K27-altered diffuse midline glioma suggests the potential therapeutic strategy

Diffuse midline glioma with H3K27-altered (DMG) is a lethal pediatric malignancy that primarily occurs in the brainstem of children. In adults, DMG arising in the spinal cord is rarely reported and remains poorly understood. The cellular architecture and clinical outcomes of DMG vary depending on the tumors location. To dissect the genomic and transcriptional architecture of a cohort of spinal cord DMG patients, we conducted whole-exome sequencing and single-cell RNA sequencing on 19 tumor samples from 7 patients. We identified previously underappreciated stem-like cells associated with hypoxia in malignant tumor cells, which were present in all samples of spinal cord DMG but absent in published intracranial DMG, corroborating cellular heterogeneity based on tumor location. We discovered that tumor-associated myeloid cells constituted the largest population of non-malignant cells in adult spinal cord DMG. Our research revealed a transition from microglia to macrophages, characterized by enhanced cell-to-cell interactions mediated through the VEGF signaling pathway network. Notably, we found that epigenetic agents can repress the expression of hypoxia-related gene programs in patient-derived spinal cord DMG cultures and inhibit cell proliferation in vitro. Collectively, our study reveals a crucial anatomical dimension that DMG exhibits a location-specific genomic and transcriptional landscape despite shared H3K27 alterations, providing the paradigm for developing precision therapeutic strategies that extend beyond DMG to other molecularly defined yet anatomically divergent malignancies.

cancer biology↗

bioRxiv2025

Xcr1+ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression

BackgroundAtherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1+ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in the development of atherosclerosis remains highly controversial. ResultsWe first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4+ and CD8+ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1+ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1+ cDC1 cells via Xcl1 by establishing Xcl1 and ApoE deficient mice. Xcl1 knockout mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. ConclusionsOur results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.

immunology↗

bioRxiv2025

Deep-learning-enabled multi-omics analyses for prediction of future metastasis in cancer

Metastasis remains the leading cause of cancer-related mortality, yet predicting future metastasis is a major clinical challenge due to the lack of validated biomarkers and effective assessment methods. Here, we present EmitGCL, a deep-learning framework that accurately predicts future metastasis and its corresponding biomarkers. Based on a comprehensive benchmarking comparison, EmitGCL outperformed other computational tools across six cancer types from seven cohorts of patients with superior sensitivity and specificity. It captured occult metastatic cells in a patient with a lymph node-negative breast cancer, who was declared to have no evidence of disease by conventional imaging methods but was later confirmed to have a metastatic disease. Notably, EmitGCL identified HSP90AA1 and HSP90AB1 as predictable biomarkers for future breast cancer metastasis, which was validated across five independent cohorts of patients (n=420). Furthermore, we demonstrated YY1 transcription factor as a key driver of breast cancer metastasis which was validated through in-silico and CRISPR-based migration assays, suggesting that YY1 is a potential therapeutic target for deterring metastasis.

bioinformatics↗