Biology subjects

Chen, Y.

Publications and source records attributed to Chen, Y..

At least 307 records · Page 17Linked to original sources

bioRxiv2026

Stage-adaptive integration of polydopamine promotes hPSC-derived alveolar organoids differentiation and maturation

Human pluripotent stem cell (hPSC)-derived alveolar organoids (ALOs) have emerged as a powerful tool for modeling human lung development and disease, and accelerating respiratory drug discovery. However, achieving the functional maturation of ALOs remains challenging. Polydopamine (PDA) is a mussel-inspired polyphenolic biomaterial with antioxidant and adhesive properties that can be deployed as surface coatings and nanoparticles (NPs) in cell culture systems. Here, we integrate PDA coatings and NPs sequentially in a stage-adaptive manner throughout the hPSC-derived ALOs differentiation system and study their contributions to ALOs maturation. Our results demonstrated PDA coating yielded more anterior foregut endoderm (AFE) spheroids by strengthening the interaction between Matrigel and substrate. Bulk RNA-seq revealed enrichment of cell-cell and cell-extracellular matrix interactions by PDA. The subsequent incorporation of PDA NPs in Matrigel at lung progenitor cells (LPCs) stage significantly mitigated reactive oxygen species (ROS) accumulation and enhanced LPCs generation. Functionally, AT2 cells in ALOs exhibit characteristic lysosome-to-lamellar body (LB) maturation due to the traffic of internalized PDA NPs to endolysosome. Transcriptomics further indicated enrichment of endocytic-phagosome and epithelium development pathways by PDA treatment. Together, our study establishes a stage-adaptive-integrated PDA strategy throughout hPSC-to-ALOs differentiation and demonstrates that PDA robustly enhances ALOs maturation and secretory function. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/708928v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@88208dorg.highwire.dtl.DTLVardef@1111590org.highwire.dtl.DTLVardef@9ea9b0org.highwire.dtl.DTLVardef@969fad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Lessons from the equator: a window on the future of vibriosis in a warming Earth

Vibrios are important aquatic human pathogens, causing gastroenteritis, wound infections, and cholera. Vibriosis (non-cholera infection) has been increasing in temperate climates due to correlation between Vibrio abundance and water temperature. However, how warming oceans differentially influence various Vibrio species, and whether incidence is higher in tropical regions, remains understudied. We assembled the first comprehensive dataset of culture-confirmed vibriosis cases outside a temperate climate from equatorial Singapore. Comparison to cases from the detailed United States (US) CDC COVIS system revealed that vibriosis incidence is over two times higher in Singapore than the United States. Causative species also differ markedly, with Vibrio fluvialis and non-toxigenic Vibrio cholerae dominating in Singapore (>40%) but are much less prominent in the United States (<15%). Singapore cases have remained stable in the last decade, while US incidence is rising rapidly, especially for V. fluvialis and V. cholerae (13% and 17% per year). Differences in causative species in Singapore and the United States suggest ecological factors may shape infection dynamics, with some species benefitting more from warming oceans, raising their equatorial prominence. Incidence is stable in Singapore, likely due to slower warming of waters near the equator. In contrast, vibriosis in the United States will likely continue to increase steadily, with changing species composition, likely becoming tropicalized.

microbiology↗

bioRxiv2026

A foundation AI model enhances electron microscopy image analysis

Electron microscopy (EM) and advanced volume EM have extensive applications in deciphering cellular ultrastructures for life sciences. However, quality issues of EM images significantly impede the precise analysis and discovery of nanoscale biological structures. Here, we present an unsupervised Foundation Model for Five Tasks (DF5T) model for image enhancement through denoising, deblurring, super-resolution, two-dimensional (2D) inpainting, and three-dimensional (3D) isotropic restoration. DF5T was trained on an extensive dataset of multi-source membrane-bound organelle EM images, consisting of a total of over 2.25 million images. On unseen data, DF5T outperformed the existing state-of-the-art models in all five tasks. Furthermore, DF5T substantially compensates for missing three-dimensional structural information and reveals significant ultrastructural alterations in organelle geometry following chemical treatment. We demonstrate that DF5T significantly enhances electron microscopy images quality by improving the accuracy of downstream organelle segmentation and 3D structural restoration, thereby contributing to future advances in biological research.

cell biology↗

bioRxiv2026

A vagal gut-brain axis for feeding induced gastric secretion

Feeding begins with food-seeking and ends with nutrient absorption and waste elimination. Although meal-related sensory cues are known to shape feeding behavior, how they engage neural circuits to control digestion remains unclear. We dissected vagal gut-brain-gut pathways that mediate meal-induced gastric secretion. Vagal afferent neurons innervating the stomach were necessary and sufficient for secretion. Among those, Glp1r and Sst neurons robustly drove acid, pepsin, and gastrin secretion, whereas Oxtr and Vip neurons had little effect. Piezo2 was expressed in Glp1r mechanosensory afferents, and conditional deletion of Piezo channels attenuated distension-evoked secretion. On the efferent limb, genetically defined vagal motor neuron subsets differentially recruited secretory outputs: Cck neurons broadly increased acid, pepsin, and gastrin, whereas Grp neurons preferentially drove acid secretion. Finally, enteric circuit dissection revealed modular output control: Calb2 enteric neurons potently drove secretion with minimal motility effects, Grp enteric neurons coupled secretion to motility, and Cysltr2 enteric neurons selectively modulated acid output. Together, these results define a cell-type resolved vagal-enteric architecture for gastric control and show that secretory and motor programs can be segregated across dedicated enteric neuron subtypes.

neuroscience↗

bioRxiv2026

ALKBH5 Promotes Hepatic Gluconeogenesis via m6A-mediated Stabilization of Ogt mRNA

Excessive hepatic glucose production is a hallmark of fasting hyperglycemia in type 2 diabetes mellitus, yet the epitranscriptomic mechanisms that sustain this dysregulation remain incompletely understood. Here, we show that dexamethasone/forskolin-induced gluconeogenic activation triggers widespread remodeling of RNA m6A methylation in mouse primary hepatocytes. Among the m6A regulators examined, the demethylase ALKBH5 is robustly induced both in vitro and in fasted livers. This induction is mediated by the glucocorticoid receptor, which binds to the Alkbh5 promoter and activates its transcription. Functionally, ALKBH5 overexpression enhances gluconeogenic gene expression and glucose production, whereas both global and hepatocyte-specific Alkbh5 knockout mice exhibit suppressed hepatic gluconeogenesis. Mechanistically, we identify Ogt as a primary downstream target, defining an ALKBH5-OGT epitranscriptomic axis in hepatocytes. ALKBH5 demethylates and stabilizes Ogt mRNA, thereby elevating OGT expression and promoting gluconeogenic gene expression. Consistently, the pro-gluconeogenic effects of ALKBH5 are largely abrogated by OGT knockdown. Finally, pharmacological inhibition of ALKBH5 with 18l effectively improves glucose tolerance and suppresses hepatic gluconeogenesis in both wild-type and db/db mice. Together, these findings reveal a glucocorticoid-responsive epitranscriptomic mechanism whereby ALKBH5 stabilizes Ogt mRNA to drive gluconeogenesis and highlight ALKBH5 as a promising therapeutic target for type 2 diabetes mellitus.

molecular biology↗

bioRxiv2026

Diverse Mechanisms of SMARCB1 Inactivation and Genome Maintenance Defects in Ultra-Rare Malignant Rhabdoid Tumors

Malignant rhabdoid tumors (MRTs) are extremely rare and highly aggressive pediatric cancers classically defined by biallelic loss of the SMARCB1 gene, with rare involvement of SMARCA4. However, the molecular mechanisms leading to this loss are not yet fully understood. MRTs occur predominantly in infants, with the highest incidence in children under one year of age. Clinically, they are characterized by early metastatic dissemination and dismal outcomes, with 5-year event-free survival rates below 20%. There are currently no curative therapies for these patients. Here, we performed integrated genomic, transcriptomic, and epigenomic profiling of 16 patient-derived MRT models including intracranial, renal, and soft tissue origins. While SMARCB1 deficiency was ubiquitous, we observed substantial heterogeneity in the mechanisms driving its inactivation. Only two tumors harbored detectable coding single-nucleotide variants in SMARCB1; the predominant mechanisms involved large-scale deletions and broad loss-of-heterozygosity (LOH) on chromosome 22, with extensive LOH in tumors lacking point mutations or focal deletions, consistent with allelic loss as a frequent "second hit." In contrast, SMARCA4 remained intact across all models, reinforcing the mutual exclusivity of SMARCB1 and SMARCA4 alterations. Structural analyses revealed extensive variation, including more than 400 events per tumor on average and candidate gene fusions such as AHI1:MYB, whereas alterations in TP53 and BRCA1/2 genes were infrequent. Transcriptomic and epigenomic profiling showed heterogeneity driven by tissue of origin, disease progression, and therapeutic response, with subtype-specific programs and epigenetic modulation of DNA repair and immune-related genes (SLFN11, MGMT, LIF) linked to treatment sensitivity. Collectively, our findings refine the molecular definition of MRTs, showing that while SMARCB1 loss remains the foundational driver, tumor behavior is further shaped by structural variation, impaired DNA repair pathways, and dynamic epigenetic landscapes. These integrated changes contribute to tumor heterogeneity, progression, and differential therapeutic vulnerabilities. Beyond advancing mechanistic understanding and identifying candidate biomarkers for patient stratification, our multi-omics dataset represents a valuable resource for the research community, supporting future studies and efforts to improve clinical management of this highly aggressive pediatric malignancy.

cancer biology↗

bioRxiv2026

MYC-ATF4-ASS1 axis governs intracellular arginine synthesis and dictates the immune microenvironment in melanoma

Drug resistance is a major challenge for both targeted therapies and immunotherapies in cancer. Arginine starvation has proven a promising strategy to overcome recurrent tumors. However, key molecules involved and how immune responses are elicited are not well understood. Here we identify in melanoma cells MYC-ATF4-ASS1 signaling as a pathway, which not only governs intracellular arginine synthesis but also modulates antitumor immunity. ATF4 knockout in melanoma cells phenocopied ASS1 knockout in the same cells, both showing greater sensitivity to arginine depletors such as ADI-PEG20. A combination strategy of BRAF/MEK inhibitors and an arginine depletor shows significant therapeutic effects in a immune-compromised mouse model. Both Atf4 and Ass1 knockout melanomas exhibited enhanced infiltration of Cd8+ T cells and significantly reduced tumor growth in a syngeneic mouse model. Single cell transcriptomics profiled the reshaped tumor microenvironment and revealed that a subset of resident macrophages were reprogrammed by endogenous arginine blockade. Overall, our findings reveal that the MYC-ATF4-ASS1 axis not only controls arginine vulnerability of melanomas but also shapes the immune microenvironment.

cancer biology↗

bioRxiv2026

Benchmarking niche identification via domain segmentation for spatial transcriptomics data

Tissue niches are spatially organized microenvironments in which coordinated multicellular interactions shape cellular states and biological functions. Currently, niche identification is routinely performed using domain segmentation frameworks. While interrelated, spatial domains and niches are not fundamentally equivalent. The former emphasizes intra-domain compositional consistency and transcriptomic homogeneity, whereas the latter is defined by the emergent properties of localized signaling gradients and the functional reciprocity between key cell lineages. Here, we present a high-resolution reference by thoroughly annotating single-cell resolution CosMx ST data of a human follicular lymphoid hyperplasia lymph node, a dynamic, non-compartmentalized tissue containing several critical immune niches defined by specific lineage architectures. We systematically benchmarked 16 contemporary domain segmentation algorithms, demonstrating that most methods in their default configurations fail to recapitulate biologically defined niche boundaries. Our analysis reveals that the definitive, disjoint spatial distributions of key functional lineages are frequently obscured by the stochastic infiltration of peripheral cell types. Such reduction in the spatial signal-to-noise ratio represents a primary bottleneck for existing algorithms, which prioritize local transcriptomic variance over global architectural logic. Following this observation, we demonstrate that strategic weighting of core functional lineages can restore the resolution of spatial niches in select domain segmentation frameworks. Cross-comparison against compartmentalized tissues further underscores the unique challenges of niche identification in non-mechanically separated environments and clarifies the fundamental divergence between structural domain segmentation and functional niche discovery. Our work delineates the limitations of current paradigms and advocates for the development of specialized computational approaches tailored specifically to the complexity of functional microenvironments.

bioinformatics↗

bioRxiv2026

Single-cell Analysis of Paired FFPE Placentas Reveals Trophoblast Reprogramming and Immune Dysregulation in Chronic Villitis of Unknown Etiology

Villitis of unknown etiology (VUE) is a common placental inflammatory lesion associated with adverse pregnancy outcomes, yet its mechanisms remain unclear. Mechanistic studies are hindered by reliance on archived formalin-fixed paraffin-embedded (FFPE) tissues, which are incompatible with standard single-cell methods. Here, we develop an FFPE-compatible single-nucleus RNA sequencing strategy and apply it to paired placentas from sequential pregnancies. VUE placentas exhibit pronounced immune expansion and disrupted trophoblast differentiation. A distinct extravillous trophoblast population and a subset of syncytiotrophoblasts aberrantly express classical MHC class I molecules, promoting natural killer cell engagement and indicating loss of trophoblast immune privilege. Pro-inflammatory maternal macrophages infiltrate, while fetal Hofbauer cells are reduced and transcriptionally reprogrammed. Increased intracellular viral burden and JAK-STAT signaling correlate with aberrant MHC class I expression, suggesting stress-induced local alloimmune activation. These findings define a cellular basis for disrupted maternal-fetal immune tolerance in VUE and demonstrate the utility of FFPE-based single-cell transcriptomics in placental disease.

cell biology↗

bioRxiv2026

Benzoxaboroles are structurally unique binders of eukaryotic translation initiation factor 4E

Benzoxaboroles offer unusual reactivity and protein recognition for the development of small molecule drugs. Despite this potential, they are uncommon in drug discovery or in fragment screening libraries. We synthesized a series of structurally related benzoxaboroles containing a diazirine/alkyne tag to enable in-cell photoaffinity labeling experiments. A subset of this library was found to have high selectivity for eukaryotic translation initiation factor 4E (eIF4E). The benzoxaborole-eIF4E interaction was found to be stereoselective in nature and competitive with the 7-methylguanosine cap of mRNA. Site of labeling experiments revealed that the benzoxaborole fragment interacts with the cap binding pocket of eIF4E. In silico modeling of the modified protein suggests that H-bonding interactions between the main chain of Trp102 and the side chain of Asn155 to the amide carbonyl and anionic boronate of the benzoxaborole, respectively, drive affinity for this challenging to drug pocket.

cancer biology↗

bioRxiv2026

Biodegradable Intra-arterial Devices for Focal Drug Delivery to Targeted Organs

This study presents the development of biodegradable intra-arterial drug delivery (IADD) devices for the focal treatment of targeted organs. The IADD devices are fabricated using magnesium (Mg) and poly(glycerol sebacate) (PGS), leveraging their biocompatibility and tunable biodegradability, and are loaded with two model drugs, dexamethasone (DEX) or cisplatin (CIS). The IADD devices with helical and linear designs were fabricated for focal drug delivery to targeted organs and characterized for their microstructure and composition using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The results confirmed the successful incorporation and stability of the drugs within the device. The IADD devices demonstrated in vitro release of DEX and CIS over 30 days, with drug-dependent and fabrication-dependent release profiles. The IADD devices demonstrated cytocompatibility with endothelial cells and sustained pharmacological activity against glioma cells throughout the in vitro release period. DEX-loaded IADD devices were implanted into the artery upstream of a target organ in rat models. The devices implanted into the renal artery to target the kidney and the carotid artery to target the brain achieved 109-fold and 68-fold improvements, respectively, in organ vs systemic drug levels compared to oral drug administration. Arterial histology and explanted-device analysis provided preliminary evidence of local vascular tolerability and device integrity over the examined implantation period. Overall, these results support IADD devices as a proof-of-concept approach for focal intra-arterial drug delivery to targeted organs, demonstrating substantially elevated target-organ drug levels relative to systemic exposure. HighlightsO_LIIntroduction of a novel intra-arterial drug delivery (IADD) platform C_LIO_LIIADD devices were fabricated from bioresorbable Mg and drug-loaded PGS C_LIO_LIDEX- and CIS-loaded IADD devices were evaluated for in vitro release and bioactivity C_LIO_LIIADD delivery achieved marked DEX enrichment in the kidney and brain C_LIO_LIPost-implantation studies support preliminary vascular safety C_LI

bioengineering↗

bioRxiv2026

SPrOUT: A computational and targeted sequencing approach for mixed plant DNA identification with Angiosperms353

PremiseThe identification of plant species from mixed samples is crucial in various fields, including ecological surveys, conservation efforts, and food and dietary supplement safety. Traditional methods face potential challenges due to the high costs of DNA sequencing, inefficiencies in computational workflows, and incomplete sequence databases. Methods and ResultsThis study introduces a novel approach using the Angiosperms353 target sequencing kit for efficient taxonomic identification of angiosperm DNA in mixed samples. Our method assembles short pair-end reads for each mixed sample. Using gene sets of Angiosperms353 from 871 species, we apply phylogenetic inference to categorize the variance in phylogenetic distance across genes to identify the presence of taxa in mixed plant samples. The pipeline reaches 98.1 to 99.6% accuracy, 92.9 to 100% precision for identifying unknown taxa in in-silico mixes, and 90.7% accuracy and 98.0% precision for mock supplement mixtures. We explored the parameter cutoffs of the pipeline to offer an empirical range for different applications. ConclusionsThe Angiosperms353 and HybPiper assembly proved effective in sorting mixed plant DNA samples. Our method offers a framework for scientific and practical applications in plant species identification in both single and mixed samples.

bioinformatics↗

bioRxiv2026

CellAwareGNN: Single-Cell Enhanced Knowledge Graph Foundation Model for Drug Indication Prediction

Graph foundation models have emerged as powerful tools for drug repurposing by enabling the prediction of novel drug-disease indications from large biomedical knowledge graphs. A representative example is TxGNN, which was previously developed and trained on PrimeKG, a comprehensive biomedical knowledge graph covering over 17,000 diseases. While TxGNN demonstrates strong performance, existing biomedical knowledge graphs largely lack fine-grained, cell-type-specific expression context. This limits their ability to capture disease mechanisms driven by dysregulated cellular programs, such as immune cell-specific pathways in autoimmune diseases. Moreover, prior evaluations typically test only randomly selected subsets of diseases, leaving many diseases unexamined and limiting conclusions about model performance across the full disease spectrum. To address these limitations, we first update PrimeKG to PrimeKG-U by incorporating expanded and curated biomedical knowledge and then develop TxGNN-U as a stronger graph-based baseline. Building on this foundation, we introduce CellAwareGNN, a graph foundation model that integrates single-cell genomics into PrimeKG-U. We construct a single-cell-enhanced knowledge graph, scPrimeKG, by incorporating cell-type-specific gene expression signatures from the OneK1K dataset, expanding PrimeKG from approximately 8.1 million edges and 129k nodes to over 14 million edges and 147k nodes. CellAwareGNN is pre-trained on all relation types in scPrimeKG and evaluated on drug indication prediction with explicit coverage of all diseases in the knowledge graph. CellAwareGNN consistently outperforms TxGNN and TxGNN-U. For drug indication prediction, CellAwareGNN achieves an AUPRC of 0.826, representing a 1.2% improvement over TxGNN-U (0.816) and a 3.4% improvement over TxGNN (0.799). Notably, for autoimmune diseases, CellAwareGNN attains an AUPRC of 0.864, improving by 2.0% over TxGNN-U (0.847) and 6.0% over TxGNN (0.815). Importantly, CellAwareGNN prioritizes promising repurposing candidates, including Ocrelizumab for Pemphigus via CD20-expressing B cells, Methotrexate for Pemphigus through DHFR and ATIC activity in T and B cells, and Rosiglitazone for Rheumatoid Arthritis through PPAR-{gamma} activation. These results demonstrate the value of incorporating cell-type-specific expression context to improve both predictive performance and biological interpretability in graph-based drug repurposing. CCS ConceptsO_LIApplied computing [->] Health informatics; Bioinformatics; C_LIO_LIComputing methodologies [->] Knowledge representation and reasoning; Neural networks. C_LI ACM Reference FormatXinmeng Zhang, Eugene Jeong, Chao Yan, Yubo Feng, Linshuoshuo Lyu, Xingyi Guo, and You Chen. 2026. CellAwareGNN: Single-Cell Enhanced Knowledge Graph Foundation Model for Drug Indication Prediction. In Proceedings of the 32nd ACM SIGKDD Conference on Knowledge Discovery and Data Mining V.2 (KDD 2026), August 9-13, 2026, Jeju Island, Republic of Korea. ACM, New York, NY, USA, 12 pages. https://doi.org/10.1145/3770855.3819012

bioinformatics↗

bioRxiv2026

NRF2 pathway activation and SPP1⁺TREM2⁺ macrophages drive chemoradiotherapy resistance in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive cancers, with low rates of durable response to chemoradiotherapy and limited therapeutic options for relapsed disease. To uncover mechanisms of treatment resistance and relapse, we performed comprehensive multi-omics profiling of >100 pre-treatment and post-relapse ESCC tumors from a prospective clinical trial (NCT04694391), integrating whole-exome/genome sequencing, bulk RNA-sequencing, single-cell RNA sequencing, and spatial transcriptomics. We identify somatic alterations in NFE2L2/KEAP1 in nearly 40% of relapsed patients, which are associated with upregulation of NRF2 signaling targets in resistant tumors and cell line models. At single-cell and spatial resolution, relapsed tumors are enriched for NRF2-activated epithelial cells that physically co-localize with immunosuppressive SPP1TREM2 macrophages. This co-localization suggests a synergistic interaction between NRF2-driven tumor programs and macrophage-mediated immune suppression that promotes relapse after chemoradiotherapy. Our findings nominate NFE2L2/KEAP1 mutations as predictive biomarkers for patient stratification and highlight therapeutic targeting of NRF2 signaling and SPP1TREM2 macrophages as rational strategies to overcome resistance in ESCC.

cancer biology↗

bioRxiv2026

Cell Type Architecture and Positional Gene Gradients in an Adult Animal at Subcellular Resolution

The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3, ptpn11, pi4ka, upf3b, and cul1, revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

developmental biology↗

bioRxiv2026

4D Single-Cell Spatial Transcriptomics Reveals Dynamic Morphogenetic Gradients and Regenerative Domains in Planarians

Regeneration relies on precise spatiotemporal gene expression and cellular responses to establish tissue identity and body patterning. Using high-resolution Stereo-seq (715 nm) on 353 sections from 16 whole animals at 8 regeneration timepoints, we constructed a 4D spatiotemporal transcriptomic map of planarian regeneration. Our analysis captured 36 refined cell types from 3,508,004 segmented cells, enabling genome-wide transcriptional imputation of gene expression dynamics across body axes at cellular, tissue, and organismal scales. We identified dynamic positional gradients and distinct spatially distributed cell types during regeneration, including an injury-induced Anterior Regenerative Zone (ARZ). The ARZ exhibited enriched positional signals in epidermal, muscle, and neural cells and was regulated by Mediator 8, which is crucial for polarity remodeling and blastema formation. This study provides a comprehensive spatial molecular and cellular map of regenerative processes, highlighting injury-induced spatial domains and key regulatory factors in planarian regeneration. We also provide an interactive web portal, offering a valuable resource for exploring and analyzing regeneration mechanisms in a spatiotemporal context.

developmental biology↗

bioRxiv2026

MG53 Protects Against Intestinal Inflammation by Inhibiting NLRP3 Inflammasome Activation

Background and ObjectivesInflammatory bowel disease (IBD) involves dysregulated immune responses and chronic intestinal inflammation. The nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in IBD pathogenesis, but regulatory mechanisms remain not fully understood. Mitsugumin 53 (MG53, also known as TRIM72), originally identified as a critical membrane repair protein, has emerged as a novel regulator of inflammatory processes. To investigate the protective role of MG53 in colitis and elucidate its mechanisms in regulating NLRP3 inflammasome activation in IBD. MethodsWe used dextran sodium sulfate (DSS)-induced colitis models comparing MG53 knockout (MG53-/-) and wild-type (WT) mice, assessing disease severity, MG53 tissue uptake, and therapeutic effects of recombinant human MG53 (rhMG53). In vitro studies examined rhMG53s effects on NLRP3 inflammasome activation, caspase-1 cleavage, interleukin-1{beta} (IL-1{beta}) secretion, and MG53-NLRP3 interactions. ResultsMG53-/- mice showed more severe colitis with increased weight loss, higher disease activity scores, shortened colons, and greater inflammation. DSS treatment induced the accumulation of circulating MG53 in inflamed colonic tissue. rhMG53 administration ameliorated colitis severity in MG53-/- mice and dose-dependently suppressed NLRP3 inflammasome activation in vitro. MG53 interacted with NLRP3 and reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and NLRP3 oligomerization without affecting upstream signaling or NLRP3 stability. ConclusionMG53 is a physiological regulator of NLRP3 inflammasome activation that protects against colitis, suggesting therapeutic potential for IBD.

immunology↗

bioRxiv2026

Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Pharmacological control of emergence from general anesthesia remains strikingly limited. Clinically available antagonists are largely drug-class specific, leaving recovery dependent on anesthetic clearance rather than to an actively programmable switch in brain state. Through phenotypic screening of a structurally diverse natural-product library, we identified BN3 (L-(-)-camphor) as a broad-spectrum emergence agent. BN3 robustly shortened recovery from propofol anesthesia across species--from mice and rats to rabbits, dogs, and rhesus monkeys--and remained effective after continuous infusion. In rodents, BN3 also accelerated emergence from mechanistically distinct anesthetics, including etomidate, remimazolam, sodium {gamma} - hydroxybutyrate, midazolam, ketamine, sodium pentobarbital, and isoflurane. EEG recordings revealed a rapid cortical shift from slow-wave dominance to a wake-like high-frequency spectrum. Mechanistically, BN3 preferentially recruited ventral tegmental area (VTA) glutamatergic neurons: chemogenetic silencing abolished the BN3-evoked EEG spectral shift and strongly attenuated behavioral acceleration of emergence, whereas optogenetic activation of these neurons was sufficient to promote recovery. BN3 increased glutamate release in the nucleus accumbens and medial prefrontal cortex, and projection-specific inhibition of VTA[->]NAc or VTA[->]mPFC outputs blunted BN3-induced emergence. These findings define a VTA-centered glutamatergic arousal circuit that can be pharmacologically recruited as a common gateway for anesthetic-independent emergence.

neuroscience↗