Biology subjects

Yi, S.

Publications and source records attributed to Yi, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Deciphering Spatial Cellular Organization through RNA-Anchored Multi-Omics Deconvolution

Spatial technologies that jointly profile RNA and additional molecular layers provide a comprehensive view of tissue organization, yet their limited resolution results in measurements that reflect mixtures of multiple cell types. While RNA-based deconvolution methods are well established, incorporating co-profiled non-transcriptomic modalities without compromising cell-type identifiability remains an open challenge, as reliable references are largely restricted to transcriptomic data. Here we present SMODER, an RNA-anchored framework for spatial multi-omics deconvolution that treats transcriptomes as the primary determinant of cell identity while incorporating complementary molecular modalities in a constrained manner. By adopting an asymmetric integration strategy, SMODER preserves RNA-driven cell-type resolution and enables robust estimation of cell-type compositions across spatial locations. Across simulations and diverse spatial multi-omics datasets spanning protein, chromatin accessibility and histone modification assays, SMODER consistently outperforms existing methods in both accuracy and spatial coherence. Beyond deconvolution, SMODER denoises multi-omic signals and enables cell-type-aware analysis of regulatory programs. Application to spatial CUT\&Tag--RNA-seq and {RNA--ATAC-seq} data reveals spatially resolved epigenetic repression and cis-regulatory relationships linked to gene expression.

bioinformatics↗

bioRxiv2026

Sleep spindle deficits in childhood absence epilepsy improve with antiseizure treatment and disease resolution

Childhood absence epilepsy (CAE), the most common childhood epilepsy syndrome, is associated with bursts of generalized thalamocortical spike-wave discharges and cognitive impairment, yet the physiological mechanisms linking disease activity, treatment, and cognition remain unclear. Sleep spindles, generated by thalamocortical circuits, are associated with cognitive function and may be disrupted by epileptic activity. Here, we retrospectively studied 87 EEGs from 53 children with active and resolved CAE and 87 age- and sex-matched controls to evaluate sleep spindle activity across disease states and its association with antiseizure medication (ASM) exposure. We found that children with active CAE had reduced spindle rates across all cortical regions compared to those with resolved CAE and controls, with the largest reduction in the frontal region, where epileptic spike activity was also most prominent. Spindle rate was inversely correlated with epileptic spike rate, consistent with a shared thalamocortical circuitry. The association between ASM exposure and spindle rate varied by disease state. In active CAE, treated children had higher spindle rates than untreated children. In resolved CAE, treated children had lower spindle rates than untreated children. In contrast, ASM-related differences in spike rate were more limited, although a medication-specific reduction was observed in active CAE. These findings support sleep spindle rate as a candidate physiological marker of disease state and ASM exposure in children with CAE. Given the established role of sleep spindles in memory consolidation, these findings support testing of whether spindle disruption provides a mechanistic link between epileptic thalamocortical activity and cognitive vulnerability in CAE.

neuroscience↗

bioRxiv2026

Hygrochastic Seedpods: Engineering Microclimates for Forest Restoration

Forest restoration at scale depends on sowing seeds directly onto the land, yet seedling establishment is often poor and inconsistent. Seed enhancement technologies, such as priming, coating, and pelleting, improve germination under water, temperature, and salinity stress by supplying polymers, nutrients, or microorganisms at the seed surface. Being mainly conformal films, they act continuously once wetted and cannot gate when a seed is exposed to the soil. They also enclose no air volume, so the microenvironment they create is inseparable from the surrounding soil and has been inferred from plant performance rather than measured directly. Whether an engineered carrier can instead set both the state and the duration of the post-dispersal microenvironment, and how such an effect can be directly quantified, remains unexplored. Here we show that hygrochastic seedpods hold seeds in a timed, directly measurable microclimate and accelerate seedling emergence. The pods are programmable, responsive conical shells enclosing an air cavity around the seed. Two design solutions were investigated in parallel: wooden seedpods that crack open upon hydration, and poly(vinyl alcohol)/boric acid seedpods that gradually disintegrate after sustained wetting. In both, wax coatings act as a programmable diffusion-limited timer that sets activation from hours to days. The pod cavity permits direct sensing and monitoring, which no coating geometries allow. As directly measured during the initial phase after deployment, seedpod interiors ran 2 - 3 C warmer and drier than the surrounding soil, and these differences persisted after opening. Across indoor and field trials in several tree species, pods accelerated early seedling emergence without penalizing subsequent growth. These results identify artificial hygrochastic seedpods as a transient ecological mediator that regulates both the timing of seed exposure and the microclimate around the seed, offering a strategy for improving forest restoration under variable environmental conditions.

bioengineering↗

bioRxiv2026

scOLAR: Ontology-Anchored Open-Set Annotation of Single-Cell RNA-seq Data

Single-cell RNA sequencing profiles cellular heterogeneity at atlas scale, making automated annotation essential. However, target datasets often contain novel cell types missing from incomplete references. We present scOLAR, an ontology-guided open-set framework that learns prototypes over the Cell Ontology and uses both reference and target expression to annotate known classes while detecting unfamiliar populations. Guided by ontology hierarchies and decision-boundary regularization, scOLAR penalizes coarse-lineage misclassification and groups novel cells without requiring predefined cluster counts. Across benchmarks, scOLAR achieves a novelty-detection AUROC of 0.9726 and an average precision of 0.9871, enabling structured post-hoc lineage-level interpretation of populations absent from the reference.

bioinformatics↗

bioRxiv2026

Epigenetic age acceleration is associated with contaminant exposure in common dolphins (Delphinus delphis)

Metals and per- and polyfluoroalkyl substances (PFAS) represent a significant environmental concern, yet their association with epigenetic age acceleration (EAA) remain largely understudied in marine mammals. Here, associations between EAA in common dolphins (Delphinus delphis) and life history (sex and sexual maturity), trace metals, and PFAS were investigated. EAA was calculated as the residual in the regression of epigenetic age vs chronological age, hence providing a direct measure of the deviation of the epigenetic age of an organism (positive or negative) by comparison with expectation, given their actual chronological age. Sixteen trace elements were quantified in hepatic and renal tissues (n = 53). In addition, 28 PFAS were quantified in hepatic tissue (n = 58). Associations between EAA and explanatory variables were assessed using regression-based and multivariate modelling approaches (linear models and canonical analysis of principal coordinates). No effect of sex was observed, although sexual maturity did significantly increase EAA. Exposure to metals was significantly associated with EAA, explaining 55.4% of the variation, with hepatic metals (Se, Zn, Cu, Al, Mn) driving this relationship. Although EAA was not significantly related to the total PFAS exposure overall, a subset of PFAS variables (PFBA, PFDA, PFHxS-B, PFNA) showed significant association with EAA after adjusting for sex and sexual maturity. Together, these subsets of metal and PFAS variables, in addition to the selenium-to-mercury (Se:Hg) molar ratio, explained 66.7% of the variation in EAA. Our results identify sexual maturity and specific contaminant mixtures as key potential drivers of EAA in common dolphins, highlighting the possible use of EAA as a biomarker of environmental and physiological stress in marine mammals.

zoology↗

bioRxiv2026

Engineering of CAR-less lentiviral vectors via ER retention-mediated CAR blockade

Chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment of various tumor types by redirecting and activating T cells against tumor cells. However, CAR-T cell manufacturing approaches remain challenging and limit their widespread use in clinical settings. In vivo CAR-T therapy bypasses ex vivo cell manufacturing and patient preconditioning limitations; however, it faces a significant safety concern as CAR proteins on viral packaging cells are incorporated into budding virions, leading to off-target transduction of tumor cells. Here, we address this risk by developing the CAR-Less ER-Anchor Vector (CLEAN-V) system. By exploiting endoplasmic reticulum (ER) retention, CLEAN-V prevents the CAR protein from trafficking to the cell surface during viral packaging, thereby blocking its incorporation into the viral envelope. CLEAN-V particles exhibit near-complete loss of CAR-mediated tumor cell transduction. Furthermore, CLEAN-V integrates seamlessly into existing third-generation LVV workflows in four- or five-plasmid formats and generates CAR-T cells with preserved phenotypic and functional integrity. These results establish CLEAN-V as a robust platform for developing safe, targeted lentiviral vectors for in vivo CAR-T therapy.

bioengineering↗

bioRxiv2026

Role of stereochemistry on electron transport in peptides

Stereochemistry underlies structure-function relationships across biology and materials science, ranging from proteins to electronic and spintronic materials. In this work, we investigate the electron transport properties of different oligopeptide stereoisomers using experiments and computational modeling. Single-molecule electronic experiments show that stereochemical modifications in tyrosine-based peptides lead to significant variations in molecular conductance along the peptide backbone due to enhanced stacking interactions and electronic coupling of aromatic side chains. In addition, stereochemical variations in alanine-based peptides give rise to changes in conductivity due to secondary structure interactions arising from {beta}-turn conformations. All-atom molecular dynamics (MD) simulations and quantum mechanical calculations are used to understand the molecular origins of the effect of stereochemistry on the structural and electronic properties of peptides. Overall, this work shows that stereochemical modification of non-terminal amino acids effectively controls electron transport due to aromatic side chain interactions or secondary structure effects. These insights open new avenues for the molecular design of peptide-based electronic materials with enhanced function.

biophysics↗

bioRxiv2026

Human meningiomas arise from developmental meningeal mosaicism

Meningioma is the most common primary intracranial tumour, yet its genetic origin and the temporal sequence of mutational events remain poorly defined. Here, we analysed 80 triple-matched tumour, histologically normal meninges, and blood samples from 22 patients. NF2 or TRAF7 driver mutations are detectable in phenotypically normal meninges in 81.8% of cases (95% CI: 59.7-94.8%; VAF [~]0.02%), corroborated by high-depth sequencing, single-cell cloning, and phylogenetic analysis. By distinguishing developmental mosaic mutations from postnatal tumour-private mutations, we revealed distinct mutational signatures and resolved the temporal sequence of meningioma evolution. The developmental origin was further underscored in patients with multiple meningiomas, where identical driver mutations were shared across genomically distinct tumours and meninges, and in intraventricular meningiomas (IVM), where driver mutations were detected in distant cranial dura. Reconstruction of mutational timing revealed lineage-specific trajectories, linking mosaicism to diverse disease presentations including solitary meningioma, IVM, meningiomatosis, and NF2-related schwannomatosis. Together, these findings reveal an early origin of human meningioma, in which developmental mosaicism establishes a pre-neoplastic field within the meninges, providing a developmental framework for adult tumourigenesis.

Cancer Biology↗

bioRxiv2026

A Genetic Tool for Specific Tracking of Mature Neutrophils

Tracking mature neutrophils remains challenging due to the lack of reliable cell surface markers. Although CD101 is a promising candidate for mature neutrophils, its stability under pathological conditions is unclear. Using a CD101-tdTomato reporter mouse model, we confirmed that the reporting system does not alter CD101 expression, and tdTomato fluorescence is predominantly expressed in mature neutrophils across peripheral tissues. Further analysis revealed that CD101+ and tdTomato+ neutrophils display identical characteristics of mature neutrophil, including poly-segmented nuclei, cell size, and key functions under homeostasis. By comparing tdTomato fluorescence with CD101 protein levels, we demonstrate that reduced CD101 expression under pathological states was not attributed to shedding or degradation. Our finding enhances CD101 as a robust and reliable marker of neutrophil maturity, providing a foundation for future applications in spatial transcriptomics and lineage tracing studies to dissect neutrophil heterogeneity and function. Highlights of the studyO_LIIn CD101-tdTomato homozygous mice, tdTomato is predominantly expressed in neutrophils and labels nearly 100% of mature neutrophils, aligning with the phenotype of CD101+ mature neutrophils; C_LIO_LIThe CD101-tdTomato reporting system does not interrupt CD101 expression or neutrophil functions; C_LIO_LICD101 remains a stable and reliable cell surface marker for labeling mature neutrophils, even under pathological conditions. C_LI

immunology↗

bioRxiv2026

Identifying adaptive variation in spatially structured populations using low-coverage whole-genome sequencing data

Successful implementation of evolutionary programs to rescue climatically threatened species requires identification of adaptive variation. Although many genotype-environment association methods have been successful in identifying adaptive variation, current approaches can be improved in two important aspects. First, most existing methods do not account for genotype uncertainty in widely available low-coverage whole-genome sequencing data. Researchers often restrict analysis to loci for which genotypes can be inferred reliably or call the most probable genotype, allowing the use of genotype-based methods. However, discarding data and false genotype calls increase the uncertainty in estimates of genetic variation and can introduce systematic biases. Second, most methods use phenomenological approaches, such as logistic regression, to partition estimated variation into adaptive and non-adaptive components. Consequently, current approaches may fail to account for evolutionary processes, such as migration-selection balance. Structured migration between climatically disparate locations can produce deviations from a smooth S-shape response curve, which can be difficult to accommodate using generalized linear models. To overcome these challenges, we developed a method that accounts for genotype uncertainty in sequencing data and propagates this uncertainty to inform the parameters of an evolutionary model. A key feature of this model is that it describes mechanistically how genetic variation arises from joint interactions between local adaptation, structured migration, mutation, and drift. Our synthetic simulation tests reveal that accounting for genotype uncertainty and structured migration substantially reduces false negatives. We also applied our approach to analyze data on North American rosy-finches (3.7 million SNPs), a high-alpine, climatically threatened clade of bird species.

genomics↗

bioRxiv2025

Fine scale structural information substantially improves multivariate regression model for mRNA in-vial degradation prediction

The success of COVID-19 mRNA vaccines has made the in-solution stability optimization of mRNAs a key objective. However, we still lack a complete understanding of sequence metrics that influence mRNA in-solution stability. RNA secondary structure plays a critical role in protecting against hydrolysis, the primary degradation pathway under storage conditions. Yet, the structural metrics that best guide stability-focused mRNA design remain incompletely defined. Global metrics like minimum free energy and average unpaired probability have improved mRNA stability but fail to capture local structural variation relevant to RNA degradation. We demonstrate that base-pairing log odds provide fine-scale, orthogonal insight that complements global metrics and improves stability modeling. Further, by combining local and global features into a parsimonious four-feature regression model, dubbed Stability Regression Analysis using Nucleotide-Derived features (STRAND), we achieve a greater than two-fold reduction in prediction error compared to existing machine learning and deep learning approaches and demonstrate robust generalization across diverse transcript contexts. This compact and interpretable model provides an accurate and reliable framework for predicting mRNAs in-solution stability.

bioinformatics↗

bioRxiv2025

Human ribomes reveal DNA-embedded ribonucleotides as a new type of epigenetic mark

Ribonucleoside monophosphates (rNMPs) are abundant in DNA, but their distribution and function in human nuclear genomes remain unknown. Here, we mapped nearly one million rNMPs per genome across diverse human cell types, defining a nuclear "ribome" with non-random distribution patterns. rNMPs are enriched in C/G-rich sequences, epigenetically marked regions, and telomeres. Conserved ribonucleotide-enriched zones (REZs) overlap with CpG islands and R-loops. rNMP concentration near transcription start sites (TSSs) correlates positively with gene expression. Wild-type cells display a broader gene-expression range than ribonuclease H2A (RNH2A) knockouts, in which loss of rNMP cleavage causes pronounced retention of embedded rG and strand-biased rC near TSSs, both increasing with gene expression. These findings establish DNA-embedded rNMPs as a novel epigenetic mark that modulates human gene expression.

molecular biology↗

bioRxiv2025

Modeling Post-Gastrula Development via Bidirectional Pluripotent Stem Cells

The absence of stem cells capable of efficiently generating both trophoblast and epiblast lineages has hindered precise recapitulation of embryonic development. Through high-content chemical screening, we established an AL medium to generate mouse and human bidirectional pluripotent stem cells (BPSCs) characterized by concurrent OCT4/CDX2 expression. Mouse BPSCs demonstrated high plastic differentiation into trophoblast, epiblast and primitive endoderm lineages in vitro within 48 hours without exogenous induction factors and efficiently contributed to the embryo and extraembryonic tissues in vivo. Mechanistically, hyperactivation of the Wnt signaling pathway breaks the early lineage differentiation barrier by initiating a Lef1-dependent bypass. Remarkably, BPSCs can efficiently generated E8.5 embryoids that completed gastrulation and displayed advanced features such as brain development, a closed neural tube, a beating heart, somite formation, and primordial germ cells. These findings highlight BPSCs as a powerful tool for investigating early lineage specification and post-gastrulation embryonic development, with potential applications across multiple species.

developmental biology↗

bioRxiv2025

Macrophage Migration Inhibitory Factor Suppresses Natural Killer Cell Response and Promotes Hypoimmunogenic Stem Cell Engraftment Following Spinal Cord Injury

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor, could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders.

cell biology↗

bioRxiv2025

Evolution of Enhancers through Duplication

Duplication is appreciated as a key source of genomic novelty. In this study, we examined putative enhancers in the human genome to investigate how duplication influences the evolution of these enhancers. We strictly identified a set of 3,336 confident duplicate enhancer pairs and examined their genomic and evolutionary features. We found that, compared to non-duplicated enhancers, duplicated enhancers tend to be longer, more pleiotropic, closer to genes, and harbor greater numbers and more diverse groups of transcription factor binding motifs. These attributes were more pronounced for evolutionarily older duplicate enhancers. Therefore, the regulatory potentials of enhancers may facilitate evolutionary maintenance of duplicated enhancers. Utilizing chimpanzee and rhesus macaque as outgroups, we found that between 30-40% of the examined duplicate enhancers exhibit evidence of asymmetric sequence evolution. Notably, the majority of the "accelerating enhancers" in such pairs gained enhancer activities in novel tissues, particularly in immune-related tissues. Moreover, the accelerating enhancers tended to harbor transcription factor binding motifs previously implicated in human evolution, and enriched in associations with immune functions and stress responses. These findings indicate that duplication may contribute to the proliferation of highly pleiotropic enhancers, as well as gaining novel enhancer activities, and contribute to rapid evolution of the immune system.

evolutionary biology↗

bioRxiv2025

Gap-free genomes and transcriptomes uncover race-specific effectors in watermelon wilt pathogen Fusarium oxysporum f. sp. niveum

Watermelon (Citrullus lanatus L.) is one of the worlds most economically important fruit crops, yet it is susceptible to devastating diseases such as vascular wilt caused by Fusarium oxysporum f. sp. niveum (Fon), with limited effective control measures. Fon evolves rapidly in the field to overcome host resistance and global watermelon production is constantly threatened by new pathogenic races. High-quality genomic resources are key to understanding the molecular mechanisms underlying Fon virulence evolution for disease management. Here, we de novo assembled and annotated gapless genomes of three physiological races of Fon (race 1, 2, and 3), and dissected the mechanisms behind their distinctive virulence through comparative genomics and transcriptomics. Whole-genome alignments identified core and accessory chromosomes in Fon where each race carried a unique set of accessory chromosomes or regions. Comparative transcriptomics of Fon infection revealed distinctive temporal patterns of gene expression even among core gene families, particularly those related to cell wall degradation enzymes. Effectoromic prediction and comparative analysis in three gap-free genomes identified 13 race-specific effectors (RSEs) in FonR3, one (FonRSE1) of which was a critical virulence factor of FonR3 on watermelon as demonstrated via functional experiments. The gap-free genome assemblies and annotations, and the RSEs are valuable resources for studying Fon pathobiology and genome evolution, adding in the design of improved disease control strategies.

genomics↗

bioRxiv2025

Inherent Specificity and Mutational Sensitivity as Quantitative Metrics for RBP Binding

RNA-binding proteins (RBPs) regulate every aspect of post-transcriptional gene expression, yet our ability to compare how selectively different RBPs recognize their targets remains limited. Binding affinity, expressed as a dissociation constant, provides a universal quantity for comparing binding strength, but no equivalent metric exists for binding specificity. Here we introduce two quantitative metrics to fill this gap: inherent specificity, which measures how selectively an RBP distinguishes its strongest binding motif from all other sequences, and variation sensitivity, which measures tolerance to single nucleotide changes within that motif. Analyzing high-throughput sequencing data across 100 RBPs in vitro and 27 in cells, we find strong correspondence between in vitro and cellular measurements for sequence-driven RBPs. Domain swap CLIP experiments demonstrate that specificity can be transferred between protein contexts. Mathematical modeling and cellular competition experiments reveal that low-specificity RBPs can paradoxically sharpen the target discrimination of high-specificity partners by occupying non-preferred sites, an emergent property not predictable from affinity alone. These metrics and accompanying R packages provide a practical framework for comparing RBP binding behaviors and modeling how RBPs compete for RNA targets across the transcriptome.

molecular biology↗

bioRxiv2024

Cis-Regulatory Evolution of CCNB1IP1 Driving Gradual Increase of Cortical Size and Folding in primates

Neocortex expansion has a concerted relationship with folding, underlying evolution of human cognitive functions. However, molecular mechanisms underlying this significant evolutionary process remains unknown. Here, using tree shrew as an outgroup of primates, we identify a new regulator CCNB1IP1, which acquired its expression before the emergence of primates. Following the evolution of cis-regulatory elements, the CCNB1IP1 expression has steadily increased over the course of primate brain evolution, mirroring the gradual increase of neocortex. Mechanistically, we elucidated that CCNB1IP1 expression can cause an increase in neural progenitors through shortening G1 phase. Consistently, the CCNB1IP1 knock-in mouse model exhibited traits associated with enhanced learning and memory abilities. Together, our study reveals how changes in CCNB1IP1 expression may have contributed to the gradual evolution in primate brain.

evolutionary biology↗