Biology subjects

Chen, S.

Publications and source records attributed to Chen, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Gap-free telomere-to-telomere haplotypes assembly of the hybrid grouper 'Yushuban' (Cromileptes altivelis female x Epinephelus fuscoguttatus male)

The hybrid grouper 'Yushuban' (Cromileptes altivelis [female] x Epinephelus fuscoguttatus [male]) has shown promising performance in aquaculture trials, yet no complete reference genome has been available for this hybrid. We generated two gapless, telomere-to-telomere (T2T) haplotype-resolved genome assemblies of a single individual by integrating short-read, PacBio HiFi, Oxford Nanopore ultralong-read and Hi-C data. The maternal (Yushu_Calti_1.0) and paternal (Yushu_Efusc_1.0) haplotypes are 1,077.33 Mb and 1,083.36 Mb in length, with N50 values of 45.46 Mb and 45.55 Mb, respectively. Across all platforms, over 99.4% of reads mapped to each assembly, and Merqury-based quality values reached 57.7413 and 59.2068 (PacBio). BUSCO recovered 99.78% and 99.75% of complete core genes. We predicted 27,248 and 27,566 protein-coding genes, of which 98.52% and 99.23% were functionally annotated, and annotated telomeric motifs and repetitive elements (46.12% and 47.18% of each genome). These assemblies fill a gap in grouper genomic resources and provide a foundation for genetic dissection, parental genome comparison and molecular breeding of this hybrid.

genomics↗

bioRxiv2026

Uncertainty-Guided Decision-Making in Bumble Bees

The evolutionary origins of cognitive monitoring remain contested. Metacognition, the capacity to monitor one's own cognitive states, has long been linked to complex vertebrate brains, yet whether a miniature brain can evaluate the reliability of its internal representations is unknown. Here we demonstrate that bumble bees engage in uncertainty-guided decision-making. Bees dynamically adjusted opt-out choices according to perceptual difficulty, settling for a smaller guaranteed reward to avoid errors, and actively paid a reward cost to seek information under uncertainty. Without any retraining, bees transferred this 'opt-out-under-uncertainty' rule to novel tactile and working-memory tasks under an all-probe design. This strategy was stable across individuals and accurately captured by a confidence-based decision model. Our findings suggest that a brain of approximately one million neurons can support an abstract domain-general uncertainty-monitoring policy, indicating that the neural substrates for uncertainty-guided decision-making may be far more ancient and widely distributed than previously assumed.

animal behavior and cognition↗

bioRxiv2026

stEDGE enables edge-guided multiscale reconstruction of hierarchical spatial domains and transition interfaces in spatial transcriptomics

Spatial transcriptomic technologies enable high-resolution mapping of tissue architecture, yet most computational methods still represent tissues as flat spatial partitions, limiting their ability to resolve spatial domain boundaries, gradual transition regions and nested hierarchies. Here we present stEDGE, an edge-guided and interpretable framework for multiscale reconstruction of spatial domain hierarchies and transition-associated states in spatial transcriptomics. Unlike conventional domain-first approaches, stEDGE first estimates local boundary structure and uses it to guide the reconstruction of fine-grained spatial domains. We further introduce a domain transition index (DTI) to quantify domain-level transition propensity and integrate DTI with inter-domain similarity and boundary strength to organize fine domains into a coherent multilevel hierarchy. A tree-guided gene attribution strategy then distinguishes shared parent-level programs from branch-specific specialization across hierarchical spatial states. Across 15 benchmarked tissue sections spanning diverse tissues, technologies and spatial resolutions, stEDGE reconstructs developmental, inflammatory, tumor and brain architectures beyond conventional domain partitioning. Applied to cell-resolved Xenium profiling of fibrotic human lung, stEDGE further reveals lesion-associated remodeling as a coherent multiscale hierarchy in which remodeling interfaces coexist with a stable macrophage-associated airway/lumen state and spatially organized TLS-like lymphoid niches. Together, stEDGE provides a unified framework for modeling how stable compartments, domain boundaries, remodeling interfaces, localized niches and multiscale gene programs are jointly organized across spatial scales.

bioinformatics↗

bioRxiv2026

Structured cross-omics interaction discovery with a triple-graph model

Multi-omics analyses often yield fragmented pairwise associations that obscure coordinated relationships among molecular features. We developed TriGer, a triple-graph framework that identifies many-to-many cross-omics modules by combining cross-layer associations with dependency structures within each layer. In simulations with sparse or nested signals, TriGer recovered planted modules while balancing sensitivity and specificity. In inflammatory bowel disease, it identified subtype-associated metabolite--transcript modules; in colorectal cancer, it identified genus--metabolite modules whose organization was attenuated in cancer. TriGer provides an interpretable approach for studying coordinated cross-omics structure in high-dimensional molecular data.

bioinformatics↗

bioRxiv2026

Generation and application of human pluripotent stem cells derived peri-nervoids

Autologous nerve grafts remain the gold standard for peripheral nerve repair, but donor scarcity, donor-site morbidity and incomplete functional recovery limit their use. Schwann cells (SCs) drive autograft-mediated regeneration, yet their limited availability and expansion impede SC-based therapies. Here, we generated human pluripotent stem cell-derived SCs, motor neuron-enriched spinal cord organoids and nociceptive sensory neuron-enriched dorsal root ganglion organoids, and assembled them into a nerve-like construct termed the Peri-nervoid. Single-cell RNA sequencing revealed context-dependent SC plasticity: axonal co-culture promoted myelination, whereas axonal transection induced a repair phenotype resembling SC dedifferentiation during Wallerian degeneration. Following transplantation into 7-mm sciatic nerve defects in NSG mice, human SCs survived and remyelinated regenerating host axons, while axon-containing grafts enhanced regeneration relative to SC-only grafts. No abnormal proliferation, systemic toxicity or major-organ histopathology was detected. These findings position the Peri-nervoid as a scalable, developmentally inspired platform for developing engineered grafts for peripheral nerve repair.

bioengineering↗

bioRxiv2026

J-domain proteins stimulate PKL-mediated chromatin compaction at H3K4-hypomethylated genomic loci

Chromatin accessibility varies widely across distinct genomic regions in eukaryotes, yet the mechanisms governing these differential patterns remain poorly understood. Here, we identify a subfamily of functionally redundant J-domain proteins (JDPs) that assemble into a protein complex with PICKLE (PKL), an evolutionarily conserved CHD3-type chromatin remodeler, in Arabidopsis thaliana. JDPs are required not only for maintaining PKL protein stability but also for stimulating its nucleosome remodeling and ATPase activities. A previously uncharacterized histone-binding domain (HBD) within JDPs specifically recognizes the N-terminal tail of histone H3 when the H3K4me3 modification is absent. This interaction enhances PKL-mediated nucleosome sliding and ATPase activities in vitro, and promotes PKL-dependent chromatin compaction at H3K4me3-depleted genomic loci in vivo. The PKL-JDP complex drives chromatin compaction to repress developmentally regulated genes, thereby governing key developmental phase transitions, including the embryo-to-seedling transition and flowering. Collectively, these findings uncover a distinct mechanism by which the absence of H3K4me3 is sensed to initiate regional chromatin compaction, repress developmentally regulated genes, and facilitate key developmental transitions.

plant biology↗

bioRxiv2026

Large-scale structural analysis of pre-mRNA structure using RADIS

Pre-mRNA secondary structure can modulate the regulatory function of intronic sequences by masking or exposing splice-site signals and altering the accessibility of other features. Yet experimentally supported structural models for human pre-mRNAs have been largely restricted to splice-site-proximal sequences, leaving the deep intronic regions where ~70% of intronic disease-causing variants reside almost entirely unmapped. We developed RADIS (Reactivity Analysis of Deep and Intergenic RNA Structure), a strategy that yields strand-resolved chemical probing reactivity profiles across entire intron-rich loci by creating tiled arrays of RNAs that comprehensively span long genomic distances. This approach removes the abundance and locus-specificity constraints that otherwise limit pre-mRNA probing approaches. RADIS recovers known E. coli ribosomal RNA architectures and yields high-correlation with in-cell dimethyl sulfate (DMS)-MaP reactivities at representative splice sites (r = 0.87-0.90). RADIS-constrained folding of 109 5' and 88 3' splice sites uncovers an inverse relationship between base-pairing within the spliceosome footprint and splice-site strength, and partitions 81 branchpoints into three structural classes. Across 233 full-length Alu elements, sense Alu RNAs are more structured than antisense elements, and both partition into strand- and lineage-dependent structural classes. RADIS enables experimentally grounded structure analysis at disease-associated intronic and intergenic loci, complementing sequence-based variant-effect predictors.

molecular biology↗

bioRxiv2026

H3K4me3 recruits the chromatin remodeling DILL-PICKLE-PEPPERCORN complexes to promoters in plants

The plant CHD chromatin remodeler PICKLE (PKL) is a master regulator of cellular identity and differentiation, controlling developmental, hormonal and stress-response processes. Yet the molecular mechanisms underlying its function remain unclear. Here, we show that PKL forms three complexes, each composed of a protein of previously unknown function and one of three mutually exclusive novel DNAJ proteins that recruit HSP70-1. Simultaneous loss of all three DNAJs phenocopies the pkl mutant, indicating functional redundancy among PKL complexes. In vitro activity assays and cryo-electron microscopy reveal that PKL clamps nucleosomal DNA via its ATPase motor domain and recognizes H3K4me3 through its double chromodomain. Genome-wide profiling shows that H3K4me3 recognition positions PKL complexes at genic promoters to bidirectionally fine-tune gene expression. Together, these results provide structure-function insight into PKL recruitment and its control of developmental gene expression, and reveal a chaperone-coupled complex assembly that offers a broader perspective on how chaperone networks may support chromatin remodeling complexes across eukaryotes.

plant biology↗

bioRxiv2026

A genetically encoded redox bottleneck constrains human developmental rate

The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.

developmental biology↗

bioRxiv2026

Over-the-counter fiber supplementation associates with metabolic and microbial shifts in rectal mucosa

Fiber supplements are the first line of treatment for all patients with benign anorectal disease. In addition, fiber has been found to support gut microbiota and reduce inflammation; however, their integrated effect on the colonic mucosal environment is incompletely defined. We evaluated how mixed-fiber formulations may collectively shape the rectal mucosal environment through coordinated effects on microbiota composition, short-chain fatty acid (SCFA) handling, and host transcription. We evaluated multi-compartment responses to a 28-day mixed-fiber intervention in 37 participants with benign anorectal disease (~15 g/day; 7.5g psyllium husk, 8g wheat dextrin) and assessed the microbiota (16S rRNA), the metabolome (GC-MS and LC-MS), and transcriptome (subset n=10) before (PRE) and after (POST) supplementation. Changes in KEGG pathways were tested with gene set enrichment analysis (GSEA). Associations were tested by Spearman correlation, and microbiota-based prediction of SCFA responses by random-forest regression. Microbiota diversity was stable after the fiber intervention, however, 10 mucosal ASVs were differentially abundant including Parabacteroides and Lachnospiraceae NK4A136 group while SCFAs, propionate and isobutyrate, both decreased in rectal tissue and butyrate decreased in serum. To understand these shifts in the metabolome, we proceeded with the transcriptome where we identified 130 differentially expressed genes and enrichment of metabolic and SCFA-related pathways. Random forest regression captured a modest signal for serum butyrate. Taken together, short-term mixed-fiber supplementation produced selective rectal mucosal taxonomic shifts and enriched mucosal metabolic and SCFA-metabolism program despite reduced SCFA pools, suggesting that even brief over-the-counter fiber supplementation may reshape the mucosal metabolic environment.

microbiology↗

bioRxiv2026

Ancient tandem duplication of CYCLOIDEA is associated with the evolution of capitulum development in Asteraceae

Asteraceae is one of the largest and most diverse families of flowering plants. Much of their evolutionary success is attributed to their unique inflorescence structure-the capitulum. Despite their profound adaptive and taxonomic significance, the evolutionary genetic mechanisms underlying Asteraceae capitulum diversification remains poorly understood. We integrated comparative genomic analyses of 35 Asteraceae genomes with developmental transcriptome profiling of ray and disc florets. Our results uncovered a deeply conserved CYC2e-CYC2c-CYC2d-CYC2g-CYC2b tandem gene cluster that is prevalent across the Asteraceae family. We demonstrated that this tandem cluster arose during the early evolutionary diversification of Asteraceae. Subsequent lineage-specific gene retention and loss events have reshaped the composition of this cluster across different Asteraceae lineages. Notably, key members of this cluster, particularly CYC2c, CYC2d, and CYC2g, are preferentially retained in lineages with ray florets, which is consistent with their roles in regulating the ray floret development. Collectively, our findings establish a mechanistic link between the evolutionary divergence, spatiotemporal expression differentiation of the CYC2 tandem cluster as a key genetic driver underlying the morphological diversification and evolutionary success of Asteraceae.

evolutionary biology↗

bioRxiv2026

Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis

Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.

cancer biology↗

bioRxiv2026

The DYNAM-O Toolbox: Characterizing Individualized Neural Signatures in Sleep EEG

Here, we introduce the Dynamic Oscillation (DYNAM-O) Toolbox, an open-source, cross-platform (MATLAB, Python, and Rust) software package for data-driven characterization of individualized neural dynamics in sleep EEG. Conventional sleep electroencephalography (EEG) measures often rely on predefined bands, thresholds, and averages that incompletely capture transient oscillatory dynamics across the night. For example, sleep spindles, 12-16 Hz bursts of EEG activity related to memory consolidation and altered in disease states, are traditionally detected using fixed frequency and amplitude criteria. Recent studies, however, have shown that canonical spindles represent only a small subset of the tens of thousands of transient "spindle-like" oscillations occurring each night, comprising multiple event classes across a broad frequency range. Together, these classes of transient oscillations form highly individualized signatures of brain state with demonstrated utility as EEG biomarkers of disease. DYNAM-O substantially extends our transient oscillation framework and provides the first end-to-end pipeline for this analysis, from event detection to group-level statistics. It identifies transient oscillations as time-frequency peaks (TF-peaks) using a novel multi-resolution procedure that combines time- and frequency-optimized multitaper spectrograms to separate closely spaced events and refines each event's peak frequency to resolve oscillations separated by less than the spectrogram resolution. It then computes intrinsic and sleep-state-dependent extrinsic features for each event and represents the overnight distributions of TF-peaks as feature histograms spanning oscillation frequency, slow oscillation power, and slow oscillation phase, preserving continuous brain-state variation obscured by stage-based averaging. New parametric and spline-based dimensionality reduction methods distill these histograms into a small number of interpretable modes, and integrated whole-histogram statistical tests support exploratory and hypothesis-driven group analyses. As a demonstration, we analyzed sex differences in polysomnography recordings from 112 adults (C3 electrode; 67 females, 45 males; ages 20-35 years) from the Cleveland Family Study. In addition to replicating the established higher fast-spindle frequency in females, we identified greater low-alpha transient oscillatory activity in females, a novel sex difference in events ignored in traditional analyses. DYNAM-O provides an accessible and interpretable framework for studying individualized sleep physiology, with applications to longitudinal studies, group comparisons, and feature extraction for deep learning models.

bioinformatics↗

bioRxiv2026

Single-atom inhibition of oncogenic drivers through cysteine coordination

Small-molecule inhibitors rely on molecular recognition within suitable binding pockets, leaving many disease-associated proteins difficult to target. Here, we introduce the concept of a single-atom inhibitor in which gold (Au) engages critical cysteine residues of oncogenic drivers to suppress their activity. We used an AI-assisted few-shot learning approach to identify EGFR-targeting peptides for in vivo Au delivery and showed that the lead candidate, 10714, promoted Au accumulation in EGFR-expressing cells and tumors. In vivo, Au exploited its intrinsic affinity for cysteine to inhibit two structurally distinct oncogenic proteins, engaging Cys797 in EGFR T790M and the mutation-derived Cys12 in KRAS G12C adjacent to their respective nucleotide-binding pockets. Structural and computational analyses supported stabilization of inactive nucleotide-bound states, while mutation of these cysteine residues abrogated Au-mediated inhibition. 10714-Au consequently suppressed oncogenic signaling, reduced non-small-cell lung cancer cell viability, and inhibited tumor growth in EGFR- and KRAS-mutant xenograft models and patient-derived organoids. These findings establish proof of principle for single-atom inhibition across structurally distinct oncogenic drivers and suggest that localized atomic coordination could provide an alternative mode of target engagement to conventional pocket-dependent inhibition.

molecular biology↗

bioRxiv2026

Developing a sensitive indoor air surveillance approach for nosocomial pathogens and antimicrobial resistance

The role of bioaerosols in the transmission of pathogens and antimicrobial resistance (AMR) is of increasing clinical importance, particularly in settings housing vulnerable populations. Air filtration (e.g. HEPA filtration) and ventilation (e.g. minimum air changes per hour) measures are designed to restrict the airborne transmission of microorganisms. Despite these measures, airborne transmission remains a persistent issue in hospitals, workplaces, aged care, and schools, and is not typically assessed in routine surveillance for infection prevention. Here, we evaluated the efficacy of a high-volume air sampling approach to capture the indoor 'aerobiome', and investigated the potential for bioaerosols to mediate disease and AMR transmission in workplace and hospital settings. Our sampling approach demonstrates the benefits of simple decontamination procedures and personal protective equipment on the ability to distinguish genuine low biomass signals in air samples from blank controls, enabling reliable and sensitive microbial detection down to a limit of 69 bacterial cells/m3 of air. In a workplace bathroom setting, increased airborne biomass was strongly associated with human activity. This diminished significantly after a few hours of no activity, yet persisted in the indoor environment, with viable identical bacterial strains recovered from bioaerosols and bathroom surfaces across months of sampling. Applying our approach in a hospital ward, air samples from occupied patient rooms were not distinguishable from blank controls and contained negligible fungal and bacterial content, with only trace contributions from human occupancy. Our findings indicate that air filtration measures in this ward are effective at minimising airborne risks, but periodic testing of high-risk areas may be valuable in indoor settings with greater human traffic and may contribute key information to outbreak investigations.

microbiology↗

bioRxiv2026

The BAF complex works with FOS to regulate human neuronal activity-dependent ASD-associated gene programs

The BAF chromatin remodeling complex is critical to normal brain development, and rare variants within genes encoding BAF subunits are a common genetic cause of neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet the factors that direct BAF binding across the neuronal genome, the human neuronal gene programs that are regulated by BAF, and the mechanisms whereby BAF subunit perturbation leads to ASD are not known. We find that BAF binds with the activity-dependent transcription factor FOS to distal regulatory regions that, in response to neuronal activity, undergo chromatin opening and show evidence of enhancer activation. Knock-out of ARID1A, a BAF subunit implicated in ASD, leads to decreased chromatin accessibility at FOS/BAF binding sites concomitant with decreased expression of nearby activity-regulated ASD-associated genes. Additionally, we find that the FOS binding motif in FOS/BAF-bound regions is highly constrained in the human population, and that rare variants in this motif in ASD-affected individuals disrupt stimulus-dependent enhancer activation. This suggests that genetic variation in FOS/BAF-bound regions contributes to ASD pathogenesis, due to an inability to recruit FOS and BAF to enhancers to promote gene expression. Together, our findings highlight a role for BAF in mediating neuronal transcriptional programs downstream of FOS and reveal a mechanism by which non-coding variants may impact BAF function and contribute to risk for ASD.

neuroscience↗

bioRxiv2026

DYNAMIC CONFORMATIONS IN THE ACTIVATION OF PINK1 KINASE

Under mitochondrial stress, the mitochondrial kinase PINK1 is activated to phosphorylate ubiquitin, which in turn recruits the E3 ligase Parkin, thereby initiating clearance of damaged mitochondria. Dysregulation of the PINK1-Parkin signaling pathway is associated with early-onset autosomal recessive Parkinson's disease. However, the mechanisms governing PINK1 conformational dynamics and activation in response to mitochondrial stress remain poorly understood. Here, we report that Tribolium castaneum PINK1 (TcPINK1) forms specific symmetric dimers via interactions between the kinase N-lobe and the regulatory C-terminal domain. These dimers undergo dynamic conformational transitions across distinct states, including an autoinhibited state, an inactive intermediate state, a primed-activation state and an active state. Moreover, TcPINK1 undergoes lateral trans-phosphorylation through dimer-dimer interactions. Notably, symmetric dimer formation is essential for Parkin recruitment during mitophagy. These findings provide a framework for understanding the conformational plasticity and allosteric regulation of PINK1 in mitophagy.

biophysics↗

bioRxiv2026

MOLECULAR BASIS FOR PINK1 MATURATION

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a key regulator of mitophagy, has been linked to the pathogenesis of Parkinson's disease (PD). PINK1 recruits Parkin, an E3 ubiquitin ligase, triggering mitophagy in response to mitochondrial damage. During mitophagy, the quantity, stability, and activity of PINK1 must be strictly regulated; however, the mechanisms governing these parameters under cellular stress are still unclear. Herein, we determined the structural basis for PINK1 maturation mediated by heat shock protein 90/cell division cycle 37/FK506-binding protein 51 (HSP90/CDC37/FKBP51) chaperone complex. We identified PINK1-associated proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and determined the structures of the complexes using Cryo-Electron Microscopy (Cryo-EM). Results showed that FKBP51 potentially interacts with a conserved leucine-proline-phenylalanine (LPF) motif on the activation loop of PINK1 and negatively regulates PINK1 functions in mitophagy. A PINK1 mutation located at the FKBP51 recognition site is linked to mitophagy deficiency, which can be partially rescued by specific inhibition of FKBP51. These findings reveal a general mechanism for PINK1 recognition by the HSP90/CDC37/FKBP51 chaperone complex and suggest a potential approach for upregulating PINK1 activity, which is impaired in PD.

biophysics↗