Biology subjects

Fan, R.

Publications and source records attributed to Fan, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

SenNet Portal: Build, Optimization and Usage

Cellular senescence is a hallmark of aging and a driver of functional decline across tissues, yet its heterogeneity and context dependence have limited systematic study. The Common Funds Cellular Senescence Network (SenNet) Program addresses this challenge by generating multimodal, multi-tissue datasets that profile senescent cells across the human lifespan and complementary mouse models. The SenNet Data Portal (https://data.sennetconsortium.org) serves as the public gateway to these resources, providing open access to harmonized single-cell, spatial, imaging, transcriptomic, and proteomic data; senescence biomarker catalogs; and standardized protocols that can be used to comprehensively identify and characterize senescent cells in mouse and human tissue. As of April 2026, the portal hosts 2,041 publicly available human and mouse datasets across 15 organs using 6 general assay types. Experts from 13 Tissue Mapping Centers (TMCs) and 12 Technology Development and Application (TDAs) components contribute tissue data, analyze data, identify senescent biomarkers, and agree on panels for cross-tissue antibody harmonization. They also register human tissue data into the Human Reference Atlas (HRA) and develop user interfaces for the multiscale and multimodal exploration of this data. Built on a scalable hybrid cloud microservices architecture by the Consortium Organization and Data Coordinating Center (CODCC), the Portal enables data submission, management, integrated analysis, spatial context mapping, and harmonized access to cross-species data critical for aging research. This paper presents user needs, the Portals architecture, data processing workflows, and senescence-focused analytical tools; usage scenarios illustrating applications in biomarker discovery, quality benchmarking, hypothesis generation, spatial analysis, cost-efficient profiling, and cell distance distribution analysis; and utility and usage by the larger researcher community. Current limitations and planned extensions--including expanded spatial-omics releases and improved tools for senotype characterization--are discussed. SenNet protocols, code, and user interfaces are freely available on https://docs.sennetconsortium.org/apis.

bioinformatics↗

bioRxiv2026

The non-coding facet of Pink1 mRNA regulates mitochondria homeostasis

Coding and non-coding RNAs have traditionally been viewed as functionally distinct entities. Here, we found that the down-regulation of Pink1 due to Tet2 knockout (KO) in muscle cells resulted in mitochondria dysfunction and muscle fatigue. Surprisingly, both Pink1 mRNA alone and untranslatable ATG-deficient Pink1 RNA were sufficient to rescue the mitochondria defects in Tet2 KO cells. PINK1 protein was fast degraded shortly after translation and dispensable for functions of Pink1 mRNA in muscle cells. Moreover, a portion of Pink1 mRNA was located in mitochondria and interacted directly with mitochondria inner membrane located protein YME1L1, promoting its proteolytic cleavage of Opa1, a master regulator of mitochondria fusion, to generate the mature protein form. These findings uncovered a bona fide non-coding role for a canonical mRNA, suggesting that translation independent functions could be present in mRNAs with coding potentials, blurring the conventional dichotomy between coding and non-coding RNAs.

cell biology↗

bioRxiv2026

CAR-T-drug conjugate against solid tumor

Chimeric antigen receptor (CAR)-T cell therapy has been clinically successful in hematologic cancers but faces challenges in solid tumors, primarily due to limited tumor infiltration, immunosuppressive tumor microenvironments (TME), and antigen heterogeneity. While combining CAR-T cell therapy with chemotherapy can enhance antitumor activity, this often leads to substantial systemic toxicity. In this study, we introduce CAR-T-drug conjugate (CAR-T-D-C), a new class of dual-functional therapeutics that effectively addresses these obstacles by integrating click chemistry for precise conjugation of cytotoxic agents onto antigen-specific CAR-T cells. By transforming the hostile TME into an ally, this approach facilitates localized delivery of cytotoxic payload directly to the tumor site, enhancing the overall effectiveness of CAR-T therapy in solid tumors. CAR-T-D-Cs with different CAR-T cell binders exhibit robust antitumor activity across diverse solid tumor models, including both human tumor xenografts and syngeneic models. Spatial transcriptomic studies reveals that CAR-T-D-C achieves improved CAR-T tumor infiltration and functional activation within the TME. Compared to conventional CAR-T therapy, CAR-T-D-C markedly enhances immune cell infiltration, augments effector functions, promotes antigen spreading, amplifies systemic immune responses, and improves overall anti-tumor immunity. CAR-T-D-C represents a versatile therapeutic concept that combines the potency of small molecule drugs and the specificity of CAR-T cells as a 2-in-1 immunochemotherapy for treatment of solid tumors.

immunology↗

bioRxiv2025

SuperFocus enables whole-slide cell-level spatial omics from spot-based measurements and histology across modalities

Histopathology and molecular pathology are currently distinct diagnostic modalities for the most part, one revealing tissue morphology at cellular resolution and the other providing molecular measurements with limited or no spatial context. Projecting genome-scale molecular information onto histopathology images at single-cell resolution across whole tissue sections represents a long-sought goal for next-generation pathology. Here we present SuperFocus, a modality-agnostic computational platform that generates histopathology-integrated single-cell spatial multi-omics from spot-based spatial measurements acquired on the same or an adjacent section without requiring external reference data. SuperFocus combines constrained cascading imputation with feature-level and cell-level quality-control scores to reduce spurious predictions and quantify confidence. On a ground-truth spatial transcriptomics benchmark dataset, SuperFocus improves key accuracy metrics by 28-73% over existing methods. Across Patho-DBiT, spatial ATAC-RNA, spatial CITE-seq and Visium-MALDI-MSI (SMA) datasets, SuperFocus enables cell-resolved analyses of MALT lymphoma microenvironments, gene regulatory programs in human hippocampus, lipotoxic hepatocyte states in human MASH, and transcriptomic-metabolomic states linked to neurotransmission and neuroinflammation in Parkinsonian mouse brain. Overall, SuperFocus enables scalable whole-slide single-cell spatial multi-omics integrated with histopathology, bridging histology and genome-scale molecular profiling for next-generation molecular pathology.

bioinformatics↗

bioRxiv2025

A minor muscle stem cell population functions as metabolic Trojan horse fueling systemic aging by succinate induced epigenetic reprogramming

Inflammaging, the sustained chronic inflammation, is a hallmark of aging, yet its sustained activation mechanism remains elusive. Here, we identified muscle stem cells (MuSCs) as a driver of systemic inflammaging, evidenced by the multi-organ inflammation and aging phenotypes in MuSC specific Tet2 knockout mice. Tet2-Hdac11-Acod1-SDH axis maintained normal succinate level in MuSCs. Tet2 knockout disrupted this enzymatic cascade and led to succinate accumulation, fueling H4K31succ elevation to directly activate inflammatory gene transcription in MuSCs. The excess succinate was delivered to muscle fibers by sporadic fusion of Tet2 knockout MuSCs during muscle homeostasis, activated pro-inflammatory program, and transformed muscle to a persistent pro-inflammatory factor secretory organ, sustaining systemic inflammaging. Moreover, Tet2 was downregulated in aged MuSCs suggesting that this coupled metabolic-epigenetic mechanism was active in physiological aging. These findings reveal that a small subset of dysregulated MuSCs activate sustained whole-body inflammaging and multi-organ aging, providing new targets for rejuvenation strategy development.

cell biology↗

bioRxiv2025

Imaging Cellular Metabolic Rewiring with SuMMIT-SRS

Cells dynamically rewire their metabolic pathways in response to physiological and pathological cues. Such plasticity is particularly critical in neurons, stem cells, cancer cells, and immune cells, where biosynthetic demands can shift rapidly. However, current metabolic imaging techniques using isotope labeling typically track only one metabolite at a time, limiting their ability to capture the rapid dynamics of complex metabolic networks including coordinated precursor utilization, crosstalk, and turnover. Here, we present Subcellular Multiplexed Metabolic Isotope Tracing Stimulated Raman Scattering microscopy (SuMMIT-SRS), a platform that enables simultaneous visualization of multiple metabolic dynamics at subcellular resolution. By exploiting the distinct vibrational signatures of carbon-deuterium bonds derived from multiple deuterated amino acids, lipids, and monosaccharide tracers, SuMMIT-SRS maps co-regulated DNA, RNA, protein, and lipid synthesis at the same time and resolves various individual amino acid-mediated metabolic pathways within intact cells and tissues. We demonstrate SuMMITs broad utility across Drosophila fat body tissue and developing brain, tumor organoids, aged human neurons, and mouse liver, capturing cell type-specific metabolic rewiring under genetic and pathological perturbations. This approach extends SRS to multiplexed isotope tracing, offering a powerful tool to uncover dynamic and complex biosynthesis programs in development, health, and disease.

bioengineering↗

bioRxiv2025

Exploring endothelial cell environments across organs in spatially resolved omics data

Endothelial cells are ubiquitously present in the human body and line the luminal surface of blood and lymphatic vessels. The oxygen-dependence of cells impacts their proximity to blood vessels, and consequently, to endothelial cells depending on their functional properties and priorities. This paper presents cell-to-nearest-endothelial-cell distance distributions for various cell types using 399 spatially resolved omics datasets from 14 studies comprising 12 tissue types with a total of 47,349,496 cells. Additionally, we developed an open-source web-based interactive tool, Cell Distance Explorer, that allows researchers to interactively visualize cell graphs and linkages in 2D and 3D datasets. Finally, we present a hierarchical neighborhood analysis focused on the endothelial cell neighborhoods in small and large intestine datasets. This paper provides an open-access resource (datasets, tools, and analyses) to characterize and compare cell distances and cell neighborhoods in spatially resolved omics data.

bioinformatics↗

bioRxiv2025

3D multi-omic mapping of whole nondiseased human fallopian tubes at cellular resolution reveals a large incidence of ovarian cancer precursors

Uncovering the spatial and molecular landscape of precancerous lesions is essential for developing meaningful cancer prevention and early detection strategies. High-Grade Serous Carcinoma (HGSC), the most lethal gynecologic malignancy, often originates from Serous Tubal Intraepithelial Carcinomas (STICs) in the fallopian tubes, yet their minute size and our historical reliance on standard 2D histology contribute to their underreporting. Here, we present a spatially resolved, multi-omics framework that integrates whole-organ 3D imaging at cellular resolution with targeted proteomic, metabolomic, and transcriptomic profiling to detect and characterize microscopic tubal lesions. Using this platform, we identified a total of 99 STICs and their presumed precursors that harbor TP53 mutations in morphologically unremarkable tubal epithelium in all five specimens obtained from cancer-free organ donors with average-risk of developing ovarian cancer. Although these lesions comprised only 0.2% of the epithelial compartment, they displayed geographic diversity, immune exclusion, metabolic rewiring, and DNA copy number changes among lesions and normal fallopian tube epithelium discovered alterations in STIC-associated genes and the pathways they control. In sum, this platform provides a comprehensive 3D atlas of early neoplastic transformation, yielding mechanistic insights into tumor initiation and informing clinical screening strategies for detecting cancer precursors in whole organs at cellular resolution.

bioinformatics↗

bioRxiv2025

Erucamide regulates retinal neurovascular crosstalk

Neurovasculoglial crosstalk is critical in establishing and maintaining a functional neurovascular unit. Breakdown in the unit is central to many neurodegenerative disorders of the CNS of which the retina is a component. A growing literature indicated that primary fatty acid amides (PFAMs) can regulate this crosstalk between vasculature and neuronal tissues. In this study we describe a central role for erucamide, a 22:1 mono-unsaturated omega-9 fatty acid amide, in degenerating retinal tissues. Using high-resolution global mass spectrometry-based metabolomics, we cataloged metabolites in murine models of retinal degeneration and show that while PFAMs, in general, are highly dysregulated, erucamide is the one most significantly diminished during photoreceptor atrophy. Using rodent models of retinal degeneration and novel organosilane-modified porous silicon nanoparticles (pSiNPs) for the in vivo delivery of erucamide, we demonstrate that erucamide activates CD11b+ myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that stabilize retinal degeneration. We identified TMEM19 as a novel binding protein for erucamide that is crucial for human iPSC-derived macrophage precursor cells activation and subsequent neurotrophic and angiogenic factor production. These findings reveal a previously unknown PFAM pathway that is modulated during retinal degenerative diseases, demonstrating that erucamide or functional analogues and their action through TMEM19 may be useful as a therapeutic alternative to neuroprotective and stem cell-based approaches for the treatment of retinal degenerative diseases.

neuroscience↗

bioRxiv2025

Combined multi-color immunofluorescence staining and spatial in situ mRNA expression analysis identifies potential fibrosis drivers in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer. Bone marrow (BM) fibrosis in ALL has been associated with adverse outcomes, however, little is known about the mechanisms that cause fibrosis in ALL. Therefore, we established a novel and advanced analysis method by combining multi-color immunofluorescence staining with in-situ RNA expression analysis (RNAscope(R)) investigate the spatial expression of putative fibrotic drivers in ALL bone marrows. We analyzed standard BM biopsies from pediatric ALL patients. Sequential 5-color immunofluorescence (IF) staining with CD45, CD271, CD31, CD34 and DAPI was used to identify different BM cell types. Combined RNAscope(R) and IF staining was established for spatial mRNA expression analysis of transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor alpha 1 (PDGFA1), which are known to play major roles in primary myelofibrosis (PMF). PMF and normal BM samples served as controls. As expected, ALL bone marrows showed high cellularities and prominent populations of blast cells. CD271+ MSC density was increased in ALL and was associated with fibrosis in a similar manner as observed for PMF. TGFB1 and PDGFA1 expression was considerably increased in ALL megakaryocytes (MKs) compared to PMF patients and normal controls. Furthermore, MK TGFB1 and PDGFA1 expression intensities in fibrotic ALL correlated with fibrosis grade. TGFB1 and PDGFA1 were also expressed in leukemic blasts, however at lower intensities compared to ALL MKs. Taken together, advanced in-situ RNA and IF staining not only revealed increased expression of TGFB1 and PDGFA1 in fibrotic pediatric ALL, but also identified ALL blasts and MKs as their cellular origin at the single cell level. These novel data strongly suggest a role of these cytokines as potential fibrosis drivers in ALL. More broadly, our findings demonstrate that combined RNA and surface marker analysis is a powerful tool to provide new and valuable insights into bone marrow pathophysiology.

cell biology↗

bioRxiv2025

A large-scale foundation model for bulk transcriptomes

Large language models (LLMs) have emerged as powerful foundation models leading to breakthroughs in transcriptome analysis. However, current RNA-seq foundation models are exclusively pretrained on sparse single-cell RNA-seq (scRNA-seq) data, which typically detects only [~]3000 genes per cell. This thus creates a critical gap in models specifically designed for bulk transcriptomes, a fundamentally different modality capable of profiling [~]16,000 genes per sample. Here we propose BulkFormer, a large-scale foundation model for bulk transcriptome analysis. With 150 million parameters covering about 20,000 protein-coding genes, BulkFormer is pretrained on over 500,000 human bulk transcriptomic profiles. BulkFormer incorporates a hybrid encoder architecture, combining a graph neural network to capture explicit gene-gene interactions and a performer module to model global expression dependencies. As a result, despite incurring much lower training costs than scRNA-seq foundation models, BulkFormer consistently outperforms them in all six downstream tasks: transcriptome imputation, disease annotation, prognosis modeling, drug response prediction, compound perturbation simulation, and gene essentiality scoring. Notably, BulkFormer not only enhances the discovery of novel clinical biomarkers but also uncovers latent disease mechanisms by imputing biologically meaningful gene expression. Collectively, these results demonstrate BulkFormers power as a versatile and robust framework for bulk transcriptome modeling and biomedical discovery, bridging a critical gap in the current foundation model landscape.

bioinformatics↗

bioRxiv2025

Non-redundant roles of the HDAC3 corepressor complex subunits SMRT and NCOR in controlling inflammatory and metabolic macrophage pathways

Transcription factors and coregulators coordinate inflammatory and metabolic pathways in macrophages through epigenetic and transcriptional mechanisms. The HDAC3 corepressor complex plays fundamental roles in these mechanisms, with the homologous subunits SMRT and NCOR being critical for complex assembly and interactions with transcription factors and chromatin. However, the relative contribution of SMRT and NCOR in controlling complex-dependent macrophage pathways remains poorly understood. Here, we assessed their genome-wide roles in mouse macrophage RAW264.7 cells and in bone marrow-derived macrophages. Transcriptome analysis upon corepressor depletion identified six differentially expressed gene clusters. SMRT depletion primarily upregulated inflammation-related pathways, NCOR depletion primarily upregulated metabolism-related pathways. Epigenome analysis revealed that corepressor depletion differentially altered chromatin accessibility and H3K27 acetylation, consistent with transcriptome changes. Cistrome analysis revealed that both corepressors differentially influence each other at chromatin. SMRT uniquely controls the chromatin binding and nuclear localization of NCOR, GPS2 and HDAC3, thus acting as the chromatin anchor for the corepressor complex. Finally, corepressor depletion differentially modulated macrophage reprogramming in response to TLR4, IL4 and LXR signaling. Overall, our study reveals a hitherto underappreciated non-redundant role of SMRT and NCOR in coordinating chromatin accessibility, H3K27 acetylation, enhancer activity and transcription to differentially regulate inflammatory and metabolic macrophage pathways. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/653058v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d9f2dforg.highwire.dtl.DTLVardef@1d81386org.highwire.dtl.DTLVardef@e9e536org.highwire.dtl.DTLVardef@1c74c15_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Spatial epigenomic niches underlie glioblastoma cell state plasticity

IDH-wildtype glioblastoma (GBM) is an aggressive brain tumor with poor survival and few therapeutic options. Transcriptionally-defined cell states coexist in GBM and occupy defined regions of the tumor. Evidence indicates that GBM cell states are plastic, but it remains unclear if they are determined by the underlying epigenetic state and/or by microenvironmental factors. Here, we present spatially-resolved epigenomic profiling of human GBM tissues that implicate chromatin structure as a key enabler of cell plasticity. We report two epigenetically-defined and spatially-nested tumor niches. Each niche activates short-range molecular signals to maintain its own state and, surprisingly, long-range signals to reinforce the state of the neighboring niche. The position of a cell along this gradient-like system of opposing signals determines its likelihood to be in one state or the other. Our results reveal an intrinsic system for cell plasticity that is encoded in the chromatin profiles of two adjacent niches that dot the topological architecture of GBM in cartesian space.

genomics↗

bioRxiv2025

Synapses drive local mitochondrial ATP synthesis to fuel plasticity

Our brain constantly forms new memories and stabilizes existing memories. To achieve such cognitive flexibility, the brain is wired by plastic synapses that are hotspots of energy consumption. Supplying energy to distant synapses is challenging as they are distributed throughout dendrites and axons, spanning hundreds of microns from their cell body. Synapses, therefore, require an instant and local energy supply provided by mitochondria stabilized near dendritic spines. However, the mechanisms by which synapses communicate their energy demands to locally stable mitochondria to drive local energy production and sustain synaptic plasticity is unknown. Using highly sensitive spine- and mitochondrial ATP reporters and two-photon glutamate uncaging to stimulate individual spines, we find that synaptic plasticity input drives instant and sustained increase in spine ATP levels, provided by local ATP synthesis in [~]10-20 m spatially confined compartments within mitochondria. This spatially localized mitochondrial ATP generation is driven by a spatially localized mitochondrial calcium influx independent of the endoplasmic reticulum. Notably, the initial spine ATP increase, supported by local mitochondrial ATP synthesis, is independent of CaMKII and the energy demands of spine structural plasticity. Without local calcium signaling and mitochondrial stabilization, synapses do not meet their instant and sustained energy needs, resulting in synaptic plasticity defects, as observed in neurological disorders.

neuroscience↗

bioRxiv2025

Cellular and molecular mechanism for reproductive capacity of male Mongolian cattle basing on single-cell sequencing for testis

Mongolian cattle is an excellent local breed with strong reproductive ability in Inner Mongolia of China. Spermatogenesis is a comprehensive process to decide the reproductive ability. In order to understand the cellular and molecular mechanism of spermatogenesis of Mongolian cattle, scRNA-seq was used to describe the heterogeneity of cells and gene expression profile in testis. The results showed 8 cell clusters. Among somatic cells, Sertoli cells were obviously more in young cattle than that in adult cattle, moreover, there were 4 subpopulations of Sertoli cells (SC1[~]4). In the matured Sertoli cells (SC4), up-regulated genes were mainly enriched in immune system activity, enhancing immune response, and regulating cellular processes. The top 5 marker genes (BTG2, FOSB, EGR1, JUNB, CCNL1) were highly expressed in the testes of Mongolian cattle and water buffalo compared to Holstein cattle, which were highly expressed in the developing SC1. Gain/loss-of-function of EGR1 in Sertoli cells isolated from Mongolian cattle testes positively regulated the expression of FOS and JUN. The results indicated that SC1 acted as the foundation and SC4 as the matured supportive cells and EGR1 would promote the spermatogenesis by regulating AP-1 transcription factor member FOS and JUNto maintain strong reproductive capacity of Mongolian cattle.

developmental biology↗

bioRxiv2025

Inhibition of DHODH Activates Pyroptosis and cGAS-STING Pathways to Enhance NK cell Infiltration Mediated Anti-tumor Immunity in Melanoma

Cancer cells are heavily reliant on de novo pyrimidine synthesis. Suppression of pyrimidine metabolism directly inhibits tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH), a crucial enzyme governing de novo pyrimidine synthesis, is a critical player in this context. Inhibition of DHODH not only reverses immunosuppression but also instigates a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains unexplored. In this study, we found that inhibition of DHODH efficiently promotes NK cells infiltration in tumors. Suppression of DHODH led to increased oxidative stress in mitochondria, the release of mtDNA, and activation of caspase 3, which in turn activated the cGAS-STING pathway and pyroptosis in cancer cells, respectively, contributing to NK cells induced antitumor immune responses in melanoma. Additionally, we developed EA6, a novel DHODH inhibitor with higher efficacy in promoting NK cells infiltration. In summary, this study underscores that modulation of pyrimidine metabolism can effectively trigger antitumor immune responses, with a specific emphasis on NK cells. This finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/644471v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@88d4fcorg.highwire.dtl.DTLVardef@156fe1aorg.highwire.dtl.DTLVardef@448086org.highwire.dtl.DTLVardef@152079c_HPS_FORMAT_FIGEXP M_FIG C_FIG The anti-tumor mechanisms of DHODH inhibition. Inhibition of DHODH activates cGAS-STING pathways to enhance NK cell infiltration. And the tumor-infiltrating NK cells facilitate melanoma cells pyroptosis which providing a positive feedback mechanism for DHODH-mediated anti-tumor immunity.

cancer biology↗

bioRxiv2025

Comprehensive profiling of N6-methyladnosine (m6A) readouts reveals novel m6A readers that regulate human embryonic stem cell differentiation

N6-methyladenosine (m6A) methylation has emerged as a prevalent RNA modification that extensively impacts various physiological and pathological processes via various post-transcriptional readout effects in mammals. High-throughput methylome profiling has outlined the landscape of m6A modification sites, but their downstream readouts require comprehensive investigation. To this end, we systematically assessed the effects of m6A on mRNA half-life, translation efficiency, and alternative splicing across five cell lines (A549, HEK293T, HUVEC, JURKAT, and human embryonic stem cells (hESCs)) using actinomycin D-disrupted temporal transcriptome sequencing, ribosome sequencing, and ultra-high-depth transcriptome sequencing, respectively. Our analysis, coupled with the integration of public and re-profiled m6A methylome data, revealed high cell type specificity in m6A readouts where m6A level alone is insufficient to predict m6A readouts. Machine learning models focused on the RNA binding protein (RBP) binding context of m6A sites demonstrated substantial predictive ability of m6A readouts while prioritizing putative m6A readers from their informative RBP features. Four novel m6A readers (DDX6, FUBP3, FXR2, and L1TD1) were identified and validated through m6A RNA pull-down assays and transcriptome-wide RBP binding site mapping. Notably, FUBP3, FXR2 and L1TD1 were found to regulate hESC differentiation without impairing self-renewal, underscoring their critical roles in stem cell biology. Together, this study bridges the gap in understanding m6A functional readouts and lays the groundwork for future research on m6A-mediated stem cell fate decisions.

genomics↗

bioRxiv2025

Highly accurate prediction of broad-spectrum antiviral compounds with DeepAVC

Lethal viruses, such as HIV, pose a significant threat to human life, with each pandemic causing millions of fatalities globally. Small-molecule antiviral drugs provide an efficient and convenient approach to antiviral therapy by either inhibiting viral activity or activating the host immune system. However, conventional antiviral drug discovery is often labor-intensive and time-consuming due to the vast chemical space. Although some existing computational models mitigate this problem, there remains a lack of rapid and accurate method specifically designed for antiviral drug discovery. Here, we propose DeepAVC, a universal framework based on pre-trained large language models, for highly accurate broad-spectrum antiviral compounds discovery, including two models, DeepPAVC for phenotype-based prediction and DeepTAVC for target-based prediction. As a result, DeepAVC greatly outperforms other in silico methods. More importantly, in the top predictions, MNS and NVP-BVU972 were identified as novel compounds with promising broad-spectrum antiviral activities by in vitro experiments. Finally, DeepAVC demonstrates high interpretability, one of the bottlenecks of current AI methods, due to its ability of analyzing key functional groups of antiviral compounds and important binding sites on targets.

bioinformatics↗