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Biology subjects

Jia, Y.

Publications and source records attributed to Jia, Y..

At least 19 recordsLinked to original sources

Efferocytosis Remodels Osteoclast Metabolism and Enhances Antibacterial Defense

Osteoclasts are metabolically specialized for bone resorption, but how apoptotic-cell uptake shapes their immune function remains unclear. During Staphylococcus aureus bone infection, osteoclasts engulfed apoptotic neutrophils. In osteoclast cultures, apoptotic-neutrophil exposure reduced multinucleation and resorption, induced host-defense programs, and enhanced antibacterial activity, whereas macrophages showed no comparable antibacterial response. MERTK was required for efficient osteoclast efferocytosis. Ctsk-Cre-mediated Mertk deletion increased bacterial burden and bone loss, whereas transplantation of MERTK-competent bone marrow restored osteoclast efferocytosis and reduced infection-associated bone damage. Transcriptomic and extracellular flux analyses revealed enhanced glycolytic activity and altered lactate handling in efferocytic osteoclasts. Lactate supplementation reduced osteoclast formation without reproducing the antibacterial phenotype. Inhibiting lactate production or export attenuated antibacterial activity in efferocytic osteoclasts, whereas blocking lactate uptake enhanced it. These findings identify osteoclast efferocytosis as an immune adaptation that links apoptotic-neutrophil clearance to metabolic remodeling and antibacterial defense in bone.

cell biology↗

Computational modeling of VEGF-A signaling predicts lymphatic junction state

Lymphatic endothelial cell (LEC) junctions switch between continuous zippers and discontinuous buttons to control fluid, cell and lipid uptake, but how the strength and timing of signaling set junction state is unknown. Here we present, to our knowledge, the first mechanistic signaling model calibrated to LEC data, linking VEGF-A-induced activation of VEGFR2 homodimers and VEGFR2/VEGFR3 heterodimers to the balance of active RAC1 and RhoA, summarized as a predicted zippering propensity. Calibrated to human dermal LEC time courses and validated against independent receptor knockdowns, the model predicts that VEGF-A dose primarily determines how long zippering-favoring signaling lasts following stimulation, and it identifies which of the parameters related to RAC1-RhoA kinetics control this duration. Using single-cell transcriptomes from high-fat-diet-fed mice, the model predicts that obesity shortens this response in mesenteric capillary and epididymal collector LECs but prolongs it in epididymal capillary LECs. Tuning RAC1-RhoA kinetics restores baseline in each population but requires opposite adjustments, suggesting that targeting this axis must be context-specific.

systems biology↗

PaleoRigor: a bounded research agent with a reproducible evidence trail for paleomicrobiome data processing

Background: Ancient microbial evidence informs research on past health, diet, and environments, but its scarcity and susceptibility to contamination demand care in selecting and processing data. Language models can now turn a research request into an analysis plan, but an unconstrained planner may reference files that do not exist, apply operations a format forbids, or answer a question the data cannot settle. A planner used on such evidence therefore needs to be bounded, and its decisions recoverable afterwards. Results: We developed PaleoRigor around three commitments. Agent: a language model plans the analysis. Constraint: a validator checks every file reference, format and step dependency before anything runs, execution is restricted to predefined local modules, and a planning contract directs the model to refuse out-of-scope requests with a named reason code rather than answer them. Reproducibility: each run is exported with its plan, intermediate files, checksums and decisions. In a preregistered, frozen held-out evaluation, PaleoRigor passed 23 of 24 runs (95.8%; Wilson 95% confidence interval, 79.8-99.3%): 11 of 12 supported runs and all 12 prespecified boundary decisions. An ablation that removed this planning contract from the same model passed 19 of 24 (79.2%). Repeating the frozen design with a second model configuration yielded 24 of 24 successes for PaleoRigor and 19 of 24 for the ablated arm. Pooled post hoc across both configurations, PaleoRigor passed 47 of 48 runs (97.9%), compared with 38 of 48 (79.2%) for the ablated arms. All 96 run labels were recomputed from retained records and matched. Dataset-level tests matched read counts and compressed-file sizes for six public sequencing records and documented the removal of 114 duplicate sequence entries. A retraction-associated audit illustrated how expert review limited conclusions to file-level evidence. Conclusions: For paleomicrobiome data, pairing a language-model agent with explicit constraints and a reproducible record makes the agent's proposed analysis reviewable before its outputs support a biological claim. PaleoRigor delivers checked inputs, a recorded transformation history and a named reason for each request it refuses, and runs as a local desktop application. It prepares data for specialist analysis; ancient-DNA authentication and biological interpretation remain with the paleobiologist.

bioinformatics↗

Potato Agent: AI-Driven Data and Knowledge Exploration on an Agent-Ready Potato Multi-Omics Platform

Potato is an important non-cereal food crop worldwide. However, the limited number of functionally validated genes remains a major bottleneck to favorable allele stacking and genome design breeding in potato. Rapid advances in AI agents offer a promising means to support crop breeding by translating natural-language questions into coordinated data analysis and knowledge retrieval. Their reliable use for potato breeding, however, is constrained by fragmented multi-omics resources that lack consistent curation and machine-accessible interfaces. Here, we constructed an agent-ready potato multi-omics database integrating genomic resources from 150 potato accessions, 259 bulk RNA-seq samples, and 14 spatial transcriptomic datasets into a pangenome, a tissue expression atlas, co-expression networks, and spatial expression maps accessible through open APIs. We developed 39 potato-specific Agent Skills for reproducible bioinformatics analysis and comprehensive data and knowledge exploration, enabling natural-language questions to be translated into standardized data-retrieval and analysis tasks. By integrating direct evidence from potato studies, functions of homologous genes in Arabidopsis, rice, and maize, and tissue expression patterns, we generated genome-wide functional predictions for 37,658 genes in the DM reference genome. We further developed Potato Agent as a multi-user, browser-based platform with isolated workspaces and online result preview, reducing the technical burden of agent deployment and providing direct access to integrated data, knowledge, and workflows. Case studies demonstrated its capabilities in reproducible bioinformatics analysis, agent-assisted identification of a tuber development regulator, scientific data visualization, and haplotype-aware promoter analysis and sgRNA design. Together, the agent-ready database and Potato Agent provide an integrated infrastructure for functional gene discovery and hybrid breeding in potato.

plant biology↗

golgi: an open-source graphical platform for image-to-recruitment modeling of peripheral nerve stimulation

Computational models of peripheral nerve stimulation--coupling finite-element bioelectric fields to biophysical axon models--have become essential for designing electrodes and waveforms for neuromodulation therapies. Yet the established open tools are code-first and assume substantial modeling expertise, and several depend on commercial finite-element solvers, placing realistic nerve modeling out of reach for many experimentalists and clinicians. We present golgi, an open-source platform that takes a peripheral nerve from image to stimulated fiber population through a single graphical interface, with an equivalent scriptable Python API and command-line interface for batch studies. golgi integrates the full pipeline: image segmentation (or import of surfaces or masks), automated multi-region tetrahedral meshing, anisotropic finite-element solution of the extracellular field with explicit perineurium contact impedance, generation of realistic fiber populations and their three-dimensional trajectories (straight, or curved via a quasi-static streamline solver), and biophysical activation thresholds through interchangeable NEURON and a GPU-accelerated surrogate backend. We demonstrate golgi on extruded multifascicular swine and human cervical vagus nerves and on real three-dimensional, branching human and rabbit vagus nerves reconstructed from micro-computed tomography. It reproduces the physiological fiber-diameter recruitment order, quantifies fascicular selectivity and current steering with a multi-contact cuff electrode, and resolves anatomically defined nerve branches. Using this branch resolution, we find that selectively engaging a vagal cardiac branch from a proximal cuff depends on anatomy. In the rabbit, whose cardiac fibers are predominantly small and whose superior cardiac branch forms a discrete, spatially segregated tract, current steering isolates even its small cardiac (B-type) fibers; in the human cervical vagus only the large myelinated fibers are separable, because the high thresholds of the small cardiac fibers force stimulus currents that also recruit off-target fibers. Every study can be exported as an integrity-hashed, self-contained bundle whose finite-element-to-recruitment provenance is verifiable byte-for-byte with a single command--a reproducibility guarantee absent from existing tools. By combining non-specialist usability, anatomical realism, and verifiable reproducibility in one open package, golgi lowers the barrier to in-silico peripheral nerve stimulation modeling. golgi is freely available as open-source software. Author summaryElectrical stimulation of peripheral nerves treats a growing range of conditions, from epilepsy to inflammatory and cardiovascular disease. Deciding where to place an electrode and how to shape the stimulus increasingly relies on computer models that combine the electric field around the electrode with detailed models of how individual nerve fibers respond. We found that existing software for this is powerful but primarily designed for expert modelers: it generally requires programming, substantial modeling expertise, and sometimes expensive commercial software, which can limit its adoption by experimentalists and clinicians. We built golgi to remove that barrier. With golgi, a user can go from a nerve image all the way to predicted fiber recruitment through a single point-and-click interface, while advanced users keep full scripting control. golgi builds anatomically realistic nerve models, simulates how different fiber types and fascicles are recruited, and lets users compare electrode designs. Using golgi, we also found that whether a small but clinically important nerve branch--such as the cardiac branch of the vagus nerve--can be selectively stimulated depends on its anatomy. In a rabbit nerve, where this branch forms a discrete, spatially separated bundle and its fibers are mostly small, even its small fibers can be targeted from a cuff on the main trunk; in the human, only the large fibers can be reached selectively, because the small cardiac fibers are harder to excite and the stronger currents needed to reach them also activate off-target fibers. Critically, every result can be packaged so that anyone else can verify it reproduces exactly--making peripheral nerve stimulation models easier to build, share, and trust.

bioengineering↗

golgi: open-source software for automated nerve model generation and recruitment simulation

golgi is an open-source platform that takes a peripheral nerve from image to stimulated fiber population through a single graphical interface, with an equivalent scriptable Python API and command-line interface for batch and high-performance use. It integrates promptable image segmentation, automated multi-region tetrahedral meshing, anisotropic finite-element solution of the extracellular field with an explicit perineurium contact impedance, generation of realistic fiber populations and their three-dimensional trajectories, and biophysical activation thresholds through interchangeable backends-- NEURON (via PyFibers) and a GPU-accelerated surrogate (AxonML). Every study exports as an integrity-hashed bundle whose image-to-recruitment provenance is verifiable byte-for-byte. golgi lowers the barrier to in-silico peripheral nerve stimulation modeling for experimentalists and clinicians, using a fully open finite-element stack with no commercial dependencies.

bioengineering↗

Improved 3D Radial Phyllotaxis Trajectories for Uniform Density Distribution of Readout Directions and Sequential Binning

PurposeTo develop 3D radial spiral phyllotaxis trajectories that provide a uniform density distribution of readout directions and support retrospective sequential binning, thereby reducing ringing artifacts and improving image quality. MethodsUPhy trajectory redefines the polar angle to achieve uniform density distribution of readout directions. FlexiPhy further decouples the azimuthal and polar ordering of interleaves through a randomized permutation, improving robustness to sequential binning. The proposed trajectories were evaluated in vivo on 10 healthy volunteers using two gradient-echo sequences on a 3T MRI scanner. Sequential temporal reconstructions were compared with reference reconstructions using structural similarity and relative L2 error metrics. ResultsUPhy presents analytically demonstrated uniform density distribution of readout directions. Quantitative analysis shows significantly higher SSIM values and lower relative L2 errors for FlexiPhy compared with both the original phyllotaxis and UPhy trajectories after Bonferroni correction (pcorrected < 0.05). ConclusionFlexiPhy enables more reliable sequential binning reconstructions by reducing trajectory-induced ringing artifacts and temporal inconsistencies. Moreover, its randomized construction is not tied to a specific binning strategy, making it broadly compatible with retrospective binning approaches used in dynamic and motion-resolved MRI.

bioinformatics↗

GalaxyVS: Exploring 100-Billion Compounds in Seconds

We present GalaxyVS, a hardware-software co-designed virtual screening framework built to explore the 100-billion commercially accessible chemical space in seconds, deployed at the National Supercomputing Center in Tianjin. Built upon the dense vector retrieval paradigm of DrugCLIP, GalaxyVS bypasses the structural dependencies and computational overhead of classical docking to enable rapid screening against experimentally determined as well as geometrically feasible pockets on AlphaFold-predicted structures. To scale this paradigm to the 100-billion level, the system must overcome the significant computational burden of offline representation encoding, critical memory and I/O bottlenecks during online retrieval, and the risks of diversity collapse and precision loss within final screening results. Utilizing the heterogeneous supercomputing infrastructure, GalaxyVS accelerates the offline encoding through deep operator adaptations and resolves online retrieval bottlenecks via disk-native vector indexing coupled with in-memory staging to ensure both broad accessibility and high throughput. Concurrently, a two-stage refinement protocol effectively mitigates diversity collapse and ensures high-fidelity affinity ranking. Consequently, GalaxyVS achieves a daily scoring throughput of 1.5 x 1016 target-ligand pairs, representing a six-orders-of-magnitude leap over previous supercomputing records. Driven by this throughput, we screened nearly 100,000 protein structures across six species against the 100-billion compound library in just 16 hours. The resulting comprehensive cross-species interaction landscape, GalaxyDB, will be openly released at https://galaxyvs.drugclip.com.

bioinformatics↗

A Cross-tissue Temporal Multi-omics Atlas Reveals the Molecular Architecture of Pressure Injury

Pressure injury induces progressive necrosis of skin and deep muscle, yet how mechanical loading reshapes molecular programs across tissues and time remains poorly defined. To address this gap, we established a rat pressure-injury model and performed longitudinal integrated profiling of skin and deep muscle across four stages, combining transcriptomics, proteomics and untargeted metabolomics with histological assessment. This multi-layered atlas revealed a staged injury program dominated by early transcriptional activation of innate immunity and complement-coagulation crosstalk, accompanied by neutrophil-associated responses and engagement of upstream regulatory networks. As injury advanced, a second axis of remodeling emerged, characterized by sustained suppression of mitochondrial energy metabolism and oxidative phosphorylation, particularly in muscle, together with extracellular matrix and adhesion rewiring. In parallel, skin preferentially activated barrier-repair and protein-homeostasis programs, including keratinization and autophagy-linked processes, indicating tissue-specific adaptation to the same mechanical insult. Temporal clustering and pathway-network analysis further showed that immune activation and metabolic collapse are not independent events but are dynamically coupled across stages, with muscle exhibiting broader molecular reprogramming and a stronger shift toward irreversible structural failure. Together, these data define a cross-tissue, stage-resolved molecular framework for pressure injury progression and identify pathway-level windows that may inform tissue-targeted and stage-specific intervention strategies.

systems biology↗

Robust identification of cell-cell communication heterogeneity in single cells

Communication between cells modulates cell fate decisions by relaying information across tissues and inducing intracellular responses mediated by gene regulatory networks. Inference of cell-cell communication from high throughput data such as single cell transcriptomics is gaining popularity due to the high data availability and ease to automate modeling over hundreds of signaling pathways. Studying how cell-cell communication operates across biological scales and influences cell fate decisions, however, remain a major open question. Here, we present scRICH, a framework and package that integrates mechanism-based, multiscale mathematical modeling with learning strategies to capture the complexity of cell-cell communication from single-cell and spatial transcriptomics data. scRICH unravels the heterogeneity of communication behavior within cell types, links cell-cell communication to cell fate decisions by incorporating dynamical information of RNA splicing, and connects the scales of cell-cell interactions and intracellular response by constructing multilayer regulatory networks. We validate scRICH with new experiments on EGF ligand/receptor co-expression in keratinocytes from skin-equivalent organoid, and compare these computational predictions against existing CCC inference methods. Applying scRICH to multiple biological scenarios demonstrate its ability to capture emerging relations between distinct cell-cell communication pathways, interactions at the onset of cell fate decision, and emerging trends in cell-cell communications along cell lineages and in space.

bioinformatics↗

Antarctic fish cell cultures show adaptation of organelle morphology and dynamics to extreme cold

In the Antarctic Southern Ocean, cold-blooded animals have evolved to live at stable temperatures of 0{+/-}2 {degrees}C. This extremely low temperature affects their biology at every scale, from protein folding to development. However, how animal (sub)cellular organisation and dynamics are adapted to near-0 {degrees}C temperatures has not been studied. We therefore established methods to culture and fluorescently label cells from the Antarctic plunderfish Harpagifer antarcticus and a temperate comparator species, the shanny Lipophrys pholis. By imaging these cultures live at physiological temperatures, we found that subcellular organisation is broadly conserved in H. antarcticus, featuring known membranous organelles and biomolecular condensates that remain dynamic, with mitochondria in H. antarcticus and L. pholis moving at similar speeds. However, we also identified differences in organelle properties between H. antarcticus and L. pholis, including lysosomal enlargement and mitochondrial morphology changes. These differences may be functionally linked to protein misfolding and slow embryonic development in Antarctic species.

cell biology↗

MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells via cellular respiration

Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. The major enhancer regulator paralogs MLL3 and MLL4 (MLL3/4) belong to the lysine methyltransferase 2 (KMT2) family, which catalyzes the methylation of lysine 4 on histone H3 (H3K4me). MLL3/4 are required for enhancer activation and are essential for mammalian development and stem cell differentiation. Although recent studies have linked MLL3/4 with different metabolic pathways in the regulation of stem cell self-renewal and cancer cell growth, the mechanisms connecting enhancer function to metabolic control remain elusive. Here, using respiration flux assays, stable isotope tracing, transcriptomics, and stem cell biology techniques, we show that the loss of MLL3/4 impairs glycolysis and mitochondrial respiration in murine embryonic stem cells. Mechanistically, MLL3/4 deficiency suppresses the expression of the rate-limiting glycolytic enzyme hexokinase 2 (HK2) and compromises the function of the oxoglutarate dehydrogenase (OGDH) complex, thereby coordinately impairing central carbon metabolism. Remarkably, combined restoration of HK2 and OGDH rescues the metabolic defects caused by MLL3/4 loss and reinstates differentiation capacity. Taken together, our study identifies a direct link between enhancer-regulating epigenetic machineries and metabolic control of cell fate transition, providing a mechanistic framework for understanding how enhancer malfunction contributes to developmental abnormalities and human diseases.

developmental biology↗

Hyperactive STAT1 Promotes T Follicular Helper Type 1 Cell Differentiation to Trigger Autoimmunity

ABSTRACTSHeterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an inborn error of immunity characterized by immune dysregulation, recurrent infections and various autoimmune manifestations. However, the precise pathogenic mechanism by which STAT1 GOF contributes to autoimmunity remains elusive. In our cohort, STAT1-GOF patients exhibit biased circulating follicular helper T (cTfh) populations with CXCR3+ Tfh1-like features. Using a Stat1 GOF mouse model that spontaneously developed autoimmunity, we found that overactivated STAT1 promotes Tfh differentiation and disrupted T cell-dependent humoral responses with skewed immunoglobulin class switching towards IgG2. Furthermore, STAT1 GOF directly targets to Tfh and Th1 cell signature genes and thereby drives the development of Tfh1 cells with excessive IFN-{gamma} production, which implicated in autoantibody production and the development of autoimmunity. Notably, IFN-{gamma} neutralization significantly alleviated autoimmune cellular responses and autoantibody levels in mutant mice, highlighting IFN-{gamma} blockade as a promising targeted therapy for the STAT1-GOF patients with autoimmunity. Our findings suggest that proper regulation of STAT1 activity within a reasonable magnitude is crucial for ensuring optimal host-protective humoral immunity. One-sentence summaryOveractivated STAT1 promotes Tfh1 differentiation to drive autoimmunity.

immunology↗

Neutrophil-targeted delivery of circSCMH1 unlocks an acute anti-thromboinflammatory function to restore microvascular perfusion in stroke

ObjectivesFutile recanalization (FR) after endovascular thrombectomy (EVT) is driven by neutrophil-mediated thromboinflammation, yet conventional neuroprotectants fail to address the spatiotemporal complexity of stroke injury. This study aimed to identify the clinical link between circSCMH1, traditionally viewed as a late-stage repair molecule, and FR, while evaluating its hyperacute anti-inflammatory potential via a neutrophil-targeted delivery system. MethodsWe analyzed thrombi and plasma from LVO-AIS patients stratified by functional outcomes. We engineered neutrophil-targeted lipid nanoparticles (circSCMH1@pepLNP) for delivery in a mouse transient middle cerebral artery occlusion model. Therapeutic outcomes were evaluated through infarct volume measurement, histological assessment of NETosis, and intravital two-photon microscopy to monitor real-time neutrophil dynamics and capillary stalling. ResultsClinical analyses showed circSCMH1 was significantly downregulated in FR patients, with its levels negatively correlated with NET burden. Furthermore, circSCMH1-negative neutrophils exhibited a higher propensity for NETosis within the thrombus microenvironment. In mice, circSCMH1@pepLNP achieved specific neutrophil delivery, significantly reduced infarct volume, and suppressed the expression of citrullinated histone H3 and neutrophil elastase. Intravital two-photon and laser speckle imaging further confirmed that this intervention attenuated neutrophil adhesion, increased migratory velocity, and alleviated capillary stalling, thereby restoring cortical microvascular perfusion. ConclusionsOur findings associate neutrophil-specific circSCMH1 downregulation with clinical FR in LVO-AIS. Targeted intracellular delivery reveals an acute anti-thromboinflammatory function that complements established reparative properties, proposing a novel adjunctive approach for EVT to address the spatiotemporal complexity of stroke and improve clinical outcomes.

neuroscience↗

Near completely reversing the γ- to β-globin switch by enhancer release, retargeting and reinforcing

The {gamma}- to {beta}-globin switch is intricately regulated during human ontogeny, and this process is manipulated for therapeutic approaches to treat {beta}-hemoglobinopathies by activating {gamma}-globin expression. Several genetic strategies to reactivate HbF have partially reversed the {gamma}- to {beta}-globin switch and ameliorated the clinical symptoms of {beta}-hemoglobinopathies. However, whether the {gamma}- to {beta}-globin switch can be completely reversed remains unknown. Completely reversing the {gamma}- to {beta}-globin switch requires a thorough redirection of the locus control region (LCR) from interacting with the {beta}-globin gene (HBB) to interacting with the {gamma}-globin gene (HBG). Here, we found that disrupting the KLF1-mediated HBB-LCR interaction by mutating the CACCC motif in HBB leads to the release of the LCR and its retargeting to other {beta}-like globin genes. Moreover, simultaneously disrupting the KLF1-mediated HBB-LCR interaction and the epigenetic repression of HBG by combined editing of the CACCC motif in HBB and the TGACCA motif in HBG reinforces the HBG-LCR interaction, resulting in almost exclusive {gamma}-globin expression while nearly absent {beta}-globin expression, achieving near complete reversal of the {gamma}- to {beta}-globin switch. This finding demonstrates the comprehensive regulation of the {gamma}- to {beta}-globin switch by gene competition and gene silencing mechanisms. This finding also suggests that silenced genes can be fully activated through the redirection of enhancer-promoter contacts and that the specificity of enhancer-promoter contact within chromosomal domains is achieved through the transcription factor clusters binding to enhancers and promoters. Combined editing of the CACCC&TGACCA motifs also offer a more optimal therapeutic strategy for {beta}-hemoglobinopathies.

molecular biology↗

Habitat and Hydrodynamics Influence Coral Reef and Seagrass Microbial and Exometabolite Dynamics

Coral reef and seagrass ecosystems provide critical storm protection and economic revenue to tropical coastal communities. Effective monitoring and restoration strategies are essential given increasing impacts from climate change and human development. Microorganisms, and the metabolites they produce and consume, are key drivers of coastal ecosystem function. However, microbially-mediated metabolite recycling remains poorly understood, limiting its inclusion in conservation and restoration strategies. Here we examine how seawater exometabolites and microorganisms in coastal ecosystems vary in relation to habitat (seagrass or coral reef), temporal scales and hydrodynamics. We characterized benthic seawater from two St. John, U.S. Virgin Islands coral reefs (Yawzi and Tektite) and one seagrass meadow at dawn and mid-day over four consecutive days. Using quantitative metabolomics and SSU rRNA gene amplicon sequencing, we found that habitat served as the primary driver of exometabolite and microbial community composition, while daily changes and hydrodynamics strongly influenced system variability. Hydrodynamic modeling indicated offshore water intrusion at mid-day at Yawzi reef, likely driving exometabolite and microbial shifts towards oligotrophic taxa (e.g., SAR11, SAR86). In contrast, a high percentage of coastal source water in the seagrass habitat maintained stable exometabolite pools and supported diverse microbial communities. These findings demonstrate that coastal habitat and hydrodynamics strongly influence exometabolite and microbial assemblages, with lesser contributions from temporal changes. Integrating exometabolites, microorganisms, and hydrodynamics provides new insights into coastal ecosystem functioning useful for habitat monitoring and restoration strategies.

ecology↗

A transcription factor-responsive enhancer discovery platform for targeted immunotherapy

Synthetic enhancers with high specificity are crucial for therapeutic gene control. However, experimental screens and machine learning-guided design typically require context-specific datasets, limiting generalizability. Because transcription factor (TF) activity reflects cellular state, TF-responsive enhancer libraries offer a universal starting point. Here, we developed TREND (transcription factor-responsive enhancer discovery), a massively parallel reporter assay of [~]2.7 million enhancer-barcode constructs representing 57,715 designs. TREND covers 1,068 motif-annotated proteins, including 729 confirmed TFs across 49 DNA-binding domain families. Applied to ovarian cancer, TREND identified enhancers that discriminate cancer from normal epithelial cells. These enhancers enabled protein-interaction-based AND-gate circuits with reduced OFF-state leakage and amplified ON-state output, driving tumor-restricted expression of combinatorial immune effectors and robust antitumor responses in murine ovarian cancer models. TREND also identified T-cell activation-responsive enhancers with greater inducibility and lower basal activity than conventional NFAT-motif-based elements. Together, TREND provides a generalizable framework for context-specific enhancer discovery and therapeutic gene regulation.

synthetic biology↗

ecDNA-driven oncogene super-expressors shape immunoevasive tumor microenvironment

ecDNA contributes to cancer genetic heterogeneity through random segregation during mitosis. Emerging evidence links ecDNA to immune evasion, but the mechanism remains elusive. Using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC), we show that Kras and Myc oncogenes are amplified either on ecDNAs or as homogeneously staining regions (HSRs) on chromosomes. ecDNA-driven tumors are more aggressive in immunocompetent mice. Single-cell transcriptomic and histological analyses reveal that ecDNA-driven tumors rapidly establish an immunoevasive tumor microenvironment (TME), marked by increased myofibroblastic cancer-associated fibroblasts (myCAFs) and reduced T cell infiltration. Mechanistically, ecDNA heterogeneity generates a subset of cancer cells with extremely high Kras expression, termed super-expressors, which secrete amphiregulin to promote myCAF expansion and suppress T cell infiltration. Clonally organized super-expressors establish an immunoevasive niche in the TME from patients with PDAC. Our findings demonstrate a causal role of ecDNA in TME remodeling, offering insights into cancer heterogeneity and immune evasion.

cancer biology↗