bioRxiv Science⌕ Search

Biology subjects

Shao, J.

Publications and source records attributed to Shao, J..

At least 19 recordsLinked to original sources

DNA-LLM2Vec: Architecture-Aware Task-Conditioned Adaptation of Decoder DNA Foundation Models

Decoder DNA foundation models pretrain with dense next-token prediction and scale to long sequences, but their representations are directional. This is a poor fit for genomic tasks that need sequence context both upstream and downstream of a locus. Bidirectional masked-language-model encoders supply this context, but they pretrain more sparsely and scale less easily to long windows. We introduce DNA-LLM2Vec, a staged decoder-to-encoder framework that opens bidirectional context, repairs the resulting mismatch with masked next-token prediction, and applies contrastive views encoding strand and positional invariance. We instantiate it on two architecturally distinct backbones, DNAGPT and HyenaDNA, and evaluate seven biological task families (grouped from GB, NT, GUE, and GUE+EPI) with frozen linear probing. The benefits of conversion are architecture-aware and task-conditioned rather than uniform. Crop-based positional contrastive learning helps most for the extended-context families (enhancer-promoter interaction and Virus-COVID), raising frozen Avg-EPI MCC to 27.5% for DNAGPT and 26.7% for HyenaDNA, whereas for shorter, local families the results depend on backbone and tokenisation. Beyond classification, bidirectional context and MNTP improve causal-eQTL variant-effect prediction specifically at distance, and a base-pair mutagenesis diagnostic shows that adaptation organises motif-aware contact structure while reverse-complement training imprints strand-consistent geometry, yet neither predicts the best downstream view. DNA-LLM2Vec therefore produces frozen bidirectional representations whose most effective adaptation view depends on the task structure and the backbone. Code and checkpoints are available at https://github.com/semi-nothing/dna-llm2vec.

bioinformatics↗

Scalable methylome-transcriptome profiling resolves clonal organization in human hematopoiesis

Understanding human tissue maintenance and remodeling requires linking clonal ancestry to molecular state, yet scalable joint measurement remains challenging. Here, we introduce Droplet-MT and an integrated computational workflow for joint transcriptome and methylome profiling at ~10,000 cells per library. Methylation epimutations enable mutation-independent clonal reconstruction from high-coverage methylomes, while reference-based label transfer assigns cells to established clones at ~0.2% CpG coverage, reducing sequencing cost. Clone-aggregated somatic variants provide genetic annotation without additional single-cell genotyping. Across ~21,000 paired profiles from healthy blood and longitudinal acute myeloid leukemia, we resolved small and expanded clones with heterogeneous lineage output. In leukemia, the framework distinguished changes in malignant clonal abundance, state remodeling within persistent clones, and recovery of healthy polyclonal hematopoiesis. Malignant monocytes remained transcriptionally and epigenetically distinct from healthy and recovery-associated cells despite treatment-associated remodeling. Droplet-MT enables scalable analysis of human tissues by linking clonal organization with molecular state and retrospective genetic annotation.

genomics↗

Virtual-cell verification enables self-auditing AI discovery for immune rejuvenation

Artificial-intelligence agents propose drug-discovery hypotheses faster than experiments can test them, yet their conclusions are rarely verified, against the underlying biology, the predicted perturbation, or the agent's own scoring logic. We close this verification gap with an agentic framework built on three verifiers. First, PACE, a phenotype verifier, resolves immune aging into ten directionally scored, cell-type-resolved gene-set modules, selected for cross-cohort stability across four PBMC cohorts, and outperforms five established aging clocks in an independent in-house aging cohort of 434 elderly donors. Second, CellQ, a virtual-cell verifier built with multi-modal LLM, compresses each single-cell transcriptome into eight discrete tokens aligned to a language model's vocabulary through residual vector quantization; it attains state-of-the-art perturbation prediction and uniquely resolves the weak, module-level shifts that differential-expression recovery misses. Third, an Analyzer-Planner-Auditor agent verifies its own scoring logic: screening 110 compounds in primary human PBMCs, it found aged-down modules more reversible than aged-up modules and revised its objective from an equal-weight mean to a balance-constrained minimum, a self-correction that generalized to an independent 13-compound T-cell assay. By verifying its predictions and its own objective against experiment, the framework points beyond hypothesis-generating AI toward self-correcting AI scientists whose objectives could continuously evolve.

bioinformatics↗

An Integrated Multi-omics Single Cell Atlas of the Human RPE and Choroid

The retinal pigment epithelium and choroid are critical for supporting the function and maintaining the homeostasis of the outer retina, and their dysfunction underlies a range of inherited and complex ocular diseases. To comprehensively characterize the cellular, transcriptomic, and epigenomic heterogeneity and dynamics within these tissues, we assembled an integrated multi-omics reference atlas comprising 719,813 single-cell/single-nucleus transcriptomes and 234,007 snATAC-seq profiles from 102 ancestrally diverse donors spanning 0 to 99 years of age, including cells from both the macula and periphery. This atlas resolves 48 distinct cell types or states and catalogs 448,567 open chromatin regions. Specifically, we resolved five distinct RPE subpopulations organized along a central-to-peripheral spatial axis, alongside two distinct stress/senescence states. We reconstructed the transcriptomic and epigenetic zonation of endothelial cells and expanded choroidal stromal heterogeneity by characterizing 11 fibroblast and two pericyte types. Age-associated compositional analysis revealed a significant fractional depletion of melanocytes, PI16+ fibroblasts, and venule endothelial cells with age, alongside a modest relative loss of central RPE and a corresponding increase in far-peripheral RPE. Cell-type-specific aging transcriptomics uncovered shared pathways related to inflammatory responses alongside distinct cell-type-specific signatures. Notably, significant age-associated epigenetic changes concentrated in the macula during the transition from early-to-middle adulthood and remained stable into old age, with transcription factors from the AP-1/bZIP family emerging as the dominant enriched motifs. Finally, integrating this atlas with AMD GWAS data provides novel variant-to-gene evidence implicating LIPG and COL4A3 in AMD pathogenesis. Together, this multi-omics atlas serves as both an invaluable community reference and a powerful discovery engine that translates genetic risk signals into localized target cells and candidate mechanisms, laying a foundation for understanding RPE/choroid biology in health and disease.

genomics↗

Peri-Locus Coeruleus Controls Endothelial Cell Heterogeneity in Enriched Environments via Region-Specific Norepinephrine Signaling

The brain acts as a central integrator that enables organisms to interpret environmental stimuli and coordinate adaptive responses across the body. While enriched environments are known to enhance neural plasticity and cognitive function, their impact on peripheral organ systems remains less understood. Here, we show that enriched environmental conditions activate a peri-locus coeruleus (peri-LC) neuronal ensemble that preserves CD31hiEMCNhi type H endothelium, a specialized bone-associated endothelial subtype, against age-associated decline, thereby enhancing femoral bone density. Chemogenetic activation and ablation experiments further revealed that this peri-LC ensemble is functionally distinct from other sympathetic regulatory brain regions in its control of bone endothelial heterogeneity and skeletal mass. Three-dimensional bone clearing and spatial analyses showed that CD31hiEMCNhi endothelium is closely associated with sympathetic nerve terminals. The peri-LC mediates this process through sympathetic signaling and {beta}2-adrenergic receptors on bone vascular endothelial cells. In vivo imaging further demonstrated that norepinephrine release is spatially restricted, with sprouting endothelial cells near the growth plate exhibiting the highest sensitivity. Together, these findings reveal a refined brain-periphery regulatory logic in which distinct sympathetic brain circuits engage spatially restricted norepinephrine signaling to coordinate organ-specific vascular and skeletal adaptations.

neuroscience↗

An Integrated muti-omics cell atlas of the human trabecular meshwork and ciliary body

The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM/Schlemms canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type-specific programs, including OTX/PAX networks in CB epithelium and SMAD3/TGF-{beta} signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1, suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.

genomics↗

Mechanisms of CD4+ T tolerance to a corneal epithelial neoantigen

Tissue-specific peripheral tolerance mechanisms are essential to prevent autoimmunity. The cornea is immune privileged, and anterior chamber-associated immune deviation (ACAID) governs its inner surface. However, the mechanisms that apply to corneal epithelial (outer surface) antigens remain unknown. Using an inducible, cornea-restricted neoantigen mouse model, we found that the cornea relies on inducible regulatory T cells (Tregs) rather than ignorance or ACAID for its epithelial antigens. Although the cornea is both avascular and alymphatic, its epithelial antigens are still efficiently presented by ocular surface-derived antigen-presenting cells to T cells in draining lymph nodes under homeostatic conditions, leading to conventional antigen-specific Treg expansion without ocular pathology. This tolerance was not absolute: systemic immunization redirected antigen-specific responses toward pathogenic effector T cells that disrupted epithelial barrier function. These findings identify Treg induction as a dominant mechanism of corneal epithelial immune homeostasis and demonstrate that inflammatory priming can render a tolerated corneal antigen into an autoimmune target, providing mechanistic insight into dry eye pathogenesis. SummaryThis study shows that immune tolerance to corneal epithelial neoantigens relies not on immune privilege but on peripherally induced regulatory T cells in the draining lymph nodes that can be subverted by innate activation, shedding light on ocular surface disease pathophysiology.

immunology↗

Fasting primes small intestinal regeneration after damage via a microbiome metabolite chromatin axis

Fasting enhances small intestinal regeneration after radiation but the contribution of the gut microbiome to this process remains uncharacterized. We identify Akkermansia muciniphila (AKK) as a key mediator of this response. AKK was enriched in fasted mice and its antibiotic depletion abrogated radioprotection whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with AKKs metabolic output. AKK-conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced AKK-dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of persister stem cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including Clu, Olfm4, Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2. These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister stem cells for rapid regeneration of the intestinal epithelium following radiation-induced injury. Significance StatementFasting changes the gut microbiome, but how these changes help the body recover from damage is not well understood. We found that fasting increases a helpful bacterium, Akkermansia muciniphila, which produces propionate, which drives epigenetic changes by modifying histones and regulating gene activity. These changes promote the expansion of persister stem cells that help the intestine recover after radiation. This study shows how fasting and gut bacteria work together to protect healthy tissue and suggests that diet or microbial treatments could help reduce side effects of cancer radiotherapy.

cell biology↗

Multi-dimensional diffusion MRI at ultra-high gradient strength for mapping axonal architecture and microstructure in the primate brain

We present the most comprehensive sampling of the macaque and human brain with diffusion MRI to date. As part of the BRAIN CONNECTS center for Large-scale Imaging of Neural Circuits, we leverage ultra-high-gradient MRI systems, including the first-of-its-kind Connectome 2.0, for post-mortem acquisitions. Each sample is imaged for [~]250 hours at multiple spatial resolutions down to 0.25 mm isotropic for whole macaque brains and 0.4 mm isotropic for human hemispheres. Our optimized protocols allow us to sample both species across [~]50 diffusion shells varying in b-value, diffusion time, and echo time, reaching ultra-high b-values up to 64000 s/mm2 with high signal-to-noise ratio. We demonstrate that these multi-dimensional data resolve not only white matter connectional architecture but also cortical and subcortical cytoarchitectonic boundaries, at a level of detail previously inaccessible in whole-brain noninvasive imaging. As such, these data are an important resource for both technical development and basic and clinical neuroscience.

neuroscience↗

Pragmatic analysis with knowledge-guided for unraveling peptide-protein pairwise non-covalent mechanisms

Understanding peptide-protein interactions is vital for decoding cellular signaling and developing targeted therapies. However, the complexity of multi-molecular associations and diverse non-covalent interactions make accurate prediction and site-specific annotation challenging. Here, we propose KGIPA, a knowledge-guided pragmatic analysis framework that incorporates pragmatic concepts from natural language into life science, capturing the influence of biological environments on non-covalent interactions. KGIPA integrates intra- and extra-linguistic contextual information to combine multimodal single-molecule features and build residue-level interaction maps. It also uses biological prior knowledge to coordinate various non-covalent interaction types. Benchmark tests demonstrate KGIPA outperforms the state-of-the-art methods in evaluating molecular binding, including protein and peptide binding residues and residue-pair interactions. Furthermore, KGIPA demonstrates strong performance in peptide-protein binding affinity prediction and peptide virtual screening. Wet-lab experiments validate its reliability, revealing high consistency between predicted and experimentally measured binding behaviors. These results highlight KGIPAs potential to accelerate peptide drug discovery and establish pragmatic analysis as an effective paradigm for decoding the molecular language of interactions.

bioinformatics↗

A conserved and predictable pluripotency window in callus unlocks efficient transformation in grasses and beyond

A major bottleneck in plant biotechnology is the inefficient and genotype-dependent regeneration of callus, which severely limits genetic transformation and functional studies across many species. This barrier is acutely exemplified in the study of beneficial plant-microbe interactions, such as the Epichloe-grass symbiosis--a system conferring remarkable stress tolerance to its host but hindered by a lack of efficient genetic tools. To address this, we established a chromosome-scale genome for an Epichloe native host grass Achnatherum inebrians. We discovered that the expression dynamics of evolutionarily conserved cell pluripotency regulators (CPRs) including ARF5/7/19, BBM, WUS/WOX5 and CUC1/2 serve as a precise molecular predictor for callus regenerative capacity, revealing that pluripotency is dynamic and peaks within a narrow, definable time window. Harnessing this predictable window enabled the development of a highly efficient transformation system for A. inebrians (49.4% efficiency). Crucially, this CPR-based strategy proved generalizable: applied to wheat and the legume sainfoin, it pinpointed species-specific optimal regeneration windows, boosting shoot regeneration rates to 65.7% and 87.5%, respectively. Collectively, our work provides an integrated research system and a rational design principle that removes a key barrier to uncovering molecular mechanisms in plant systems, particularly the Epichloe-enhanced stress tolerance symbiosis.

plant biology↗

Comparative single-cell multiomic analysis reveals evolutionarily conserved and species-specific cellular mechanisms mediating natural retinal aging.

Biological age is a major risk factor in the development of common degenerative retinal diseases such as age-related macular degeneration and glaucoma. To systematically characterize molecular mechanisms underlying retinal aging, we performed integrated single- cell RNA- and ATAC-Seq analyses of the retina and retinal pigment epithelium (RPE) across the natural lifespan in zebrafish, mice, and humans. By profiling gene expression and chromatin accessibility, we identified extensive cell type- and species-specific aging-dependent changes, with a much smaller number of broadly expressed and conserved genes that include regulators of inflammation and autophagy. We constructed predictive aging clocks for retinal cell types and observed dynamic, reversible shifts in cellular age following acute injury. Spatial transcriptomic analysis revealed region-specific aging signatures and proximity effects, with Muller glia exhibiting pro-rejuvenating influences on neighboring neurons. Targeted Muller glia-specific induction of Yamanaka factors reduced molecular age in rod photoreceptors and bipolar cells without altering glial age. Our findings define conserved and divergent regulatory and signaling pathways mediating retinal aging, highlighting Muller glia as potential therapeutic targets for combating age-associated retinal dystrophies.

neuroscience↗

Claustrum-cortical reciprocal connections orchestrate allostatic responses following stress

Anxiety is an evolutionarily conserved response that supports threat detection and survival, yet dysregulated stress responses can drive its progression into pathological states. Here, we identify the claustrum (CLA) as a central hub that links acute stress responses to chronic affective dysfunction through cell-type-specific circuit dynamics. Acute social defeat stress robustly activated the CLA and induced anxiety-like behaviors in mice. Multimodal profiling revealed transcriptional and functional plasticity within CLA neurons, with Egr2-expressing excitatory and Gad2-expressing inhibitory populations exhibiting distinct adaptations to acute versus chronic stress. We further delineate a reciprocal CLA-anterior cingulate cortex (ACC) circuit that bidirectionally regulates stress responses in which glutamatergic CLAEgr2 [->] ACC projections promoted anxiety-like behaviors, whereas top-down ACC [->] CLAGad2inhibitory inputs constrained claustral output. Chronic stress induced hyperactivity in CLAGad2 inhibitory neurons and reshaped excitatory neuron dynamics, leading to increased intrinsic excitability, local circuit imbalance, and ultimately, depression-like phenotypes. These findings define a dynamic claustrum-centered circuit that governs the transition from adaptive anxiety to maladaptive affective states through balanced Egr2-Gad2 activity, and show that chronic-stress driven disruption of this excitatory-inhibitory equilibrium impairs stress coping and drives pathological behavioral outcomes. Graphic summaryAcute stress engages a claustrum (CLA)-centered network with activation of Egr2 excitatory neurons, promoting anxiety-like behaviors. Chronic stress drives CLAG142 neurons into a hyperactive state, enhancing local inhibition and suppressing excitatory output to induce depressive-like behaviors. A reciprocal CLAE7182[->]ACC feedforward and ACC[->]CLAG142 feedback circuit forms a state-dependent regulatory hub governing stress adaptation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/673892v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@75d664org.highwire.dtl.DTLVardef@4e5c31org.highwire.dtl.DTLVardef@86b5f2org.highwire.dtl.DTLVardef@135045_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Combining Selenocystine Based Fluorescence Assay with Structural Prediction for Enhanced Detection and Analysis of Cystine Stone Pathology

BackgroundCystine stones, a rare but recurrent type of kidney stones, primarily result from cystinuria, an inherited disorder caused by mutations in the genes SLC3A1 and SLC7A9, which encode renal cystine transporters. These mutations impair cystine reabsorption, resulting in elevated urinary cystine concentrations and stone formation. Current diagnostic methods are limited, particularly for detecting molecular-level dysfunctions. We aimed to develop a nonradioactive method for functional assessment of cystine transporters and mutation-specific pathologies. MethodsWe designed an innovative diagnostic approach combining a selenocystine-based fluorescence assay with structural predictions using AlphaFold to rapidly and accurately assess cystine transporter function and the molecular impacts of genetic mutations. ResultsOur assay demonstrated comparable transport efficiencies of cystine and selenocystine by the SLC3A1/SLC7A9 complex, and effectively differentiated mild, moderate, and severe functional impairments associated with known clinical mutations, including A354T and P482L. Structural modeling further provided mechanistic insights into mutation-induced dysfunctions. ConclusionThis integrated approach--combining a sensitive selenocystine fluorescence assay with AI-powered structural analysis--enables rapid, precise diagnosis of cystinuria variants and delivers mechanistic insights for personalized therapeutic strategies.

genetics↗

Establishment of a Systemic Lupus Erythematosus Mouse Model in Humanized CD3/CD19 Mice and Evaluation of the Efficacy of a Human Bispecific Antibody

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease affecting multiple organ systems and is considered one of the most severe autoimmune diseases worldwide, significantly impacting womens health. B cells play a crucial role in disease pathogenesis by becoming abnormally activated and producing autoantibodies that attack the bodys normal tissues, leading to inflammation and organ damage. Therefore, targeting the human B cell receptor has emerged as a promising strategy for therapeutic intervention. In this study, we established an SLE animal model using double-humanized CD3/CD19 mice, in which human CD3 and CD19 genes replaced their murine counterparts. The phenotype was confirmed by ELISA and flow cytometry. hCD3/hCD19 mice induced by a combination of pristine x 2, imiquimod (IMQ) and nephrectomy exhibited several key features of SLE, including anti-dsDNA antibody production, proteinuria, increased immune cell populations, and kidney lesions. Furthermore, treatment of these humanized mice with anti-human CD3/CD19 bispecific antibodies significantly inhibited these pathological indicators. Thus, pristine x 2, IMQ and nephrectomy induced hCD3/hCD19 mice provide a validated preclinical model for investigating novel therapeutic agents targeting B cells in SLE. Graphical abstractThis study explores the effects of different modeling strategies on agent induction, with a particular emphasis on the link between the induced agents and their corresponding clinical manifestations. Through an extensive literature review and experimental validation, a novel approach for inducing systemic lupus erythematosus (SLE) has been established. By employing gene editing techniques, mouse CD3 and CD19 antibody recognition sites were substituted with their human equivalents. This humanized mouse model enables the direct assessment of humanized bispecific antibodies in the context of SLE induction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/668572v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@652c83org.highwire.dtl.DTLVardef@4d6233org.highwire.dtl.DTLVardef@6a2f8forg.highwire.dtl.DTLVardef@1587652_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Establishment and comparison of three kinds of chronic bacterial cystitis models in mice

Cystitis is a common urinary system disease in women. However, there are currently no effective treatment options except antibiotics. Therefore, establishing an effective and stable animal model is helpful for further study of cystitis. In this study, we established three chronic cystitis models from C57BL/6 female mice inoculated with urinary tract pathogenic Escherichia UTI89 through urethral perfusion: CPP co-infection group, seven days interval repeated infection group, and two consecutive days repeated infection group. The three models were successfully constructed, and the survival rates of the three models were 66%, 75%, 100%, respectively. The bladder infection rates of the surviving mice were 100%, 100%, 50%, respectively. H&E staining showed that the inflammation and damage were the most severe in seven days interval repeated infection group. Sirius red staining showed that the degree of fibrosis was the highest in CPP co-infection group. Immunofluorescence staining of bladder inflammatory cells showed that inflammatory cells and macrophages in the CPP co-infection group and the seven days interval repeated infection group expressed more. Basal layer epithelial cell staining showed that the epithelial cells of the three infection models had different degrees of proliferation. The three strategies can all prepare mouse chronic cystitis models with their own characteristics, and these models can be used for experimental studies related to different levels of bladder infection and fibrosis, laying a foundation for further research on the mechanism of chronic cystitis.

microbiology↗

An Intrinsic-hoc Framework for Heterogeneous Cellular Senescence Elucidation Using Deep Graph Representation Learning and Experimental Validation

Cellular senescence is a primordial driver of tissue and organ aging, and the accumulation of senescent cells (SnCs) has been implicated in numerous age-related diseases. A major barrier to studying senescence is the rarity and heterogeneity of SnCs, which are not a uniform population but instead comprise diverse senotypes shaped by cell-of-origin and microenvironmental context. Such heterogeneity exceeds what classical senescence hallmarks can resolve at single-cell resolution, motivating the need for computational frameworks that can capture senotype-level diversity intrinsically. Here, we introduce DeepSAS, a deep graph representation learning framework that robustly identifies cell-type-specific SnCs and their senescence-associated genes (SnGs). DeepSAS incorporates a heterogeneous graph that integrates intracellular transcriptional states with intercellular communication cues, enabling the joint inference of senescent cells and senescence-linked genes through attention-based contrastive learning. Applied to public healthy eye and lung atlases, DeepSAS identified SnCs whose proportions positively correlate with aging. From in-house idiopathic pulmonary fibrosis (IPF) patient scRNA-seq data, DeepSAS detected 1,678 SnCs (out of 24,125 cells) and 263 SnGs across 26 cell types, including 43 SnGs that are uniquely associated with a single cell type. We generated high-resolution Xenium spatial transcriptomics data to further validate SnGs in IPF, revealing NFE2L2 as a SnG specifically enriched in CTHRC1+ fibroblasts. Notably, the ex vivo bleomycin-induced senescence in human precision-cut lung slice (hPCLS) samples similarly identified NFE2L2 as an SnG in CTHRC1+ fibroblasts, albeit with stronger transcriptional signals, suggesting mechanistic differences in senescence cells associated with chronic and acute injury. Overall, DeepSAS uncovers distinct senescence programs and infers cell-type-specific SnGs that are difficult to resolve using existing marker-based approaches. We believe it offers a generalizable and translationally relevant strategy for advancing senescence biology and therapeutic development.

bioinformatics↗

Tracing Siderophore Precursors to Primary Metabolism for Ecological Applications

Microbial fitness depends on balancing between primary metabolism supporting basic survival, and secondary metabolism producing metabolites for environmental adaptation. These two systems are interconnected, with most secondary metabolites deriving from primary metabolic precursors. However, systematic frameworks for studying their relationships across diverse microbes remain limited. Using siderophores--iron-chelating secondary metabolites crucial for microbial competition--as a model, we developed a stepwise "siderophore-monomer-precursor-pathway analysis" framework to trace the biosynthetic connections from siderophore structures to primary metabolism. We applied this framework to an expanded SIDERITE database containing 1018 siderophore structures. To demonstrate practical applications, we identified specific precursors utilized by the beneficial rhizobacterium Bacillus amyloliquefaciens but not by the plant pathogen Ralstonia solanacearum. Supplementing these precursors under iron-limited conditions enhanced both siderophore production in B. amyloliquefaciens and its inhibitory activity against R. solanacearum. This work establishes a direct link between primary metabolism and siderophore-mediated microbial interactions, offering new strategies for pathogen suppression through targeted metabolic interventions.

biochemistry↗