Biology subjects

Liu, X.

Publications and source records attributed to Liu, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Spatiotemporal atlas resolves the mesenchymal-epithelial stem cell axis governing human hair follicle aging and pathology

How adult stem cell populations coordinate tissue regeneration across physiological and pathological states remains unclear. Hair follicles contain epithelial and mesenchymal stem cells that codetermine hair regeneration. Here, we integrate a multimodal spatiotemporal atlas with functional validation to define the mesenchymal-epithelial stem cell dynamics governing human hair follicle homeostasis, aging, and androgenetic alopecia. Aging is characterized by passive depletion of hDSC-derived regenerative cues, whereas AGA involves a shift of hDSC toward an inhibitory signaling hub that promotes HFSC dysfunction. We further pinpoint hDSC-secreted PTN as a key regenerative factor that promotes hair growth and counteracts androgen-induced growth suppression. This study provides a holistic framework of adult stem cell crosstalk across physiological and pathological states, offering a mechanistic roadmap to reinstate tissue regeneration.

cell biology↗

bioRxiv2026

Stairway Plot v3: Nonparametric Demographic Inference from the Site Frequency Spectrum at Biobank Scale

Inferring the history of effective population size (Ne) from genomic data is fundamental to population genetics, but model-flexible methods have not kept pace with biobank-scale samples. We present Stairway Plot v3, which infers a nonparametric Ne (t) trajectory with bootstrap confidence intervals directly from the site frequency spectrum (SFS). By recasting the optimization as a convex problem and combining inferences across multiple sub-sampled projections, the method scales to 100,000 haploid sequences on commodity CPU hardware without a GPU. Larger samples sharpen the resolution of recent demography, and we apply the method to five human populations including 54,302 Japanese individuals, to our knowledge the largest sample used for nonparametric SFS-based Ne (t) inference.

genomics↗

bioRxiv2026

Multiomics Characterization Identifies S1P-secreting USSHigh Skeletal Muscle Stem Cells as Essential Drivers of Niche Remodeling and Muscle Regeneration

Acutely induced cellular senescence is increasingly recognized as vital for tissue repair but the precise roles of senescent cells in skeletal muscle regeneration remain paradoxical. Here, using single-cell RNA sequencing and a Unified Senescence Score (USS) methodology, we identify a distinct USSHigh (USSHi) muscle stem cell (MuSC) subpopulation emerging in early phase of acute injury induced muscle regeneration. Isolation via the surface marker MHCII enables characterization of these cells as exhibiting canonical senescent-like features. Further characterization through integrated transcriptomics, proteomics, and secretomics reveals their highly pro-inflammatory secretory capacity. Moreover, lipidomic profiling uncovers that the USSHi MuSCs undergo profound sphingolipid metabolic remodeling to generate upregulated bioactive lipid Sphingosine-1-phosphate (S1P). In vivo specific ablation of this subpopulation using a Pax7-CreERT; Ccl2-LSL-DTA genetic strategy significantly impaired muscle regeneration. Furthermore, spatial transcriptomics and cell-cell communication analyses revealed that USSHi MuSCs act as critical niche modulators, directing crosstalk with multiple cell types. Specifically, S1P is essential for mediating direct USSHi interaction with endothelial cells and USSLo cells to promote endothelial angiogenesis and MuSC expansion in the regenerating muscle. Crucially, exogenous S1P rescues the regenerative deficits caused by USSHi MuSC ablation. Altogether our findings define a senescent-like MuSC population emerging in acute injury induced muscle regeneration and provide definitive evidence to demonstrate the positive role of these cells in enhancing muscle repair via their robust secretory phenotypes and inter-cellular communicative capacity.

cell biology↗

bioRxiv2026

Functional niche attributes shape species interaction roles in ecological networks

Identifying how species interact in ecological networks is key to understanding species' contributions to ecosystem functioning, but can be difficult to establish in species-rich communities. Functional niches, which capture broader ecological strategies, are often easier to assess and could help approximate species' interaction roles. We tested this by integrating species interaction and leaf functional trait data of tree species and leaf-associated interaction types from a large-scale forest biodiversity experiment. We found that identity, variability, and similarities of functional niches shaped corresponding aspects of interaction roles. Interestingly, however, this association inversed in the case of functional niche variability, which decreased instead of increased the variability of species interactions. This suggests a potential trade-off between processes that determine variability in functional and interaction space. Furthermore, effects were not constrained within aspects, with similarities of interactions being particularly responsive to most tested niche aspects, indicating that interaction-based competition among plants is particularly sensitive to functional niche differences. Moreover, many effects of functional niches depended on tree species biomass and tree species richness, highlighting the importance of the larger ecological context for determining species interaction roles. Together, our findings show that species' interaction roles, while clearly altered by, are not simply a consequence of functional niches. Instead, interaction roles integrate multiple aspects of functional niches depending on species performances and community composition and can therefore be crucial for anticipating ecosystem change.

ecology↗

bioRxiv2026

A mycovirus identified from an outbreak fungal species complex reveals a parallel antiviral system

Mycoviruses are prevalent across major fungal lineages, yet none have been reported in the Cryptococcus gattii species complex (CGSC), the causative agent of the largest known fungal outbreak in immunocompetent hosts. Consequently, the occurrence of mycoviruses and the host determinants governing their infection in this important pathogenic clade remain unexplored. Through screening of 386 Cryptococcus isolates, we identified a mycovirus, designated CgTV1, in an environmental isolate of the Cryptococcus gattii species complex (CGSC). CgTV1 is a double-stranded RNA (dsRNA) mycovirus of the genus Totivirus, with a genome encoding a capsid protein and an RNA-dependent RNA polymerase. We showed that CgTV1 establishes a cryptic infection, because neither viral presence nor its clearance significantly alters host transcriptomic profiles, suggesting the existence of mechanisms that maintain virus-host homeostasis. Population genomic analyses reveal that an intact RNAi pathway constitutes a critical genetic barrier, and CgTV1 persistence strictly requires loss of function mutations in both AGO1 and AGO2. By pan-transcriptomics across 43 CGSC strains, we further uncovered an RNase III gene, CAI1, which exhibits high expression in the mycovirus positive isolate. Biochemical analysis indicates that Cai1 directly recognizes and degrades CgTV1 dsRNA, thereby constraining excessive mycoviral proliferation. We further demonstrate that Dicer and Cai1 act in parallel to maintain virus-host homeostasis: their combined ablation results in higher viral loads and more pronounced changes in host gene expression than ablation of either factor alone. Collectively, our findings provide the evidence of the occurrence of a mycovirus in the CGSC and reveal parallel mechanisms that enable cryptic mycoviral infections.

genetics↗

bioRxiv2026

SERINC1-dependent lipid preservation gates neocortical synaptogenesis and remote memory

Systems memory consolidation reorganizes episodic memories from the hippocampus into neocortical networks such as the anterior cingulate cortex (ACC), yet the localized molecular programs supporting this process remain unknown. Here, we show that the transmembrane lipid regulator Serinc1 is selectively induced in the ACC during neocortical memory consolidation. Loss of Serinc1 reduces ACC synapse density, blocks learning-induced de novo callosal synaptogenesis, and selectively abolishes remote memory. Lipidomic profiling reveals that SERINC1 prevents activity-dependent depletion of inner-leaflet anionic phospholipids-specifically docosahexaenoic acid (DHA) bearing-phosphatidylserine and arachidonic acid (AA) bearing-phosphatidylinositol-safeguarding signaling cascades required for structural plasticity. Targeted viral restoration of SERINC1 in the ACC rescues cortical synapse density and remote memory. Thus, long-term memory is gated by a localized program of activity-dependent neuro-lipidomic remodeling.

neuroscience↗

bioRxiv2026

Seasonal influenza vaccine strain selection by quantifying viral fitness

The long-standing challenge of seasonal influenza vaccines providing poor protection is attributed to the rapid and continuous evolution of the virus. In theory, the recommendation of vaccine strain is to predict the dominant strain with best fitness in the upcoming season. Here, we develop FutureFlu, a biologically-grounded framework that quantifies the fitness score of influenza variants in upcoming seasons, by integrating metrics on three levels: molecular genetic divergence, individual immune escape, and population-scale transmission dynamics. The fitness scores of influenza variants present strong positive correlation with their actual observed frequencies in the next seasons. Validation across 24 seasons of three influenza subtypes shows FutureFlu recommends antigenically matched vaccine strains more frequently than annual recommendations, particularly for challenging subtypes: 83.3% versus 45.8% seasons for A/H3N2, and 75.0% versus 33.3% seasons for B/Victoria. Furthermore, FutureFlu significantly outperforms the currently used methods in vaccine strain selection whether or not there is available antigenic data from hemagglutination inhibition (HI) assay, which provides a valuable supplement for WHO vaccine recommendation. To support global public health implementation, an open online platform (futureflu.com.cn) has been established to offer real-time viral fitness predictions and vaccine recommendations.

evolutionary biology↗

bioRxiv2026

A bispecific antibody targeting a membrane-proximal ASGPR1 region promotes TNF-α recruitment and uptake

Abstract Recruiting an endocytic receptor through an antibody offers a route to redirect extracellular cytokines into cells. Here, we developed BiAb J31, an IgG like bispecific antibody linking TNF recognition to a membrane-proximal region of asialoglycoprotein receptor 1 (ASGPR1). J31 was isolated by immunization with an engineered ASGPR1 extracellular domain followed by screening against wild-type ASGPR1 and HepG2 cells. Its variable domains were combined with unmodified adalimumab variable regions using knobs into holes and CrossMab engineering, with L234A/L235A/P329G Fc substitutions. BiAb J31 retained HepG2 binding and engaged both antigens in bridging assays. Sequential binding experiments demonstrated recruitment of TNF to BiAb J31 treated cells. Live cell imaging showed uptake of fluorescent antibody-containing complexes and overlap with LysoTracker-positive compartments. In HepG2 cultures containing BiAb J31, TNF and a PE conjugated detection antibody, supernatant PE fluorescence fell by approximately 60% over 90 minutes. Truncation and synthetic-peptide assays localized J31 recognition to ASGPR1 residues 62~100, outside the carbohydrate-recognition domain, and AlphaFold 3 modeling proposed an Fv peptide interface. These findings identify a membrane-proximal ASGPR1 binding antibody that is compatible with bispecific engineering and supports cellular recruitment and uptake of TNF containing complexes. BiAb J31 provides a molecular starting point for antibody based cytokine redirecting approaches.

immunology↗

bioRxiv2026

Linking plant-soil feedback with resource competition to understand plant coexistence

1. Plant-soil feedback (PSF) is increasingly recognized as an important mechanism influencing plant coexistence, but most studies have examined PSF in isolation under controlled conditions. Under natural conditions, PSF operates together with other processes such as resource competition, yet how these processes jointly shape plant coexistence across environmental gradients remains poorly understood. 2. We combined field and greenhouse experiments to assess the contribution of PSF to plant coexistence at low- and high-elevation sites in the Swiss Alps. In the field, we quantified total niche and fitness differences and predicted interaction outcomes for nine plant species pairs, integrating PSF, resource competition, and other processes. In a complementary greenhouse experiment, we used soil microbial communities conditioned during the field experiment to isolate PSF-driven niche and fitness differences for the same species pairs. 3. PSF alone generated strong fitness differences but weak niche differences in the greenhouse experiment, predominantly predicting competitive exclusion. Interaction outcomes predicted from PSF alone corresponded poorly with those in the field, suggesting that PSF in isolation poorly explain plant coexistence under natural conditions. Nevertheless, PSF-driven niche and fitness differences were related to those quantified in the field, which were likely driven largely by resource competition, suggesting that PSF may contribute to coexistence by reinforcing or counteracting other ecological processes. These relationships varied between elevations, highlighting the context dependence of PSF contributions to coexistence. 4. Synthesis. Our study shows that the impacts of plant-soil feedback on plant coexistence cannot be understood from their effects in isolation. Instead, their contribution depends on how they interact with other ecological processes and on the environmental context in which these processes operate. Together, our findings emphasize the need to move beyond studying PSF in isolation towards quantifying how it combines with other mechanisms that drives coexistence under natural conditions.

ecology↗

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

ERBB2 establishes the timing of progesterone priming required for uterine receptivity

Progesterone is essential for establishing uterine receptivity and sustaining early pregnancy. However, how the uterus acquires the competence to respond to progesterone at the appropriate time remains poorly understood. Here we show that ERBB2 governs the timing of progesterone responsiveness required for uterine receptivity. In endometrial samples from women with recurrent spontaneous abortion (RSA), ERBB2 is downregulated specifically in the stromal compartment, accompanied by a parallel reduction in stromal progesterone receptor (PGR). Uterine deletion of Erbb2 in mice blunts the rise of stromal PGR at the onset of the receptive window, deferring implantation and impairing decidualization despite normal circulating progesterone and estrogen. Epithelial deletion has no such effect, placing the requirement in the stroma. High-dose progesterone fails to rescue the phenotype; advancing progesterone priming by 24 hours restores stromal PGR, HAND2, Bmp2, and on-time implantation. Collectively, the present study provides evidence that ERBB2 directs the temporal window of stromal progesterone priming by setting the threshold for PGR induction, thereby synchronizing the maternal-fetal interface and safeguarding pregnancy.

developmental biology↗

bioRxiv2026

An Oxidative Stress-Associated Seven-Gene Prognostic Signature in Lung Adenocarcinoma: Integrative Transcriptomic Analysis Across Public Cohorts

Lung adenocarcinoma is molecularly heterogeneous, and oxidative-stress programs can support either tumor restraint or tumor adaptation depending on cellular context. This study integrated public lung adenocarcinoma transcriptomic cohorts to identify oxidative-stress-associated expression features and evaluate their prognostic relevance. Expression profiles from The Cancer Genome Atlas, Genotype-Tissue Expression project, and GEO series GSE31210, GSE40791, and GSE30219 were analyzed. Differential expression, weighted gene co-expression network analysis, functional enrichment, univariable Cox regression, and least absolute shrinkage and selection operator Cox modeling were combined to derive a risk signature. Immune-cell enrichment, gene set enrichment analysis, gene set variation analysis, and pan-cancer analyses were used for biological characterization. A total of 1,305 genes differed between tumor and control samples, including 498 upregulated and 807 downregulated genes. Intersection of differentially expressed genes, the oxidative-stress-associated co-expression module, and the oxidative-stress gene set yielded 44 genes enriched in responses to reactive oxygen species and hydrogen peroxide, antioxidant and peroxidase activities, focal adhesion, Rap1 signaling, and PI3K-Akt signaling. A seven-gene signature comprising FBLN5, HBB, FYN, HGF, TFAP2A, PLIN5, and F2RL1 stratified the 523-sample training cohort and the 207-sample internal validation cohort into groups with different overall survival. Time-dependent areas under the receiver operating characteristic curve at 1, 3, and 5 years were 0.677, 0.622, and 0.649 in training and 0.613, 0.691, and 0.706 in internal validation. In the 85-case GSE30219 external cohort, corresponding values were 0.588, 0.661, and 0.631; survival separation followed the expected direction but did not reach statistical significance (log-rank P = 0.100). Seventeen immune-cell signatures differed between risk groups, while high-risk tumors were enriched for cell-cycle, DNA-replication, mismatch-repair, glycolytic, E2F, G2M-checkpoint, MYC-target, and mTORC1-related programs. The signature therefore captures reproducible oxidative-stress-associated transcriptional variation with moderate prognostic discrimination. Its clinical utility requires prospective evaluation, complete clinical adjustment, and experimental validation.

cancer biology↗

bioRxiv2026

Meta-analysis of gut microbiome in largemouth bass (Micropterus salmoides) under different aquaculture systems

The teleost gastrointestinal tract hosts metabolically active microbial assemblages that play critical roles in nutrient use, immune regulation, physiology, behavior, growth, reproduction, and health status. However, the extent to which aquaculture production systems restructure these communities remains poorly defined. In this study, metagenomic sequencing was applied to characterize gut microbiota in largemouth bass (Micropterus salmoides) reared under four representative farming conditions: industrial aquaculture (IA), captive pond-based farming (CA), ordinary pond aquaculture with healthy fish (PH), and ordinary pond aquaculture with diseased fish (PD). Results revealed that the four groups exhibited pronounced differences in microbial diversity, taxonomic composition, functional capacity, carbohydrate-active enzyme profiles, and antibiotic resistance genes (ARGs). Notably, bacterial taxa accounted for more than 95% of the gut microbial communities across all groups. IA fish showed greater microbial richness and diversity than CA and PH fish, consistent with a more complex and potentially more stable intestinal ecosystem under industrialized rearing conditions. Taxonomic profiling at both the phylum and genus levels identified production system-specific microbial signatures. In particular, opportunistic pathogens, including Aeromonas veronii and Aeromonas hydrophila, were disproportionately enriched in CA fish, suggesting a microbiota profile associated with increased disease vulnerability. Functional prediction analysis further indicated distinct metabolic states among groups, with purine and fatty acid metabolism enriched in PD fish, potentially reflecting disease-associated disruption of host-microbiota interactions. Carbohydrate-active enzyme analysis revealed substantial variation in microbial carbohydrate-processing potential, whereas ARG profiling indicated that farming conditions were linked to distinct gut resistome patterns. Collectively, these findings identify aquaculture regimes as a key ecological driver of intestinal microbiome structure in largemouth bass and provide a mechanistic basis for optimizing microbiome-informed health management in aquaculture systems. Keywords: Largemouth bass (Micropterus salmoides); gut microbiota; aquaculture modes

microbiology↗

bioRxiv2026

Dissociable changes in temporal precision and causal expectations following perceptual training

A common behavioral gain does not necessarily reflect a common learning mechanism. Perceptual learning may sharpen sensory evidence without updating higher-level expectations about its causes. Across three experiments, we examined audiovisual binding and its plasticity in children with ADHD and typically developing children. Children with ADHD were more susceptible to the sound-induced flash illusion (Experiment 1) and showed markedly flatter temporal tuning of it (Experiment 2), yet conventional temporal binding window (TBW) estimates did not distinguish the groups, behavior alone could not localize the difference. Following six days of simultaneity-judgment training, both groups became comparably less susceptible to the illusion. A temporally explicit two-dimensional Bayesian causal inference model, however, revealed sharply different latent changes. Typically developing children reduced their causal prior expectation that auditory and visual signals shared a common cause. Children with ADHD showed no corresponding prior recalibration but instead exhibited a marked reduction in temporal uncertainty, indicating more precise perceptual evidence that did not propagate to the slower, more abstract estimate of environmental causal structure. Thus, perceptual learning converged at the behavioral level while diverging computationally. These findings argue against unitary accounts of multisensory plasticity and show how the same perceptual endpoint can conceal adaptation at different levels of the inferential hierarchy.

neuroscience↗

bioRxiv2026

Altered stimulus-specific adaptation at the auditory cortex of a mouse model of Fragile X Syndrome

Auditory hypersensitivity or decreased sound tolerance is a common phenotype of Fragile X Syndrome (FXS). Impairments in adaptation, defined as the reduction in the neuronal responsiveness to repeating sounds, can contribute to this prevalent phenotype. Previous studies on event-related potential observed impairments in mismatch negativity (MMN) in both FXS individuals and in the FMR1-knockout (KO) mouse model of FXS. Therefore, in the present study we characterized stimulus-specific adaptation (SSA), a neural correlate of MMN, at the auditory cortex (AC) of anesthetized (with ketamine/xylazine) female and male postnatal day 20 (P20) wild-type (WT) and FMR1-KO mice, using the oddball paradigm with either 4 Hz or 1 Hz repetition rate. We observed robust SSA at the 4 Hz repetition rate of the oddball paradigm in the AC neurons of all four groups of animals. We also noted that the strength of SSA diminished between 4 to 1 Hz repetition rate. In addition, at both the 4 Hz and 1 Hz repetition rate, reduced SSA was observed particularly in the male FMR1-KO mice compared to their WT counterparts, while female WT and FMR1-KO mice displayed similar SSA. In terms of sex differences, male FMR1-KO mice had lower SSA than female FMR1-KO mice, while SSA was similar in male and female WT mice. Overall, our observation of reduced SSA in the male FMR1-KO mice suggests that impairments in neuronal adaptation potentially contribute to the auditory hypersensitivity phenotype particularly within the male population.

neuroscience↗

bioRxiv2026

AutoScreen: AI Co-Scientist System for Target Discovery in Functional Genomics

Target discovery in functional genomics remains largely manual and time-consuming, lacking systematic tools for efficient and reproducible gene-level hypothesis generation. We introduce AutoScreen, an AI co-scientist system supporting target discovery through both Pre-screen Design, which constructs perturbation libraries de novo from free-text research descriptions, and Post-screen Analysis, which re-ranks experimental screen hits by integrating statistical scores with biological context. AutoScreen leverages the complementary strengths of multiple specialist agents that perform deep research into multi-modal evidence, information restructuring, parallel searches across >26 biomedical databases, evidence synthesis, and target review to provide transparent, explainable gene prioritization with pipeline provenance. Across 320 genome-scale CRISPR screens as expert-curated benchmarks, AutoScreen achieved a ~19% increase in validated-hit recovery among its top 100 predictions, relative to the strongest agent baseline, and required a 1.2-fold smaller library to recover the same number of hits at the top-500 reference point. AutoScreen reached mean average precision more than two orders-of-magnitude above random baseline. Further, we validated AutoScreen in cancer immune-evasion case studies focusing on natural killer (NK) and T-cell therapeutics. AutoScreen recovered NK-resistance genes that were initially lower-ranked in a leukemia screen, moving MUC1, PDPN, and LRRC15 from raw ranks of 118, 81, 1384 to 5, 44, 659, respectively. In follow-up tumor killing assay with primary human NK cells, individual perturbation validated all three hits successfully. Next, in prospective benchmarking across two cytotoxic T-cell-killing screens, AutoScreen recovered 77.1% of ground-truth hits called by the consensus of two gold-standard analysis pipelines (FDR<0.1), achieving 8% improvement over the strongest general-purpose LLM agent baseline. Finally, we re-analyzed >500 public datasets to construct the AutoScreen Resource Hub, a growing knowledge base of pre-computed, annotated reports for CRISPR screens, RNA-seq differential expression, and gene-level UK Biobank genome-wide association studies. This agentic AI approach enables real-time genomics benchmark construction that are continuously updated, expanded, for evaluating frontier AI co-scientists. Overall, AutoScreen enables AI-powered target discovery to be more auditable, scalable, extensible, and reproducible.

bioengineering↗

bioRxiv2026

TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction

Objective: Toll like receptor (TLR) activation by cartilage derived damage-associated molecular patterns contributes to osteoarthritis (OA) pathogenesis, but the role of synovial fibroblasts in this process remains incompletely understood. We investigated the TLR responsiveness of human OA synovial fibroblasts and determined how TLR activation influences fibroblast-mediated regulation of chondrocyte function. Design: Primary synovial fibroblasts isolated from OA patients were characterized for TLR expression and stimulated with agonists targeting TLR1/2 to TLR9. Inflammatory mediator production, matrix metalloproteinase expression, mitochondrial respiration, and transcriptomic responses were assessed. Functional effects on cartilage homeostasis were evaluated using autologous chondrocyte spheroid co-cultures. Results: Approximately 50% of cells within OA synovial membranes were fibroblasts (CD45-CD31-PDPN+). Synovial fibroblasts expressed multiple TLRs at both the transcript and protein levels. Activation of TLR1/2, TLR4, TLR5, and TLR2/6 induced robust expression of IL-6, IL-8, G-CSF, MMP3, and MMP10, with minimal effects on mitochondrial respiratory function. Transcriptomic analysis revealed activation of inflammatory pathways together with enrichment of antigen presentation and protein translation programs. In autologous co-culture, TLR1/2-activated synovial fibroblasts promoted inflammatory and catabolic gene expression, suppressed anabolic gene expression, and impaired chondrocyte spheroid growth. Conclusions: Human OA synovial fibroblasts are highly responsive to TLR activation and acquire a pro-inflammatory, cartilage-degrading phenotype that directly impairs chondrocyte homeostasis. These findings identify synovial fibroblasts as key effectors of innate immune signalling within the OA joint and support targeting shared TLR-mediated pathways in joint-resident cells as a potential disease-modifying therapeutic strategy.

immunology↗

bioRxiv2026

Prenatal 3i-0777 treatment attenuates left ventricular hypertrabeculation and dysfunction in a retinoic acid-induced mouse model

Excessive left ventricular trabeculation and thinning of the compacted myocardium arise during cardiac development and may be accompanied by myocardial dysfunction. Gestational exposure to all-trans retinoic acid (ATRA) induces a comparable phenotype in mice, providing a model for evaluating prenatal pharmacological intervention. We examined whether 3i-0777, a small-molecule enhancer of GATA4-NKX2-5 transcriptional synergy, could attenuate these structural and functional abnormalities. Pregnant C57BL/6NCrl dams were randomly assigned to untreated control, vehicle control, ATRA, or ATRA plus 3i-0777 groups (12 independent litters per group). Both ATRA-exposed groups received ATRA (50 mg/kg) on embryonic day (E)12.5. In the ATRA plus 3i-0777 group, 3i-0777 (15 mg/kg) was administered as a separate injection concurrently with ATRA at E12.5, followed by 5 mg/kg every 8 h (three doses per day) on E13.5-E15.5. At postnatal day 1, one pup was randomly selected from each litter for echocardiography and subsequent histomorphometry. The echocardiographic and histomorphometric ratios of non-compacted to compacted myocardial layer thickness (N/C ratios) were higher, and the absolute magnitude of global longitudinal strain (|GLS|) was lower, in the ATRA group than in either control group (all adjusted P < 0.001). Compared with the ATRA group, the ATRA plus 3i-0777 group had lower echocardiographic and histomorphometric N/C ratios (0.58 {+/-} 0.19 vs 2.19 {+/-} 0.18 and 0.90 {+/-} 0.33 vs 2.46 {+/-} 0.48, respectively), higher |GLS| (25.9 {+/-} 2.5% vs 15.3 {+/-} 2.7%), and a smaller left ventricular internal diameter at end-diastole (1.15 {+/-} 0.06 vs 1.42 {+/-} 0.10 mm; all adjusted P < 0.001). These findings provide proof of concept that ATRA-induced left ventricular hypertrabeculation and dysfunction can be pharmacologically attenuated in utero.

developmental biology↗