Biology subjects

Xiao, L.

Publications and source records attributed to Xiao, L..

At least 19 recordsLinked to original sources

bioRxiv2026

A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control across syngeneic models, including tumors resistant to PD-1 blockade, and enhanced checkpoint therapy without overt toxicity. Treatment rapidly depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, and blocked tumor explant-induced expansion and suppressive activity of mouse and human PMN-MDSCs. mSWI/SNF antagonism collapsed chromatin accessibility and PU.1/C/EBP{beta} occupancy at regulatory elements that sustain PMN-MDSC identity. Thus, suppressive neutrophils harbor a druggable chromatin vulnerability that can be exploited to restore cancer immunity.

cancer biology↗

bioRxiv2026

A haplotype-based breeding framework for the precise pyramiding of elite QTL alleles: a lettuce case study

The efficient pyramiding of favorable alleles underlying complex traits remains a major challenge in crop breeding as most quantitative trait loci (QTLs) have not been resolved to causal genes, limiting their direct application in marker-assisted breeding. Although haplotypes provide more informative genetic units than individual markers, existing haplotype-based studies have largely focused on genetic interpretation and elite haplotype discovery, whereas computational frameworks for translating haplotypes into breeding decisions remain limited. Here, we developed HAPBDB, a haplotype-guided breeding framework that directly translates regional haplotypes into parental selection, cross design, and elite QTL pyramiding, and applied it to a lettuce genomic breeding panel. HAPBDB accurately reconstructed functional haplotypes at known loci and resolved elite haplotypes for five major QTLs controlling flowering time and yield. Integrating haplotype information across loci enabled systematic identification of accessions carrying complementary elite haplotypes and rational design of crosses that maximized favorable haplotype accumulation while minimizing segregating loci. Experimental validation using QTL-specific molecular markers demonstrated concordance between predicted and observed multi-locus genotypes across all designed F hybrids. Our results demonstrated that regional haplotypes can serve as practical breeding units even when the underlying causal genes remain unknown, thereby enabling the direct utilization of genetically mapped QTLs for precision breeding. By bridging the gap between genomic discovery and practical breeding, HAPBDB provides a practical framework for converting genomic information into breeding decisions and accelerating precision improvement of complex traits.

bioinformatics↗

bioRxiv2026

Adipose GPD2 Couples Glycolytic Signals to Epigenetic Control of Metabolic Homeostasis

The glycerol-3-phosphate shuttle (G3PS) is a classic reducing equivalent transferring system, yet its role in adipose metabolism remains poorly understood. Here, we identify mitochondrial glycerol-3-phosphate dehydrogenase (GPD2), the core enzyme of G3PS, as a critical orchestrator of adipose thermogenesis and systemic metabolic homeostasis. Adipocyte-specific GPD2 knockout mice exhibited impaired thermogenic capacity and energy expenditure, rendering them susceptible to obesity and metabolic dysfunction. Mechanistically, GPD2 deficiency elevated cytosolic NADH, which suppressed glycolysis and decreased the levels of key metabolites, such as acetyl-CoA, thereby diminishing H3K27ac at thermogenic gene loci and silencing these genes. NADH depletion with an NADH oxidase rescued both glycolysis and thermogenic gene expression. In support of this mechanism, we defined a previously undescribed enhancer of Ucp1 whose H3K27ac was tightly controlled by GPD2. Remarkably, replenishing the acetyl-CoA pool or directly restoring H3K27ac at the Ucp1 enhancer reversed UCP1 expression in GPD2-deficient adipocytes. Importantly, we find that human adipose GPD2 expression is inversely correlated with BMI, WHR, and HOMA-IR, underscoring its clinical relevance. Collectively, our findings establish GPD2 as an essential node in the metabolic-epigenetic axis that governs thermogenic activation and energy balance.

biochemistry↗

bioRxiv2026

Striatal Dopamine at Learned Sequence Boundaries Sustains Birdsong

Phasic striatal dopamine has been implicated in the initiation of well-trained action sequences in reward-guided tasks. Whether such signals also support natural skills learned without explicit cues or immediate rewards remains unknown. Using birdsong as a model of a naturally learned, skilled vocal behavior, we found that dopamine transients accompany the initiation of song sequences. These transients emerged during learning, shifting from later phases of the sequence toward sequence onset as song matured. Temporally targeted optogenetic inhibition of dopamine signaling at sequence onsets disrupted the maintenance of learned song, resulting in the gradual and severe deterioration of adult song. Thus, phasic dopamine signaling at sequence initiation develops during learning of a natural skilled behavior and is required for its long-term maintenance. One Sentence SummaryDopamine transients at song motif onset are required to maintain accurate adult zebra finch song, a naturally learned skilled behavior.

neuroscience↗

bioRxiv2026

WattmaMod enables high-resolution and extensible RNA modification profiling for nanopore direct RNA sequencing

Nanopore direct RNA sequencing enables direct profiling of RNA modifications on native transcripts, but accurate multi-modification detection remains limited by non-stationary signals and heterogeneity across chemistries. Here, we develop WattmaMod, a deep learning framework for multi-modification detection from nanopore direct RNA sequencing data. It combines self-supervised pretraining, supervised contrastive fine-tuning, and low-label incremental adaptation to improve representation learning and support efficient extension to low-resource modification types. The framework further incorporates wavelet-guided multi-scale encoding and dynamic cross-attention fusion to model raw signals and event-level features. Results show that WattmaMod achieves robust detection of multiple RNA modifications, including m6A, m5C, m1A, A-to-I, m7G, hm5C, m1{Psi}, f5C, ac4C, m5U and {Psi}. It also extends efficiently to low-resource modification types with minimal labeled data, generalizes across sequencing chemistries and species, and predicts potential higher-order local organization among distinct RNA modifications. WattmaMod thus provides a scalable framework for high-resolution epitranscriptome profiling and expands RNA modification analysis beyond single-site prediction to coordinated multi-modification characterization.

bioinformatics↗

bioRxiv2026

Comprehensive Complete-Genome Analysis of Lactobacillaceae and Bifidobacteriaceae Reveals Strain-Specific Metabolic Interactions in Chinese Gut Microbiota

Bifidobacteriaceae and Lactobacillaceae are key probiotic families and widely used in food production, yet a comprehensive understanding of strain functions and their gut microbial interactions based on complete genomes remain understudied. Here we constructed a complete-genome dataset of 3,300 strains from these two families, including 1,151 newly isolated from China. Compared with draft assemblies, complete genomes substantially recovered a gene functional landscape encompassing stress tolerance, surface exopolysaccharide synthesis, nutrient utilization, and mobile genetic elements. Major species from both families exhibited a prevalence >60% in the Chinese population, far higher than that in US/Dutch cohorts. Notably, as a core probiotic species with remarkable genomic plasticity and gut-adaptive potential, Lactiplantibacillus plantarum stood out in our dataset for its enriched functional profile and was particularly abundant in the Chinese population. Moreover, compared with non-Chinese genomes, our isolates of key species displayed less metabolic complementarity and stronger competition with potentially pathogenic keystone species in the gut, thereby linking strain origin to enhanced probiotic potential and ecological fitness to benefit human gut health.

microbiology↗

bioRxiv2026

Neuromodulation of Foxp2+ hypothalamic neurons induces therapeutic hypothermia

The inability to selectively trigger therapeutic hypothermia independent of environmental cooling has hindered causal analysis of its broader physiological benefits. Here, we employed P57, a natural product that pharmacologically induces therapeutic hypothermia circumventing external cold stress, to identify the neuronal substrates underlying hypothermia-induced antitumor effects. Integrating functional ultrasound imaging, activity-dependent neuronal labeling, and single-nucleus RNA sequencing, we identify a previously unrecognized population of Foxp2 neurons in the medial preoptic area (MPA) that are selectively activated by P57. Inhibition of MPA Foxp2+ neurons abolishes P57-induced hypothermia, whereas the paraventricular hypothalamus (PVH) serves as a critical downstream node. Importantly, targeted activation of MPA Foxp2 neurons is sufficient to induce sustained hypothermia, suppress systemic metabolism, and inhibit tumor growth, providing causal evidence that neuronally driven reductions in core body temperature can exert antitumor effects. Together, these findings establish MPA Foxp2 neurons as a controllable node for therapeutic hypothermia induction and demonstrate that neuromodulation of defined neuronal populations can achieve therapeutic benefit by directly controlling physiological states.

neuroscience↗

bioRxiv2026

Cardiac oxidative stress monitoring enabled by hierarchical mechanical adaptation

Soft bioelectronics have advanced cardiac monitoring through electrophysiological tracking, yet this alone cannot resolve the metabolic pathology essential to surgical decision-making. However, real-time molecular sensing on beating hearts remains unresolved due to deformation-induced sensor failure and stress-induced metabolite artifacts. This challenge is exemplified by ischemia-reperfusion injury (IRI), a major cardiac surgery complication characterized by reactive oxidative species (ROS) bursts, where true pathological ROS signals being confounded by mechanotransduction-induced ROS artifacts. Herein, we propose an enzymatic cardiac oxidative stress biosensor (E-cardiac) with hierarchical mechanical adaptation: macro-scale biofluid-mediated contact, micro-scale fiber reorganization, and nano-scale enzymatic confinement within gold nanoarches dissipate interfacial stress. This produces ultrathin ([~]460 nm), soft (0.79 kPa) E-cardiac with robust electrochemical stability (100% strain), low detection limit (380 nM), rapid adhesion (<3 s), stable biosensing on beating heart, as well as minimal invasive deployment capability. Mechanical analysis and cellular studies confirm mitigated stress-induced ROS and absent PIEZO channel activation. Validated across cardiomyocytes, ex vivo tissues, multi-species ischemia models (mouse, rat, rabbit, pig), rat ischemia-reperfusion injury, and Langendorff hearts simulating graded perfusion deficits, E-cardiac quantitatively differentiates IRI severity (sham < ischemia < reperfusion) as well as detecting the "ECG blind window". The E-cardiac platform provides real-time metabolic feedback for surgical guidance during cardiac procedures, enabling timely intervention before irreversible damage.

bioengineering↗

bioRxiv2026

Complete genome-derived metabolic interactions reveal impact of gut ecology on human health

Metabolic interactions govern gut microbiome assembly, yet functional rules remain obscured by genomic incompleteness and fragmentation. Here, we leverage 1,150 complete genomes to construct genome-scale metabolic models, demonstrating that draft genomes introduce systemic artifacts missing critical transport functions. We observe that metabolic interactions are intrinsically driven by genomic traits and niche specialization rather than random association. We stratifies strains into four ecological groups, including active players, resource predators, utilizers, and contributors, each of which exhibits distinct metabolite exchange/competition signatures. This functional architecture is strongly coupled to secondary metabolism. Applying this framework to inflammatory bowel disease revealed distinct temporal dynamics of ecological groups across disease subtypes, where group-specific dysbiosis predicted clinical phenotypes better than whole community profiles. Furthermore, integrating metabolic and co-occurrence networks to identify keystone for classifiers as features significantly improved disease diagnosis. Our study provides novel insights into gut metabolic interaction landscape, bridging the gap between genomic potential and clinical utility for precision microbiome therapeutics.

microbiology↗

bioRxiv2026

Complete Genomes of Cultivated Gut Bacteria Reveal Mobile Genetic Element-Driven Functional Diversity with Therapeutic Implications

Cultivated bacterial isolates are essential for elucidating gut microbiota functions, yet reliance on fragmented draft genomes and limited mobile genetic element (MGE) annotation has constrained high-resolution analyses. Here, we present the Cultivated Complete Genome Reference (CCGR), a comprehensive compendium of 1,150 fully circularized human gut bacterial genomes. Overcoming draft limitations, CCGR achieves chromosome-scale resolution and reveals distinct evolutionary strategies shaping gene topological organization in response to bacterial growth. Furthermore, we decode the dynamic landscape of MGEs, demonstrating that broad-host-range phages follow strict positional patterns by integrating at conserved chromosomal hotspots flanked by nutrient transporter loci. Importantly, we provide mechanistic in vivo evidence that accessory genomic elements drive strain-level functional heterogeneity. Specifically, the plasmid-encoded scrK gene in Levilactobacillus brevis involved in fructose catabolism is required to mitigate fructose-diet-exacerbated colitis. Collectively, CCGR establishes a framework linking chromosomal architecture and MGEs to bacterial evolution and host health, enabling precise, strain-resolved functional investigations.

microbiology↗

bioRxiv2026

Single-cell transcriptomic atlas of mouse oocyte development from growth to ovulation

Oocyte growth and maturation depend on tightly coordinated programs within oocytes and their surrounding granulosa cells, yet defining the transcriptional continuum of growing oocytes has been challenging due to their large size and the limitations of current droplet-based and spatial transcriptomic platforms. Here, we optimized a high-density array-based platform called Stereo-cell for high-throughput dual-modality profiling of large mouse oocytes, allowing for both the preservation of morphology and transcript capture. By integrating unsupervised transcriptomic clustering with cell morphological features, we delineated successive temporal windows from growing oocytes to metaphase II and uncovered stage-linked shifts from early programs toward later programs. We also profiled the ovarian somatic fraction, reconstructed granulosa-cell subtype relationships, and placed ovarian cell states in tissue context using single-cell-resolution spatial data.

developmental biology↗

bioRxiv2026

A tunnel microtract organ for T cell progenitor homing is formed by neural crest morphogenesis via Sox10-Cdc42 axis

Thymic colonization by T cell progenitors (TCPs) is essential for adaptive immunity, yet the guiding tissues remain elusive. Here, we unveiled a tunnel microtract (TMT) as an organ indispensable in TCPs homing in both zebrafish and mouse. Disruption of TMT leads to compromised T cell development. Specifically, the zebrafish TMT were positioned bilaterally beneath the fifth branchial levator muscle, connecting the thymus and kidney. They are semi-coiled, non-vascular, non-lymphatic tubes of epithelial signatures. Impressively, Sox10 activates Cdc42 to promote F-actin remodeling in neural crest cells (NCCs), leading to precise elongation and tight packaging of a low-permeability TMT. Remarkably, a homologous CD34 TMT was observed in mice, which bilaterally enveloped the embryonic thymus and extended into the thyroid cartilage. Sox10-Cdc42 signalling functioned recapitulatively in NCC morphogenesis during its construction. These findings establish TMT as an unappreciated NCC-derived organ in TCPs homing, with implications in T cell development and immune disorders.

developmental biology↗

bioRxiv2026

Divergent condensates tune transcriptional responses during stress

Dynamic reorganization of the transcription machinery within nuclear membrane-less compartments is an emergent feature of mammalian stress response, associated with critical cellular decisions. However, mechanisms governing the subcellular formation of these stress-induced condensates and their role in transcription regulation remain poorly understood. Here, we find that heat shock factor 1 (HSF1), transcriptional mediator of protein and cellular homeostasis, forms condensates during various adverse conditions, but these assemblies exhibit context-dependent divergent transcriptional outcomes. During heat shock, HSF1 orchestrates the coordinated assembly of transcription hubs via canonical activation, including post-translational modifications (PTMs), trimerization, and DNA binding. While HSF1s disordered regions restrict condensate formation in unstressed situations, they promote stress-induced condensate maturation to transcriptionally active states. Strikingly, HSF1 condensates that form during other environmental and chemotherapeutic stresses stall at distinct stages of hub formation, assemble independent of PTMs, and exhibit reduced sub-condensate dynamics. These aspects culminate in attenuated genomic occupancy and transcriptional output at HSF1-associated loci, consistent with functional impairment of HSF1 and the transcription machinery via sequestration. Our work suggests that stress-induced transcription factor condensates drive conserved responses during physiological perturbations, but can be inactivated during pathological insults, rationalizing HSF1 and transcriptional dysfunction across degenerative diseases and toxic exposures.

molecular biology↗

bioRxiv2026

Radiation-Driven Prediction of Daily Irrigation Demand under Different Electrical Conductivity Scenarios in Greenhouse Tomato

In soilless greenhouse tomato cultivation, daily transpiration and irrigation demand are largely governed by solar radiation, while irrigation-solution electrical conductivity (EC) used for salinity management may further modulate plant water use. This study developed a low-input, radiation-driven modeling approach to predict daily irrigation demand under contrasting water-salt management scenarios. Two tomato cultivars were grown under four treatments: conventional baselines (CK1, CK2) and regulated scenarios combining irrigation volume with solution EC (low-water high-EC, TK; high-water moderate-EC, TC). Daily irrigation volume (I) and drainage were recorded, and daily cumulative radiation (G) was derived from photosynthetically active radiation (PAR). Within each treatment, we compared a radiation-only baseline model with an EC-adjusted model and evaluated predictive performance using 5-fold blocked time-series cross-validation. Results showed strong positive correlations between G and I across all treatments (p < 0.001). The EC-adjusted models achieved cross-validated root-mean-square errors (RMSE) of 0.815-1.393 L d-1 per trough and Nash-Sutcliffe efficiencies (NSE) of 0.407-0.730. Incorporating EC yielded a small but consistent improvement under the TK scenario ({Delta}RMSE = -0.014 L d-1; {Delta}NSE = +0.019), whereas its effect was negligible or slightly negative under CK1, CK2, and TC, highlighting scenario dependence. Our radiation-driven framework, with an optional EC correction, offers a practical and scalable tool for daily irrigation forecasting and supports integrated water-salt management in soilless greenhouse tomato production.

plant biology↗

bioRxiv2025

A gastric microbial chromatin remodeler drives gastric cancer progression and immune evasion by reprogramming the host epigenome

Emerging evidence highlights the crucial role of microbial communities in modulating cancer development and progression. In gastric cancer (GC), we identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium that drives both tumor progression and immune evasion. We define a novel mechanism in which SA secretes extracellular vesicles (saEVs) that translocate the bacterial chromatin remodeler saSNF2 into host cell. There, saSNF2 partners with host transcription factor TEAD1--through its ATPase activity and participation in BAF complex assembly--to coordinately activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which in turn stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while also amplifying other TEAD1 target genes to fuel tumor progression. Functionally, saEVs promote tumor growth and limit CD8+ T-cell infiltration in vivo. Strikingly, pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. Our results establish SA as a multifaceted driver of GC and reveal the saSNF2-ZDHHC11 axis as a promising target to potentiate immunotherapy.

cancer biology↗

bioRxiv2025

Temporal structure of chemical stress controls single-cell inhibition and recovery in photosynthetic microorganisms

Although fluctuating conditions are a hallmark of microbial habitats, how the timing of chemical stress influences single-cell inhibition and recovery is not well resolved. Using a microfluidic platform, we continuously tracked photosynthetic performance in thousands of individual cells of a coral-associated microalga (Symbiodiniaceae sp.) exposed to identical cumulative doses of the photosystem II inhibitor diuron delivered either as constant or fluctuating profiles. Fluctuating exposure produced stronger early inhibition than constant exposure, but as concentrations declined it enabled partial recovery that did not occur under time-averaged constant conditions. These dynamics revealed distinct response subpopulations that differed in both the magnitude and timing of inhibition, including groups that regained activity exclusively under fluctuating stress. Quantifying per-cell decline kinetics showed that fluctuating exposure synchronizes the onset of inhibition across cells, creating a narrow temporal window in which a subset of cells can recover once stress levels fall, whereas constant exposure yields more heterogeneous but uniformly declining trajectories. These results demonstrate that stress timing, not cumulative dose alone, governs whether photosynthetic inhibition is reversible at the single-cell level. More broadly, our findings illustrate how temporal variability and intrinsic phenotypic heterogeneity jointly govern cellular function, highlighting stress timing as an important and often overlooked axis shaping microbial performance in dynamic environments. Significance statementEnvironmental stress in nature is rarely constant; instead, it fluctuates over minutes to days. Yet most laboratory assays rely on static exposures, leaving the role of stress timing poorly understood. Using microfluidics, we imposed precisely timed chemical stress on individual cells of a coral-associated microalga and monitored their photosynthetic performance continuously. Fluctuating exposure caused strong initial inhibition but later allowed partial recovery in a subset of cells, revealing functional heterogeneity that constant stress concealed. These results show that when stress occurs, its temporal structure can be as important as how much stress is delivered. By uncovering mechanisms that govern reversibility and heterogeneity in a key coral symbiont, this work provides a mechanistic basis for understanding microbial responses in dynamic environments.

ecology↗

bioRxiv2025

The Structural Basis of Pacs1-Wdr37 Complex Assembly and Stability

Phosphofurin acidic cluster sorting protein 1 (Pacs1) is a multidomain adaptor proposed to bind transmembrane cargo proteins to facilitate their intracellular trafficking. Pacs1 also forms a complex with WD-repeat protein 37 (Wdr37), which is essential for lymphocyte homeostasis. Despite numerous proposed binding partners, a validated structure for Pacs1-containing protein complexes is lacking. Here, we present the cryo-electron microscopy structure of the Pacs1-Wdr37 complex. Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR), the domain previously linked to cargo recognition. This interaction stabilizes Wdr37 and is critical for the expression of both proteins. A gain-of-function mutation in PACS1 (R203W) causes a highly penetrant neurodevelopmental syndrome. This pathogenic mutation lies on a solvent-exposed surface of the FBR and does not disrupt complex formation. Instead, Pacs1-R203W remains dependent on Wdr37 for stability and its levels can be reduced through targeted Wdr37 proteolytic degradation. Structural homology of the FBR to synaptotagmin C2 domains reveals a previously unrecognized ability of Pacs1 to bind negatively charged phospholipids through a unique positively charged cleft. Together these findings define the structural basis for Pacs1-Wdr37 complex assembly and stability, present potential strategies for Pacs1-mediated neurodevelopmental disease, and suggest novel Pacs1 functions in membrane association.

biochemistry↗

bioRxiv2025

Macrophage EHD1 promotes inflammation and stabilizes sortilin to accelerate atherosclerosis

BackgroundMacrophages are key players in the pathogenesis of atherosclerosis. They trigger immune responses through their cell-surface receptors. However, how macrophages regulate those receptors in response to pro-inflammatory stimuli is not completely understood. Endocytic membrane trafficking involving receptor internalization, followed by endosomal transport and recycling of the internalized receptors, plays essential roles in balancing cell-surface receptors to meet cellular needs. Here, we explored the role of the endocytic regulator EHD1 in immune responses in macrophages and determined its contribution to atherosclerosis progression. MethodsEHD1 expression profiles in mouse and human plaques were determined by single-cell RNA sequencing (scRNA-seq) and immunofluorescence staining. Bone marrow transplantation (BMT) by transplanting bone marrow cells from Ehd1-/- or littermate wild-type mice to irradiated Ldlr-/- mice was performed to determine the effect of EHD1 deletion on atherosclerosis progression. In vitro mechanistic studies including inflammation signaling and endocytosis assays were performed in bone marrow-derived macrophages. ResultsEHD1 expression in macrophages is enhanced as atherosclerosis progresses in both mice and humans. Histological analysis of aortic root sections from BMT mice showed that EHD1 deletion reduces lesion size. ScRNA-seq of aortic CD45+ cells demonstrated that EHD1 deletion attenuates pro-inflammatory responses and cell-cell interactions. Mechanistic studies revealed that EHD1 accelerates the endocytic recycling of TNFR2 and activates NF-kB, leading to increased expression of inflammatory cytokines. Moreover, EHD1 interacts with retromer and stabilizes sortilin, a retrograde cargo of retromer and a risk factor for atherosclerosis. ConclusionsEHD1 promotes inflammation by enhancing TNFR2-NF-kB signaling and stabilizing sortilin, leading to accelerated atherosclerosis. Our study reveals novel roles for EHD1-mediated membrane trafficking in macrophage function and paves the way to innovative therapeutic strategies that aim to address dysregulated membrane trafficking in atherosclerosis.

cell biology↗