Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 307 records · Page 17Linked to original sources

bioRxiv2025

Intratumoral microbiota-derived S1P sensitizes the combination therapy of Capecitabine and Nivolumab

Clinical responses of colorectal cancer (CRC) treatments vary considerably due to the heterogeneity of tumor micro-environment (TME), where intratumoral microbiota may reshape the unique inflammation imprints. However, its complex mechanistic underpinnings remain incompletely elucidated. Herein we sought to delineate the critical role of intratumoral microbiota in potentiating combination therapeutics against CRC. By comparing germ-free (GF) and specific pathogen-free (SPF) mouse models of 33 potential CRC treatments, we screened out the combination regimen of Capecitabine-Nivolumab significantly augmented by intratumoral microbiota in tumor regression and survival prolongation. The enrichment of Bacteroides fragilis induced by Capecitabine-Nivolumab was concomitant with elevated microbial sphingosine-1-phosphate (S1P), which further upregulated tumoral PD-L1 expression by enhancing histone deacetylation at the CD274 locus. Activation of microbial sphingosine kinase 2 (SphK2) ultimately led to an expansion of effector memory CD8+ T cells and reduction of exhausted T cell subsets within TME. To conclude, these findings advance our understanding of the intricate interplay among intratumoral microbiota, sphingolipid metabolites and immunochemotherapeutics. It highlights microbial sphingolipids as potential predictive biomarkers for strategies of targeting intratumoral microbiota in CRC management.

microbiology↗

bioRxiv2025

The intratumoral microbiome is negatively associated with malignancy in dermatofibrosarcoma protuberans

In recent years, growing evidence demonstrated the critical roles of intratumoral microbes in tumors. However, the characteristics of intratumoral microbiome in dermatofibrosarcoma protuberans (DFSP) and their associations with tumor malignancy remains unexplored. Here, 106 whole-genome sequencing (WGS) data of the paired biopsy and blood samples from 53 DFSP patients were utilized, in which we extracted high-quality non-human reads to assign microbial taxonomic annotation by Kraken2 and PlusPF database. Meanwhile, significantly elevated non-human reads, microbial abundance, and bacterial load were detected in tumor compared to blood samples. To minimize the impact of contaminants and noise, we conducted a series of filtering procedures and treated blood samples as negative controls. Notably, we found that over 98% of intratumor microbes belonged to bacteria, and that the dominant taxa and alpha-diversity of intratumoral bacteria all exhibited significantly negative correlations with Ki67 expression in tumors. Specifically, the 84 key intratumoral species were identified to be associated with the reduced tumor malignancy, as evidenced by the diminished Ki67 expression, decreased tumor volume, and fewer COL1A1-PDGFB fusion events. These findings highlighted the tumor-suppressive potential of intratumoral microbiome, thereby providing a novel insight into DFSP pathogenesis and clinical management. IMPORTANCETo our knowledge, this is the first study to explore the intratumoral microbiome in DFSP. Microbial DNA signatures could be detected by whole-genome sequencing (WGS) and enabled a comprehensive view of the microbial landscape, thus we analyzed 106 WGS data of the paired biopsy and blood samples from 53 DFSP patients. Our analysis revealed that the dominant taxa and alpha-diversity of intratumoral microbiome all showed significantly negative correlations with Ki67 expression of tumor samples. This study indicated the tumor-suppressive role of intratumoral microbiome in DFSP and highlighted the potential clinical significance in understanding DFSP pathogenesis and guiding therapeutic management strategies.

microbiology↗

bioRxiv2025

WNK1 kinase activity is required for maintenance of podocyte structure

The filtration-function of glomeruli requires slit diaphragms formed by interdigitating podocyte foot processes, which are actin-based membrane protrusions. Dysregulation of mechanisms that maintain these membrane extensions lead to foot process effacement, proteinuria, and progression to chronic kidney disease. Building on our previous work that showed WNK1 kinase activity is necessary for the maintenance of normal biomechanical properties of glomeruli and podocyte foot process architecture, we tested the hypothesis that WNK1 kinase activity affects the structure of podocyte foot processes through modulation of actomyosin activity and focal adhesion complexes. Using a WNK1 kinase specific inhibitor, we determined by immunofluorescence microscopy of nascent focal adhesions, podocyte membrane spreading/extensions, and NMII paralog localization and extent of activation calculated from quantification of phosphorylated myosin, that all were sensitive to WNK1 kinase activity. Moreover, biochemical evidence of WNK1 kinase activity-dependent signalosomes supports a role for WNK1 in the maintenance of podocyte foot processes, and sarcomere-like structures (SLSs) that are induced in models of podocyte injury. Using primary and immortalized podocyte cell lines developed from control and Col4a3-/-Alport Syndrome model mice, we measured WNK1 kinase activity-dependent improvement in properties of injured podocytes in vitro. Physiological relevance of WNK1 kinase activity-dependent structural maintenance of podocyte foot processes was confirmed by significant acute proteinuria measured in response to WNK1 inhibition in vivo. Collectively, the results provide evidence that WNK1 kinase signalosome activity that includes formation of nascent focal adhesions and regulation of NMII localization and activity at membrane protrusions and extensions, are necessary for physiological maintenance of slit diaphragms. SignificanceTerminally differentiated podocytes are arborized cells with interdigitating foot processes that form the renal filtration barrier. Loss of foot process structural integrity causes progressive proteinuria, which can lead to irreversible renal injury, but the mechanisms that maintain foot process structure are incompletely understood. We report evidence that WNK1 kinase activity is required for maintenance of normal glomerular filtration in vivo, and this is mediated in part through WNK1 activity-dependent modulation of non-muscle myosin II activity, and formation of nascent focal adhesions that are necessary for lamellipodial extensions. Using glomeruli and podocyte cell lines developed from an Alport Syndrome podocyte injury model, we show that aspects of abnormal podocyte structure associated with chronic kidney disease can be suppressed through increased WNK1 activation.

cell biology↗

bioRxiv2025

Single-cell spatial map of cis-regulatory elements for disease-related genes in the macaque cortex

Single-cell spatial transcriptomes have demonstrated molecular and cellular diversity in the brain1, 2, 3, 4, 5, 6, 7, 8, but gene regulatory mechanisms underlying transcriptomic profiles and disease pathogenesis remain largely unknown in primates. Here we performed single-nucleus Assay for Transposase-Accessible Chromatin followed by sequencing (snATAC-seq) for [~]1.6 million cells from 142 cortical regions of two male cynomolgus monkeys (Macaca fascicularis), and identified distinct chromatin accessibility profiles of cis-regulatory elements (CREs) for various cell types. By integrative analysis with large-scale spatial transcriptome data, we found that these CREs showed laminar and regional preferences, with their regional accessibility exhibiting striking dependence on the regions hierarchical level. Cross-species comparison of snATAC-seq data revealed human/macaque-enriched layer-4 glutamatergic neurons and LAMP5/LHX6-expressing GABAergic neurons as well as human/macaque-biased CREs for genes related to neurodevelopment and psychiatric diseases. Importantly, risk single-nucleotide polymorphisms for many brain disorders strongly associated with human/macaque-biased CREs in glutamatergic neuronal types and those for Alzhemers disease strongly associated with CREs exclusively in microglia. Our results provided the basis for understanding the spatial gene regulatory mechanisms underlying cellular diversity and disease pathogenesis in the primate cortex.

neuroscience↗

bioRxiv2025

Trends Assessment of the Genetic Mutation Induced Protein-Protein Interaction Variation via Protein Large Language Driven Method

Protein-protein interaction (PPI) variations are widely observed in many principal biological processes related to various diseases, while genetic mutation is one of the most common factors resulting in those variations. Unraveling these underlying biomolecular interactions is a key challenge that hinders a profound understanding of disease mechanisms. Although current models can accurately predict quantitative binding affinity, their application in pathogenic research is limited by difficulties in defining trend types, particularly extreme "disrupting" cases, along with poor generalizability beyond single-point mutations (SNP) and insufficient biological interpretability. Here, we present TAPPI, an interpretable large language model-driven deep learning framework, to perform Trends Assessment of Protein-Protein Interaction. It categorizes PPI variations trends into four types: disrupting, decreasing, no effect, and increasing, enabling fine-grained functional assessments and bridging genetic mutation and disease mechanisms. The framework generalizes effectively across both single-point and multi-point mutations and captures complex trend outcomes relevant to diverse disease landscapes. In benchmark evaluations, TAPPI achieved the state-of-the-art prediction performance and demonstrated biological relevance through interpretable results. In external datasets from Autism Spectrum Disorder, Lennox-Gastaut syndrome, and Epileptic Encephalopathies, given the premise that TAPPIs predicted results align with pathogenic patterns, these results reveal how genetic mutations indirectly perturb disease-associated pathways and supporting our perspective of "crucial disrupting" and "bridging mutations-disease". In summary, accurate, interpretable, and pathogenically relevant prediction of PPI variations trend predicted by TAPPI provides a novel approach for mechanistic discovery.

bioinformatics↗

bioRxiv2025

Memo-Patho: Bridging Local-Global Transmembrane Protein Contexts with Contrastive Pretraining for Alignment-Free Pathogenicity Prediction

Understanding the pathogenic impact of protein mutations remains a fundamental challenge in genomic medicine, particularly for transmembrane proteins (TMPs), a functionally critical yet structurally under-annotated class that includes numerous drug targets. Current variant effect predictors often fall short in this domain due to computational burdens, reliance on multiple sequence alignments (MSAs), and limited ability to generalize to TMP-specific constraints. Here we present Memo-Patho, an alignment-free deep learning framework specifically optimized for TMP mutation pathogenicity prediction. Memo-Patho integrates global and local representations from protein language models (PLMs) and predicted structural features. Furthermore, it introduces a contrastive pre-training strategy that learns discriminative features by comparing benign and pathogenic mutations within the same protein backbone. This design enables the model to capture functional disruptions in challenging contexts without structural or evolutionary alignments. Memo-Patho outperforms state-of-the-art predictors on two types of TMP benchmark datasets (accuracy up to 0.93) and unseen-protein generalization tasks, showing strong agreement with evolutionary conservation profiles. Its predictions are further validated on a manually curated KCNQ1 dataset of 55 ion channel variants, achieving an accuracy of 0.84 and outperforming existing tools. The model also supports high-throughput scanning, efficiently analyzing over 15000 variants in under 80 minutes. Our results establish Memo-Patho as a fast, generalizable, and biologically grounded approach for variant effect prediction in TMPs. Its alignment-free design, contrastive learning paradigm, and clinical robustness mark a step forward towards scalable interpretation of TMP variation for both basic research and precision medicine applications.

bioinformatics↗

bioRxiv2025

Dynamic Resting-State Network Markers of Disruptive Behavior Problems in Youth

BackgroundChildhood disruptive behavior problems are linked to aberrant integrity within large-scale cognitive control networks. However, it is unclear if transitory or dynamic variation in the functional brain architecture is a marker of disruptive behavior problems. The current study tested whether functional connectivity across dynamic networks is distinctly associated with the transdiagnostic symptom domain of disruptive behavior problems in children. MethodsParticipants were aged 9-10 years from the Adolescent Brain Cognitive Development (ABCD) Study, who completed resting-state fMRI (N=877). We employed a dynamic connectivity approach leveraging a hidden semi-Markov model (HSMM) to identify transient properties of brain networks and states. Models estimated the time spent in each state (occupancy time) and the number of consecutive timepoints in a state (dwell time) for each participant. Linear regression models were utilized to identify distinct associations between dynamic properties (occupancy and sojourn times) and severity of disruptive behavior problems, accounting for other commonly co-occurring symptoms. ResultsDynamic network markers of disruptive behavior problems included increased time in network states characterized by globally aberrant connectivity patterns in circuitry involved in cognitive control including frontoparietal and dorsal attention networks. Replication of findings was found in a held-out sample of resting-state fMRI runs in which greater severity of disruptive behavior problems was uniquely linked to greater occupancy time in similarly characterized brain states. ConclusionTransdiagnostic, dynamic resting-state markers of disruptive behavior problems in youth may assist in the development of brain-based biomarkers for monitoring treatment outcomes, assessing circuit target engagement and informing clinical decisions.

neuroscience↗

bioRxiv2025

PML1-Mediated Feedforward Loop Through PI3K and MAPK Axes Drives Endocrine Resistance

Treatment of estrogen receptor-positive (ER+) breast cancer is significantly hindered by endocrine resistance. We identified PML1 as a key therapeutic entity that can be targeted to overcome resistance. Endocrine-resistant breast cancer cells share three key characteristics: elevated PML1 protein levels, enhanced activity of PI3K, MAPK, or both signaling pathways, and reduced ER activity. We developed a PML1 gene signature that predicts poor prognosis and correlates strongly with PI3K, MAPK, and endocrine resistance gene signatures, as evident by cellular studies, scRNA-seq analysis, and spatial transcriptomics of endocrine therapy-treated tumors. This signature is present in endocrine-resistant breast cancer cells harboring the Y537S ER mutation. We consistently demonstrate high PML1 protein levels across cells resistant to various treatments, including 4-hydroxytamoxifen, fulvestrant, elacestrant, and CDK4/6 inhibitors. Furthermore, treatments with these therapeutic agents or knockdown of ESR1 mRNA also increase PML1 protein levels. Mechanistically, we show that ER inhibition through fulvestrant treatment activates PI3K and MAPK signaling, which enhance PML1 protein stability and synthesis. PML1 then drives a feedforward loop by stimulating the expression of cytokine and growth factor mRNAs, including CCL5 and HBEGF, further amplifying PI3K and MAPK signaling. Consequently, in endocrine-resistant cells, endocrine therapies, while inactivating ER, paradoxically reinforce this loop through increased PI3K/MAPK activation and PML1 protein accumulation, ultimately compromising therapeutic efficacy. Finally, we demonstrated that arsenic trioxide, an FDA-approved, PML-reducing drug, effectively disrupts this feedforward loop, offering a promising strategy for treating resistant metastatic breast cancer. STATEMENT OF SIGNIFICANCEEndocrine resistance remains a major obstacle in treating estrogen receptor-positive metastatic breast cancer. Our study identifies PML1 as a central mediator of this resistance, revealing how it maintains a self-reinforcing signaling network through PI3K and MAPK pathways by enhancing the production of cytokines and growth factors. The clinical significance of our findings is threefold: we establish PML1 as a biomarker for therapy resistance, demonstrate its mechanistic role in treatment failure, and show that FDA-approved arsenic trioxide can disrupt PML1-driven resistance. These insights provide a direct path to clinical translation, as combining arsenic trioxide with existing therapies could benefit patients with limited treatment options.

cancer biology↗

bioRxiv2025

Multimodal cortical connectome in the default mode network across the adult lifespan

The default mode network (DMN) critically underpins cognitive and affective functions throughout the adult lifespan; however, detailed insights into its complex neuroarchitecture and connectivity patterns across aging remain limited. Leveraging the open-access CamCAN dataset, comprising structural and diffusion magnetic resonance imaging (MRI) alongside magnetoencephalography (MEG) data from 599 adults spanning ages 18 to 88 years, we systematically investigated age-associated changes in multimodal connectomes within the DMN. Our analyses revealed a progressive decline in both structural and functional connectivity among DMN subregions with advancing age. Additionally, MEG-based connectivity assessment demonstrated age-related decreases in high-frequency oscillatory activity (alpha, beta, gamma bands) accompanied by increases in low-frequency oscillations (theta band). Integrating structural data with neurophysiological measures further revealed age-dependent shifts in neurophysiological-structural coupling within the prefrontal cortex, characterized by strengthened coupling at theta frequencies but weakened coupling at higher frequencies. Conversely, coupling within the posterior cingulate cortex consistently declined across all examined frequency bands. Notably, theta-band coupling within the prefrontal cortex significantly correlated with age-related memory performance variations. Collectively, our findings delineate nuanced changes in DMN information transmission dynamics across adulthood, underscoring its promise as a neurobiological biomarker reflective of cognitive aging heterogeneity.

neuroscience↗

bioRxiv2025

Isoform-Specific Roles of NTRK2 in Pulmonary Vascular Regeneration

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endothelial dysfunction, a key driver of BPD pathogenesis in human, remain poorly understood. Here, through multiomic profiling of vascular endothelial cells isolated from control and BPD patient lungs, we uncovered an expansion of general capillary endothelial cells (gCap) with aberrant expression of the neurotrophic receptor tyrosine kinase 2 (NTRK2) in BPD. Importantly, we identified a pathological NTRK2 isoform switch that dictates the regenerative capacity of gCap cells. Full-length NTRK2 (NTRK2-FL) promoted gCap regeneration in response to hyperoxic injury, whereas RBFOX2-mediated splicing of NTRK2-FL into a truncated isoform (NTRK2-T1) contributed to maladaptive responses and irreversible alveolar simplification in severe BPD cases. Restoring NTRK2-FL using lipid nanoparticle-delivered mRNA promoted angiogenesis and reversed alveolar simplification in vessel organoids and BPD-like mice. These findings identified NTRK2 isoform imbalance as a key driver of endothelial dysfunction and support isoform-specific RNA therapy as a promising strategy for vascular regeneration and repair. HIGHLIGHTS* Multiomic and spatial profiling reveal abnormal gCap subtype in human BPD lungs * NTRK2 isoform switch dictates endothelial regeneration in response to hyperoxic injury * RBFOX2 mediates splicing from NTRK2-FL to NTRK2-T1, driving irreversible alveolar damage * NTRK2-FL mRNA therapy restores vascular regeneration after injury

developmental biology↗

bioRxiv2025

An intercellular signaling pathway in the mouse retina connects Kv2.1, GLT-1, and nitric oxide synthase 1 to optic nerve regeneration

We report here that a multicellular signaling pathway in the mouse retina targeting glutamate homeostasis and nitric oxide production is activated upon optic nerve injury and modulates reti-nal ganglion cells (RGCs) ability to mount a robust regenerative response. A novel highly sen-sitive and specific NO sensor (FL2) revealed that optic nerve injury leads to a rapid, prolonged elevation of NO in the inner retina. Amacrine cell-specific genetic deletion of the neuron-specific isoform of nitric oxide synthase (NOS1, nNOS) or the NOS1 inhibitor N(w)-propyl-L-arginine (L-NPA) suppressed optic nerve regeneration. Steps leading to NOS1 activation are shown to in-clude Kv2.1 phosphorylation and activation, reversal of glutamate uptake by the glutamate transporter GLT-1 (EAAT2), and subsequent NMDA receptor activation. Conditional knockout of the glutamate transporter GLT-1 in bipolar cells, intraocular injection of the GLT-1 blockers dihydrokainate (DHK) or WAY213613, the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5), or the Kv2.1 blockers RY796 or stromatoxin all sup-pressed NO generation and strongly diminished RGCs ability to respond to Pten deletion and other factors. Thus, optic nerve injury activates a sequence of pathophysiological changes in retinal interneurons that gates RGCs ability to regenerate injured axons. Significance StatementCells use extracellular signals to coordinate responses to injury and to promote repair and re-generation. The NMDA receptor, which has a high affinity for glutamate and is functionally cou-pled to nitric oxide synthase, has the potential to mediate such responses by responding to changes in extracellular glutamate. In the mouse retina after optic nerve injury, potassium channels in retinal ganglion cells, glutamate transporters in neighboring cells, and NMDA recep-tors in amacrine cells, are all involved in a pathway that regulates the generation of nitric oxide, which we show promotes axon regeneration after injury.

neuroscience↗

bioRxiv2025

Hidden in plain sight: Bacterial genomes reveal thousands of lytic phages with therapeutic potential

Phages are typically classified as temperate, integrating into host genomes, or lytic, replicating and killing bacteria. Lytic phages are not expected in bacterial genome sequences, yet our analysis of 3.6 million bacterial assemblies from 1,226 species revealed >100,000 complete lytic phage genomes, which we term Bacterial Assembly-associated Phage Sequences (BAPS). This represents a [~]five-fold increase in the number of phages with known hosts and fundamentally reshapes our understanding of phage biology. Identifying BAPS has enabled the discovery of entirely novel phage clusters, including clusters distantly related to Salmonella Goslarviruses in E. coli, and Shigella, while significantly expanding known genera such as Seoulvirus (from 16 to >300 members). Notably, close relatives of therapeutic lytic phages were also detected, suggesting clinical isolate sequencing unknowingly archives viable phage candidates. The discovery of complete, lytic phage genomes within bacterial assemblies challenges long-standing assumptions and reveals a vast, untapped reservoir of phages.

microbiology↗

bioRxiv2025

Hyper-Glycosylation as a Central Metabolic Driver of Alzheimers Disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimers Disease Related Dementias (ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

neuroscience↗

bioRxiv2025

Episodic events are flexibility encoded in both integrated and separated neural representations

This study investigates how the brain encodes episodic events to support diverse memory functions. Thirty-six participants viewed movies simulating real-life interactions while EEG was recorded. They first watched movies featuring two characters (AB), followed by scenes where one original character interacted with a new one (BC). Memory was assessed for direct (AB and BC), indirect (AC) associations, and source memory about whether two characters had appeared together. Source memory was more accurate when participants correctly inferred indirect associations. Time-resolved representational similarity analysis (RSA) of EEG data revealed both neural pattern similarities and dissimilarities during AB and BC encoding. Pattern similarities, indicating memory integration across episodes, predicted successful indirect associations. Conversely, dissimilarities predicted accurate source memory, indicating the preservation of distinct memory traces. These findings suggest that episodic events are flexibly encoded through both integrated and segregated neural representations, enabling the brain to support multiple memory functions depending on task demands.

neuroscience↗

bioRxiv2025

Bridging Hearts and Muscles: Genetic Insights into Cardiac Structure and Sarcopenia

BackgroundCurrently, the link between cardiovascular diseases and sarcopenia is increasingly garnering attention from researchers. However, studies exploring the association between cardiac structure and sarcopenia are sparse. This study aims to investigate the potential genetic links between cardiac structural features and sarcopenia. MethodsDuring the discovery phase, we employed Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) to assess the genetic correlation and causality between traits related to cardiac structure and sarcopenia, with further validation of the results using validation set data. In the study, we established a scoring system to identify high-confidence trait pairs. For these pairs, we conducted sensitivity analyses to assess their heterogeneity and pleiotropy. Additionally, we undertook follow-up studies of these trait pairs, including using mediation analysis to evaluate the potential mediating effects of lipids, and enrichment analysis to explore possible shared biological pathways linking these characteristics. ResultsThe genetic correlation analyses during the discovery and validation phases identified 5 pairs (in forward analysis) and 16 pairs (in reverse analysis) of high-confidence trait pairs. As a key sarcopenia-related feature, appendicular lean mass (ALM) exhibited positive causal relationships with several cardiac structural features, including the volumes of the left and right atria. Mediation analysis suggested that certain lipids, such as phosphatidylcholine, might mediate these causal relationships. Notably, gene and pathway enrichment analyses revealed that genes associated with significant SNPs in high-confidence trait pairs were enriched in multiple key biological processes and pathways, such as tube morphogenesis, cardiac right ventricle morphogenesis, and muscle system processes in the forward analysis, as well as skeletal system development, heart development, and hemopoiesis in the reverse analysis. Cell-type enrichment analysis pointed to endothelial cells, smooth muscle cells, fibroblasts, and mesenchymal stem cells. ConclusionsThis study provides evidence for genetic relationships between cardiac structures and sarcopenia-related traits. These findings may enhance our understanding of the biological mechanisms underlying age-related diseases and provide scientific basis for developing future preventive and therapeutic strategies.

genetics↗

bioRxiv2025

NOTCH1 Acts as a Tumor Suppressor That Induces Early Differentiation in Head and Neck Cancer

We identified frequent inactivating notch1 mutations in HNSCC over a decade ago, indicating its role as a tumor suppressor--unlike its oncogenic function in leukemias and salivary gland tumors. However, there has been much debate in the literature regarding a possible oncogenic role in HNSCC as well, based on reports that notch1 signaling drives tumor growth and a cancer stem cell phenotype in some HNSCC tumor lines and patient samples. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to the prognosis and personalized therapy of patients with either wild-type or mutated NOTCH1. Here we present a systematic and comprehensive investigation unequivocally demonstrating that notch1 signaling functions as a tumor suppressor in HNSCC regardless of mutation or activation status and leads to reduction in frequency of cancer stem cells. We develop a robust gene expression signature of notch1 activation based on experimental data that when applied to patient samples shows notch1 signaling is associated with very early differentiation, an altered tumor microenvironment, and better prognosis-- consistent with a tumor suppressive role. Our work unifies the field by reconciling conflicting data and providing critical insights into the biological and clinical significance of the NOTCH1 pathway in HNSCC.

cancer biology↗

bioRxiv2025

Isoform switch of CD47 provokes macrophage-mediated pyroptosis in ovarian cancer

Cancer cells expressing CD47 escape macrophage phagocytosis by binding to the SIRP ligand expressed on macrophages. CD47 targeted therapy offers a promising approach to cancer treatment. Here we report that two major isoforms of CD47 differ in ovarian cancer and normal tissues. The truncated isoform lacking exon 9 and exon 10 (CD47-S) was exclusively expressed in normal tissues, whereas the full-length isoform (CD47-L) was predominantly expressed in ovarian cancer tissues. Interestingly, CD47-S was unable to locate at the cell surface to bind with SIRP as CD47-L did, and thereby inactivated "dont-eat-me" signal. Mechanistic investigations revealed that splicing factor HNRNPA1 promoted splicing switch from CD47-L to CD47-S through exon 9 and exon 10 skipping. We further developed antisense oligonucleotides (ASOs) that effectively switched CD47-L to CD47-S. Importantly, ASOs treatment evoked macrophage-mediated antitumor immune response, thereby triggered pyroptosis of ovarian cancer cells. Moreover, CD47-targeting ASOs significantly reduced tumor growth in patient-derived xenograft. Together, ASO-mediated isoform switch of CD47 has emerged as a promising strategy to improve immune responses against tumors.

cancer biology↗

bioRxiv2025

Small non-coding RNAs encapsulating mammalian cells fuel innate immunity

Cell surface RNAs, notably glycoRNAs, have been reported, yet the exact surface RNA compositions in different cell types remain unclear. Here, we introduce a comprehensive suite of methodologies for imaging, profiling, quantifying, and exploring the biological functions of specific surface RNAs. Utilizing these techniques, we have identified diverse non-coding RNAs present on mammalian cell surfaces. We confirm the membrane anchorage and quantify the abundance of several representative RNAs on human primary cells. Notably, we discover a significant prevalence of Y RNAs on the surfaces of human monocytes and B cells. We find that these Y RNAs on human monocyte surfaces enrich extracellular histones, regulating interleukin-6 (IL-6) gene expression and subsequent protein secretion upon histone stimulation via NF-{kappa}B and AP-1 activation. Our study not only presents effective approaches for investigating surface RNAs, but also uncovers a previously unrecognized immune activation pathway mediated by surface Y RNAs on monocytes. In briefA comprehensive profiling of surface RNAs across diverse mammalian blood cell types unveil abundant Y RNAs on the surface of human monocytes. Subsequent investigations uncover functional roles of surface Y RNAs on monocytes as "immune sentinel" to enrich extracellular histones, revealing a previously unknown pathway of innate immune activation. HighlightsNovel methodologies for cell surface RNA mapping, validation and functional interrogation. Sequencing of surface RNAs across various mammalian blood cell types offers detailed maps of surface RNAs. Abundant Y RNAs localize on human monocyte surfaces and capture extracellular histones released by adjacent ruptured cells. Surface Y RNAs enrich extracellular histones to facilitate transcription and secretion of IL-6 through NF-{kappa}B and AP-1 activation.

molecular biology↗