Biology subjects

Yan, M.

Publications and source records attributed to Yan, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Early-life core microbiota are associated with postlarval survival of Penaeus vannamei: A meta-analysis

Larviculture is critical to the production of Penaeus vannamei, the world's leading farmed shrimp species, but remains constrained by erratic postlarval survival. Although early-life microbiome establishment is increasingly recognized as essential for larval health and survival, microbiome-based hatchery interventions are hindered by limited understanding of larval core microbiota. Here, we synthesized publicly available and self-generated 16S rRNA gene amplicon datasets of larval and rearing-water microbiota from 13 studies encompassing seven major producing regions worldwide to characterize shrimp larval core microbiota, their assembly processes, and their associations with larval survival. Although larval prokaryotic communities exhibited stronger geographic variation than developmental-stage succession, a conserved set of dominant bacterial families, including Roseobacteraceae, Vibrionaceae, Flavobacteriaceae, Moraxellaceae, and Pseudoalteromonadaceae, consistently prevailed across developmental stages and regions. By integrating occupancy, persistence, and ecological network centrality analyses, we demonstrated that common, temporal, and ecological core microbiota differ substantially in composition, diversity, stage specificity, and ecological roles in network stability. Compared with non-core taxa, core taxa were generally assembled more deterministically, irrespective of core category, suggesting stronger host selection and/or more rapid dispersal during microbiome establishment. Core microbiota also generally showed stronger associations with postlarval survival than total communities or non-core taxa, although contrasting survival associations among core members indicated that core microbiota are not ecologically homogeneous. Our work provides the first systematic categorization and characterization of larval core microbiota throughout the shrimp larviculture cycle, offering new insights into the ecological significance of core microbiota and identifying potential universal targets for microbiome-based intervention in shrimp larviculture.

microbiology↗

bioRxiv2026

Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control

Local tumor therapies rarely induce systemic immunity capable of controlling metastatic disease. Here, we engineer an mRNA lipid nanoparticle (LNP) platform to coordinate innate immune sensing and T cell activation in situ through co-delivery of an autoactivated cyclic GMP-AMP synthase mutant (cGASR241E) and membrane-tethered IL-12 (IL-12TM). cGASR241E mRNA LNPs autonomously generated cyclic GMP-AMP in vivo, activating host STING signaling and initiating antitumor responses. Co-administration with IL-12TM mRNA LNPs promoted localized cytokine production, reduced regulatory T cells, and restored effector function in tumor-infiltrating T cells. This combination elicited systemic antitumor immunity and suppressed distal tumors across multiple mouse models. The therapeutic efficacy required CD8+ T cells and IFNg; signaling in host, supporting a model in which innate DNA sensing is coupled to IL-12-mediated T cell functional reinforcement. In addition, the combination enhanced responsiveness to PD-L1 blockade. Together, these findings establish a clinically translatable strategy to integrate cGAS-STING activation with cytokine-driven T cell programming to drive systemic tumor control.

cancer biology↗

bioRxiv2026

A pan-genomic and methylomic analysis reveals a distinct signature in Vibrio alginolyticus isolated from wild fish

Vibrio alginolyticus is a ubiquitous opportunistic pathogen in estuarine and marine ecosystems and a leading cause of vibriosis in humans and aquatic animals. Yet genomic and epigenomic landscapes of V. alginolyticus from wild fish remain poorly defined. Here, we present a pan-genomic and methylomic framework based on 89 high-quality V. alginolyticus genomes, including 46 newly sequenced isolates recovered from 105 wild marine fish representing 17 species in Hong Kong waters of the South China Sea, plus all publicly available complete genomes. We reported a 32.38% prevalence of V. alginolyticus in wild fish. Phylogenomic analysis resolved four distinct clades, with Clade IV dominated by wild-fish isolates and characterized by low virulence and low antimicrobial resistance. Pan-genomic analysis revealed a closed pan-genome with a substantially depleted accessory genome in Clade IV. We identified a total of 763 antimicrobial resistance (AMR) genes from 89 strains, which covered 32 gene types and spanned four resistance mechanisms, with efflux pumps as the most prevalent strategy. Critically, resistance genes were almost exclusively chromosomal rather than plasmid-borne. Virulence profiling confirmed the presence of tlh and T6SS genes but the absence of the high-risk human pathogenic factors tdh and ctxB. Methylomic analysis using nanopore sequencing uncovered 355 DNA methyltransferases and 140 strain-specific methylation motifs with dominance by 6mA. Notably, 71.90% of methyltransferases resided in the accessory genome and were disseminated by mobile genetic elements, especially plasmids. Motif combinations were highly strain-specific and largely decoupled from phylogeny, except for a shared motif signature defining Clade IV. The GATC motif was essential across all V. alginolyticus strains and showed significant enrichment in virulence gene regions but not in AMR gene loci, revealing differentiated epigenetic modification characteristics. This study nearly doubled the number of high-quality complete genomes available for V. alginolyticus and provides the first comprehensive methylomic characterization for this species. Our findings reveal a phylogenetically distinct, low-virulence, low-resistance V. alginolyticus clade widely shared among wild fish, with important implications for One Health surveillance and evolutionary adaptation of marine pathogens.

genomics↗

bioRxiv2026

Ileal Gpbar1 gates depressive phenotypes via gut to brain "vagal-NTS-PVN"GABAergic axis

Depression represents a typical mental condition, yet whether intestinal metabolic signals drive central neural circuits remains unclear. Here we identify ileal enteric neuronal Gpbar1 as a previously unrecognized peripheral node that coordinates gut-to-brain communication to prevent depression-like behavior through a vagus-dependent, nucleus tractus solitaries (NTS)-paraventricular nucleus (PVN) signaling axis. The enteric plexus Gpbar1 is predominantly expressed on a subpopulation of GAD1-positive GABAergic neurons. Chronic restraint stress suppresses Gpbar1 expression, triggers glycolytic reprogramming and mitochondrial distress in both ileum and hypothalamus. Oral Gpbar1 agonism with INT-777 reverses hypothalamic HK2/TOM20 alterations and behavioral abnormalities by enhanced ileal mTOR/HIF-1 alpah signaling and glycolysis-related metabolite shifts, an effect specifically abolished by subdiaphragmatic vagotomy or chemogenetic silencing of PVN GABAergic neurons. Our findings establish ileal Gpbar1 as a gut-derived metabolic sensor that engages a defined vagal-brainstem-hypothalamic inhibitory circuit to regulate depressive phenotypes, shifting the roadmap from brain-centered to gut-initiated antidepressant mechanisms and unveiling a compelling peripheral therapeutic strategy that bypasses intractable central brain-directed intervention.

neuroscience↗

bioRxiv2026

Testing a Mates Brain: Courtship signals may reveal signaler decision-making capacity

IIt has been suggested that courtship signals reflect a potential mate's learning ability or nervous system competence. However, there is no rigorous theory that explains how features of sexual signals represent a nervous system's "quality". Such a theory may provide a mechanism for mate assessment via sexual signals and offer an explanation for why courtship signals are rhythmic and stereotypic. In our paper, first we use a general model of optimal neural decision-making to show that variance in an organism's solution time for a given fitness problem lowers the fitness gain rate; more specifically, in well-supported "competing accumulator" models of decision making, we show that noise in the slope of spike rate increase in evidence accumulators increases both reaction time and the probability of a sub-optimal decision. In conclusion, higher timing regularity leads to quicker and better decisions. This finding accords with extensive human study data showing that variance in reaction times is negatively associated with various measures of motor and cognitive performance. Thus, selection should favor individuals that require potential mates to advertise courtship signal regularity to indicate their nervous system's general timing consistency (the timing-consistency signaling theory). The focus on signal consistency (rather than on signal duration or power) may account for why courtship signals are typically rhythmic, are often multi-modal, and why rhythmic signals are also employed in territorial contests. One of the model's several predictions is that individuals should favor potential mates with lower noise in courtship signal features such as inter-pulse intervals.

animal behavior and cognition↗

bioRxiv2026

Comparative genomics reveals shared accessory regions between members of two Fusarium species complexes virulent on garden pea

The contribution of accessory or conditionally dispensable chromosomes to host-specific virulence was first demonstrated in members of the Fusarium solani species complex (FSSC) that are pathogens of garden pea, Pisum sativum L. The phenomenon has since been shown to exist in many fungal plant pathogens, including the closely related F. oxysporum species complex (FOSC). Genome analysis of members of the FSSC and FOSC pathogenic on pea revealed a diverse size range of the accessory genome of these fungi. Despite the [~]65 million years of diverging time, regions on a chromosome known to carry host-specific virulence factors for pea, including the cytochrome P450 pisatin demethylase (PDA) and other pea pathogenicity (PEP) genes, were present in all genomes of these pea pathogens. Genes directly involved in virulence on pea - PEP2, PDA, and PEP5- were the most frequently clustered together. Transcriptome analysis of fungal mycelia treated with the pea phytoalexin pisatin, identified 1,155 differentially expressed genes where many were involved in cellular stress responses. As wilt pathogens that invade host xylem, members of the FOSC encode more putative effectors, when compared to those in the FSSC, and several FOSC effectors were identified to confer race specificity. The conservation of part of the accessory genomes across two evolutionarily diverged species complexes suggests a common origin. Horizontal transfer of accessory chromosomes containing genetic loci involved in pathogenesis for garden pea offers a parsimonious explanation of the polyphyletic origin of host specificity.

genomics↗

bioRxiv2026

Piezo1 transduces mechanical signals to inhibit osteoclast fusion and coordinate bone homeostasis

Osteoclasts originate from bone marrow-derived macrophages, and their maturation relies on fusion of pre-osteoclasts into mature osteoclasts that maintain bone homeostasis. Previous studies established that mechanical signals regulate osteoblast activity in bone homeostasis, although whether such signals regulate bone homeostasis by acting on osteoclasts remains unclear. Herein, membrane tension decreased during pre-osteoclast fusion, accompanied by reduced Piezo1. This suggests that mechanical stimulation inhibits fusion of monocytes into osteoclasts through Piezo1. Piezo1-knockout monocytes (CTSKCre; Piezo1fl/fl) attenuated the anabolic effect of exercise on bone mass in vivo, whereas shear stress inhibited osteoclast fusion in vitro. Piezo1 activation elevated E-cadherin, which anchors Merlin. This led to hyperactivation of the Yes-associated protein (YAP) signaling pathway, subsequently activating TAX1BP1 and suppressing NF-{kappa}B signaling as well as osteoclast differentiation and maturation. Thus, physical exercise activates a Piezo1-E-cadherin-Merlin-YAP axis that prevents osteoclast fusion, presenting a druggable mechanotransduction pathway for osteoporosis.

cell biology↗

bioRxiv2026

Organelle partitioning in the multi-budding yeast Aureobasidium pullulans

Cellular organelle content is fairly constant within a given cell type. This is accomplished in part by ensuring equitable organelle partitioning during division. Much of our understanding of organelle inheritance has come from investigating cells that divide in half producing two daughter cells. However, more elaborate division strategies that give rise to multiple daughters are not uncommon in nature. Here, we present the first characterization of organelle inheritance in a fungus that grows by multi-budding, producing several (2-20) daughter cells in a single cell cycle. We find that some organelles (mitochondria and ER) are evenly delivered to all growing buds, while others (vacuole and peroxisomes) are more variably inherited. We discuss the implications of even and uneven inheritance for this polyextremotolerant fungus capable of growing in dynamic, and diverse, environments.

cell biology↗

bioRxiv2026

Metagenomic strain-resolved DNA modification patterns link extrachromosomal genetic elements to host strains

DNA modification is central to microbial defense against extrachromosomal genetic elements (ECEs), consequently ECEs tend to adopt their hosts modification patterns. Shared ECE-host modification patterns enable linking ECEs to their hosts, but modification detection tools are designed for single genomes and are ineffective at metagenome scale. Here, we present MODIFI, software for detecting DNA modifications in metagenomes. MODIFI assumes that each k-mer in a metagenome is mostly unmodified and calculates background signal levels for that k-mer from PacBio HiFi reads, eliminating the need for matched control experiments. MODIFI ECE-host linkages were validated using >1,000 isolate and mock microbiome datasets. Illustrating the approach, we identified 315 strain-resolved, non-redundant ECE-host linkages in environmental and human metagenomes. In infant gut microbiomes, a chromosomal inversion in Enterococcus faecalis alters host and associated plasmid methylation motifs simultaneously. Overall, MODIFI solves a major bottleneck in DNA modification analysis and provides a foundational tool for understanding microbial epigenomics.

microbiology↗

bioRxiv2025

Revealing the pervasive landscape of MGE-host interactions in situ with single-cell genomics

Mobile genetic elements (MGEs), including plasmids and viruses, drive microbial evolution and ecosystem dynamics, yet their distribution, host range, and functions remain poorly understood, especially among uncultivated lineages. Using [~]60,000 single-cell amplified genomes (SAGs) from host-associated and environmental microbiomes, we identified MGEs internal to or attached to individual cells, directly linking them to their hosts. Between 25% and 75% of cells contained at least one MGE, with gut-derived SAGs showing the highest MGE load. While most MGEs exhibited narrow, species-specific host ranges, a subset spanned multiple species and higher taxonomic ranks. We detected MGE clusters and complete, nearly identical genomes repeatedly associated with hosts across phyla, suggesting both genuinely broad host ranges and recurrent DNA entry events. We also identified microbial species acting as major donors or recipients in antibiotic resistance gene (ARG) exchange, and MGEs, including unclassified types that mediate extensive horizontal transfer of auxiliary functions. Together, these findings illuminate MGE-host associations and underscore that the genetic content of microbial cells is fundamentally linked to their MGEs in nature.

microbiology↗

bioRxiv2025

Primate-specific adaptation of Ku protects transcriptomic integrity by suppressing Alu-mediated alternative splicing

Accurate pre-mRNA splicing is essential for the transfer of genetic information but faces unique challenge in higher primates due to the massive expansion of intronic Alu elements1-3. While studying Ku, the Ku70/Ku80 heterodimer best known for initiating non-homologous end-joining (NHEJ) by encircling DNA ends4, we discovered that Ku expression increased markedly during primate evolution in parallel with Alu expansion5. Ku binds double-stranded RNA (dsRNA) stem-loops, including those at the antisense Alu (asAlu) elements within introns5. Here, we show that Ku-depletion in human cells has a broad impact on splicing largely independent of cell-cycle states, NHEJ, or innate immune signaling, significantly affecting ~8-10% of quantifiable alternative splicing events. Mechanistically, Ku directly binds exonic asAlu to prevent their aberrant inclusion and binds asAlu within inverted-repeat Alu (irAlu) pairs flanking canonical exons to prevent exon skipping6. Among human tissues, Ku expression in the brain is consistently ~50% lower, correlating with more permissive expression of Alu-derived splice variants, particularly those encoding mitochondrial proteins and RNA-binding factors. Correspondingly, heterozygous Ku loss in patient causes developmental delay, neurological dysfunction, and acidosis. Together our findings identified Ku as a critical suppressor of Alu-associated alternative splicing co-opted during evolution with implications for primate brain function and human disease.

molecular biology↗

bioRxiv2025

Structural basis of the π-stacking network governing cofactor-substrate cooperativity of SbSOMT

SAM-dependent methyltransferases are ubiquitous enzyme catalyzing methylation of substrate by consuming S-adenosyl methionine (SAM) cofactor. In this study, we discovered the positive cofactor-substrate cooperativity of SbSOMT and uncovered the underlying mechanism at structural basis. The binding kinetics analyses show that SbSOMT exhibits bilateral positive cooperativity except the unproductive pairing between SAM and product due to the steric hindrance of an additional methyl group. Unprecedentedly, two cofactor-analogous inhibitors, S-adenosyl homocysteine (SAH) and sinefungin demonstrated opposite effects on substrate binding kinetics while attaining positive cooperativity. SAM-resembling sinefungin demonstrated higher foldchange in the acceleration of substrate association rate constant than deceleration of dissociation rate constant. Integrating SbSOMT structural insights at multiple states, we identified the dynamical W279-driven {pi}-stacking network governs the cofactor-substrate cooperativity. SbSOMT exhibits closed conformation at first-ligand bound states, where the C-terminal W279 serves as the central plane for {pi}-{pi} interaction between N-terminal H196, catalytic H282, and/or substrate. We propose that the binding of first ligand overcome the energy barrier represented by W279 {pi}-stacking network, leading to the conformational landscapes in favor to second binding event. Our study highlights the intrinsic design of SbSOMT in pertaining enzyme competency and serves as a foundation to expand the knowledge and applications of cofactor-substrate cooperativity of the structurally diverse methyltransferases.

biophysics↗

bioRxiv2025

Allocation of resources among multiple daughter cells

Cell division commonly produces two daughter cells, but there are many exceptions where large cells produce multiple daughters. Multiple fission of some green algae and bacteria, cellularization during embryogenesis of plants and insects, and growth of Ichthyosporeans, Chytrids, and Apicomplexans all provide variations on this theme. In some yeast species, a large multi-nucleate mother cell grows multiple buds (daughters) simultaneously. Here we address how mothers partition growth equally among their buds in the multi-budding yeast Aureobasidium pullulans. Bud growth is directed by actin cable networks that appear to be optimized for even partitioning despite complex cell geometries. Even partitioning does not rely on compensatory mechanisms to adjust bud volumes, but rather stems directly from effective equalization of polarity sites. These results reveal how conserved cell polarity and cytoskeletal networks are adapted to build complex morphologies in fungi.

cell biology↗

bioRxiv2025

New Insights into Microbial Nitrogen Utilization in the Rumen Enabled by Genome-Resolved Multi-Omics

Optimizing nitrogen (N) utilization in ruminant production systems holds both economic and environmental significance. However, traditional paradigms of N metabolism, derived primarily from well-studied model rumen bacteria, cannot fully capture the diverse and complex N metabolic dynamics within the rumen ecosystem. To address this gap, we utilized comparative genomics and genome-resolved multi-omics analyses using a curated set of microbial genomes to investigate N assimilation and regulation in rumen microbes. We discovered that canonical mechanism of ammonia assimilation and regulation, such as the glutamine synthetase (GS)/glutamate synthase (GOGAT) pathways and its regulatory proteins, are absent in the genomes of many key and predominant rumen microbes, which likely utilize alternative pathways for ammonia assimilation. These findings challenge the applicability of E. coli-based N regulation models to rumen bacteria. We further linked polysaccharide utilization and ammonia assimilation across hundreds of rumen microbial species. Furthermore, we identified specific microbial species involved in ureolysis and denitrification, as well as phages carrying auxiliary metabolic genes that perform N assimilation. Using an animal trial involving 11 pairs of lamb twins in a crossover design, we demonstrated that dietary crude protein (CP) concentrations had minimal impact on rumen microbiome composition and expression of N assimilation genes. Instead, shifts in concentrate levels triggered alterations in N assimilation, including increased expression of amino acid biosynthesis pathways. These findings indicate a nuanced, species-specific microbial response to dietary interventions, highlighting the limitations of traditional N metabolism models applied to rumen microbes and the need for more granular studies of rumen microbial ecosystems.

microbiology↗

bioRxiv2025

Improved Prediction of Bacterial Type VI Secretion Effector Proteins Using an Integrated Convolutional Neural Network Model Combining N-terminal Signal Sequences, Evolutionary Information and Pre-Trained Protein Language Features

Type VI secretion system effectors (T6SEs) are crucial for bacterial pathogenicity, making their accurate identification essential for understanding bacterial virulence mechanisms. This study analyzed the differences in amino acid composition of N-terminal signal sequences between T6SEs and non-T6SEs, uncovering distinct positional amino acid preferences in T6SEs. Using a combination of unsupervised and supervised analysis, we evaluated feature encoding methods and developed T6CNN, an ensemble model that integrates N-terminal signal sequences, evolutionary information, and pre-trained protein language features for T6SE prediction. T6CNN demonstrated outstanding performance in independent testing, outperforming existing tools with a 7.9% accuracy increase (to 0.953), a 13.2% sensitivity improvement (to 0.964), and a 6.6% specificity enhancement (to 0.951). The T6CNN model offers a reliable and accurate solution for T6SE prediction, with significant potential to advance research on bacterial pathogenicity. ImportanceThis study introduces T6CNN, a new computational model for identifying Type VI secretion system effectors used by harmful bacteria. By analyzing early protein sequences, T6CNN uncovers unique features that reliably distinguish effector proteins. Integrating evolutionary data and pre-trained protein language features, the model outperforms existing methods in accuracy, sensitivity, and specificity. This enhanced prediction tool deepens our understanding of bacterial infection mechanisms and offers researchers a valuable resource for pinpointing key virulence factors. Ultimately, T6CNN may help drive the development of more targeted antibacterial treatments and strategies to combat bacterial diseases.

bioinformatics↗

bioRxiv2025

The hollow truth: ethylene-triggered ROS, PCD, senescence, and autophagy drive hollow stem formation

Hollow stems have independently evolved multiple times across the plant kingdom, and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach (Ipomoea aquatica) is one of the few hollow-stemmed plants in the Convolvulaceae family, and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we identified programmed cell death (PCD) is involved in cavity formation of water spinach shoot tips. Single-cell transcriptome analysis further revealed that ethylene and reactive oxygen species (ROS) drive and regulate this process by activating transcription factors IaNAC074, IaNAC087, IaNAC029, IaNTL9, and IaTGA9, which initiate PCD, senescence, and autophagy, collectively controlling cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach and transient expression in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in bamboo, highlighting the conservation of PCD regulatory mechanisms in plant development. This work not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens new avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.

plant biology↗

bioRxiv2025

How Does Sampling Affect the AI Prediction Accuracy of Peptides' Physicochemical Properties?

Accurate AI prediction of peptide physicochemical properties is essential for advancing peptide-based biomedicine, biotechnology, and bioengineering. However, the performance of predictive AI models is significantly affected by the representativeness of the training data, which depends on the sample size and sampling methods employed. This study addresses the challenge of determining the optimal sample size and sampling methods to enhance the predictive accuracy and generalization capacity of AI models for estimating the aggregation propensity, hydrophilicity, and isoelectric point of tetrapeptides. Four sampling methods were evaluated: Latin Hypercube Sampling (LHS), Uniform Design Sampling (UDS), Simple Random Sampling (SRS), and Probability-Proportional-to-Size Sampling (PPS), across sample sizes ranging from 100 to 20,000. A sample size of approximately 12,000 (7.5% of the total tetrapeptide dataset) marks a key threshold for stable and consistent model performance. This study provides valuable insights into the interplay between sample size, sampling strategies, and model performance, offering a foundational framework for optimizing data collection and AI model training for the prediction of peptides physicochemical properties, especially for prediction in the complete sequence space of longer peptides with more than four amino acids.

bioinformatics↗

bioRxiv2025

Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While, the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/632747v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1188eborg.highwire.dtl.DTLVardef@1340070org.highwire.dtl.DTLVardef@108d560org.highwire.dtl.DTLVardef@f0adda_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗