Biology subjects

Xiao, P.

Publications and source records attributed to Xiao, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Dual-Binding Scaffold RRsS1 Bridges Pol IV Transcripts and DNA Templates for Robust Reproductive siRNA Biogenesis

Cytosine DNA methylation established by RNA-directed DNA methylation (RdDM) is critical for transposon silencing and genome integrity in plants. In reproductive tissues, RNA Polymerase IV (Pol IV) is recruited to specific genomic loci by DNA motifs and the transcription factor-GDE1-CLSY3/4 complex to initiate abundant siRNA biogenesis and de novo DNA methylation, but the mechanisms that stabilize the Pol IV transcription complex at these sites remain elusive. Using immunoprecipitation-mass spectrometry of the Pol IV complex, we identify Reproductive RdDM siRNA Scaffold 1 (RRsS1) as a novel Pol IV interactor. RRsS1 colocalizes genome-wide with motif-dependent RdDM factors in floral tissues. Loss of RRsS1 significantly impairs 24-nt siRNA accumulation at a subset of CLSY3/4-dependent loci, particularly those exhibiting high Pol IV enrichment. We show that chromatin association of RRsS1 is stabilized by GDE1 and CLSY3/4. Structural modeling and biochemical assays characterize RRsS1 as a chimeric protein containing HRDC, Nudix, and DRBM modules that bind single-stranded DNA (ssDNA) and double-stranded DNA (dsRNA), respectively. Together, our findings support a model in which RRsS1 acts as a dual-binding scaffold, bridging Pol IV-RDR2 transcripts to their DNA templates within transcription bubbles to ensure robust siRNA production during plant reproduction.

plant biology↗

bioRxiv2026

Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules

Blockade of signaling through the angiotensin II type 1 receptor (AT1R), a prototypical G protein-coupled receptor (GPCR), by angiotensin receptor blockers (ARBs) is a major therapeutic approach to treating a wide variety of cardiovascular and renal diseases1. Like most GPCRs, the AT1R signals through two transducers, G proteins and {beta}-arrestins2,3. Previous reports have described {beta}-arrestin-biased peptide orthosteric agonists for the AT1R with potential therapeutic advantages over currently available unbiased ARBs4-6. Here we report the DNA- encoded library screening-guided isolation and pharmacological characterization of the first small molecule AT1R allosteric ligands. We use cryo-electron microscopy, double electron- electron resonance spectroscopy, molecular dynamics simulations, and targeted mutagenesis to determine their binding sites, binding modes and conformational mechanisms driving their unique and divergent modulatory effects on G protein and {beta}-arrestin pathways. Our findings uncover new mechanisms for precisely controlling the dynamic behavior of the AT1R with implications for drug development targeting this pathophysiologically important receptor family.

biochemistry↗

bioRxiv2026

A Fungal Natural Product that Targets Cellulose Synthase Complex and Inhibits Plant Cellulose Biosynthesis

Cellulose, a primary component of plant cell walls, is synthesized by cellulose synthase complexes (CSCs) at the plasma membrane. Targeting this process with cellulose biosynthesis inhibitors (CBIs) has significantly advanced our understanding of plant cell wall formation and provided valuable compounds for herbicide development. Here, we identified a fungal natural product, 8-methyldichlorodiaporthin (MDD), as a broad-spectrum plant CBI. Structure-activity relationship analyses demonstrate that methylation modifications on the isocoumarin ring and chlorination of side chain are crucial for MDD-induced growth inhibition. A chemical forward genetic screen in Arabidopsis thaliana revealed two semi-dominant CESA1 mutations, causing A903T and H1024Y substitutions, that confer insensitivity to MDD. Both mutations locate to transmembrane domains of CESA1, and we show that MDD depletes CSCs from the plasma membrane and reduces cellulose content. Further genetic analyses indicate that the cesa1mddi1-1 A903T mutant also confers resistance to CBIs quinoxyphen and C17, but not to CBIs isoxaben, indaziflam, or ES20. Stacking additional point mutations conferring resistance to other CBIs, cesa3ixr1-1 G998D, and cesa6es20-r3 G935E into the cesa1mddi1-1 A903T background yields multiple-drugs resistant lines that maintain normal growth. These findings establish MDD, as a novel, natural CBI that likely targets CESA1, thereby extending our understanding of CSC regulation and abilities to develop multi-drugs resistant crop varieties. These findings offer new perspectives for weed management and plant biotechnology. Significance StatementCellulose, a fundamental structural component of plant cell walls, is synthesized by cellulose synthase complexes (CSCs) and represents a critical herbicide target. While synthetic cellulose biosynthesis inhibitors (CBIs) like isoxaben and quinoxyphen have helped in the elucidation of CSC function and aided in weed control, natural CBIs remain largely undiscovered. Here, we identify 8-methyldichlorodiaporthin (MDD), a fungal-derived isocoumarin natural product, as a CBI that inhibits plant growth by depleting CSCs from the plasma membrane. Genetic screens reveal MDD-resistant cesa1 mutations, and combining these with other CBI-resistant alleles yields multi-herbicide resistant plants that can grow normally. This research enhances our understanding of cellulose biosynthesis and paves the way for multi-herbicide resistant crops with agricultural benefits.

plant biology↗

bioRxiv2026

Precursor-Dependent Routing of Aromatic Amino Acids Determines Lignin Structure in Grasses by Sensitivity-Enhanced Solid-State NMR

Lignin biosynthesis in grasses exhibits unique metabolic flexibility, yet the precursor-specific routing of carbon into lignin polymers remains poorly resolved in planta. Here, we combine 13C-isotope labeling with solid-state NMR under sensitivity-enhancement by dynamic nuclear polarization (DNP), to directly track phenylalanine- and tyrosine-derived carbon incorporation into the lignin polymer in Brachypodium distachyon. Precursor-specific 13C labeling reveals that phenylalanine is the dominant contributor to canonical guaiacyl and syringyl lignins, whereas tyrosine preferentially enriches hydroxyphenyl lignin and hydroxycinnamates, including ferulates characteristic of grass cell walls. Two-dimensional 13C-13C correlation NMR resolves distinct lignin moieties arising from each precursor. Disruption of p-coumarate 3-hydroxylase (C3H) selectively impairs phenylalanine-derived lignification, while tyrosine-derived lignin remains comparatively unchanged, maintaining polymer assembly through alternative metabolic routes. These findings show precursor-dependent control of lignin composition and reveal tyrosine-mediated lignification as a compensatory pathway in grasses. This work also establishes precursor-resolved solid-state NMR and DNP as a powerful framework for dissecting lignin biosynthesis and metabolic plasticity in plant cell walls. SIGNIFICANCE STATEMENTLignin is a complex plant polymer that strengthens cell walls but also limits the efficiency of biomass processing for agriculture and bioenergy. Grasses possess a unique lignin biosynthetic flexibility that is not well understood. By combining stable isotope labeling with solid-state NMR spectroscopy, we directly traced how the aromatic amino acids, phenylalanine and tyrosine, contribute differently to lignin formation in intact grass cell walls. We show that phenylalanine primarily builds conventional lignin structures, whereas tyrosine supplies alternative phenolic components and maintains lignin synthesis even when a key biosynthetic enzyme is disrupted. This metabolic flexibility helps explain the unique structural aspects of grass cell walls and identifies precursor-level control as a promising strategy for engineering lignin composition to improve biomass utilization.

plant biology↗

bioRxiv2026

Selective Immune Silencing by Targeted TGF-β Agonists

Depletion of pathogenic T and B cells is a pillar of therapies for autoimmune, inflammatory, and transplantation-related immunological diseases. However, adverse events, safety concerns in immunocompromised patients, and disease relapse limit clinical utility. Here, we exploit the immunosuppressive properties of a transforming growth factor beta (TGF-{beta}) mimic repurposed from helminths for cell type-specific therapeutic silencing, as a new approach to complement existing therapies. Mouse CD4 and CD8 T cell-targeted TGF-{beta} agonists selectively and potently silence antigen-specific T cell responses in OVA-immunized mice by suppressing pro-inflammatory effector, cytotoxic, and T follicular helper programs, while skewing cells toward a quiescent state biased toward regulatory and type 17 T cell phenotypes. Similarly, human CD4 and CD8 T cell-targeted TGF-{beta} agonists precisely and effectively suppress live-attenuated influenza vaccine (LAIV)-induced T cell activation and expansion in human spleen organoids. Correspondingly, CD4 T cell-targeted TGF-{beta} agonist effectively ameliorated disease activity and promoted disease remission in CD4 T cell-driven models of autoimmune neuroinflammation and allergic airway inflammation, demonstrating efficacy in both prophylactic and established inflammatory settings. Moreover, both CD4 and CD8 T cell-targeted TGF-{beta} agonists ameliorated disease activity in graft-versus-host disease. Additionally, a human CD19 B cell-targeted TGF-{beta} agonist robustly inhibits germinal center B cell-to-plasmablast maturation and antibody responses in LAIV-stimulated human spleen organoids. These early-stage results suggest that cell-selective TGF-{beta} agonism merits further investigation as a versatile therapeutic approach for the precise silencing of pathogenic adaptive immune responses.

immunology↗

bioRxiv2025

PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4

PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse Acute Myeloid Leukemia cells. To investigate the mechanism of PAMD-Ch17s novel anti-leukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-ALL cell lines being highly sensitive. Surprisingly, CXCR4 knock out T-ALL cells were equally sensitive to PAMD-Ch17. Using a fluorescently tagged PAMD-Ch17, we found that the drug colocalized to the mitochondria. We also found that PAMD-Ch17 induced changes in expression of genes related to mitochondrial function, increased levels of mitochondrial superoxide, and decreased mitochondrial membrane potential. Using seahorse assays, we found that PAMD-Ch17 decreased baseline oxygen consumption, ATP production, and proton leakage. PAMD-Ch17 also decreased baseline extracellular acidification rate, indicating a decrease in overall metabolism. In mouse primary T-ALL but not healthy bone marrow cells, PAMD-Ch17 induced both mitochondrial superoxide and cell death. Using human bone marrow organoids, we found that PAMD-Ch17 induced mitochondrial superoxide and cell death in human primary T-ALL cells, but not in healthy stromal and hematopoietic cells. Collectively, our results indicate that PAMD-Ch17 has anti-leukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4 independent, mitochondrial based mechanism. These findings support further development of PAMDs as potential therapeutics for patients with T-ALL. KEY POINTSO_LIPAMD-Ch17, a polymeric drug based on AMD3100/Plerixafor, has novel anti-leukemic activities against T-ALL that are independent of CXCR4 inhibition. C_LIO_LIPAMD-Ch17 induces increased mitochondrial superoxide and cell death in primary ALL cells, but not healthy bone marrow cells. C_LI

cancer biology↗

bioRxiv2025

Rapid High-Resolution Analysis of Polysaccharide-Lignin Interactions via Proton-Detected Solid-State NMR with Application to Eucalyptus and Spruce

The plant secondary cell wall, a complex matrix composed of cellulose, hemicellulose, and lignin, is crucial for the mechanical strength and water-proofing properties of plant tissues, and serves as a primary source of biomass for biorenewable energy and biomaterials. Structural analysis of these polymers and their interactions within the secondary cell wall has been heavily relying on 13C-based solid-state NMR techniques. In this study, we explore the application of 1H-detected solid-state NMR techniques for rapid, high-resolution structural characterization of polysaccharides and lignin, demonstrated on the stems of hardwood eucalyptus and softwood spruce. We employed several strategies, including the use of synthesized 2D spectra to resolve central 1H resonances and the combined application of 3D hCCH and hCHH experiments for complete resonance assignment and unambiguous identification of lignin-carbohydrate interactions. Our findings emphasize the central role of acetylated three-fold xylan conformers, rather than two-fold, in stabilizing the carbohydrate-lignin interface, with glucuronic acid sidechains in eucalyptus glucuronoxylan colocalizing with lignin, revised cellulose-lignin interactions involving uncoated microfibril surfaces, and pectin-lignin interactions indicative of early-stage lignification. We also carefully evaluated the interference from tannins in softwood species. These results present a novel approach for rapid structural analysis of lignocellulosic biomaterials without the need for solubilization or extraction.

biophysics↗

bioRxiv2025

β-Arrestin Condensates Regulate G Protein-Coupled Receptor Function

G protein-coupled receptors (GPCRs) are the largest class of receptors in the genome and control many signaling cascades essential for survival. GPCR signaling is regulated by {beta}-arrestins, multifunctional adapter proteins that direct receptor desensitization, internalization, and signaling. While at many GPCRs, {beta}-arrestins interact with a wide array of signaling effectors, it is unclear how {beta}-arrestins promote such varied functions. Here we show that {beta}-arrestins undergo liquid-liquid phase separation (LLPS) to form condensates that regulate GPCR function. We demonstrate that {beta}-arrestin oligomerization occurs in proximity to the GPCR and regulates GPCR functions such as internalization and signaling. This model is supported by a cryoEM structure of the adhesion receptor ADGRE1 in a 2:2 complex with {beta}-arrestin 1, with a {beta}-arrestin orientation that can promote oligomerization. Our work provides a paradigm for {beta}-arrestin condensates as regulators of GPCR function, with LLPS serving as an important promoter of signaling compartmentalization at GPCRs.

cell biology↗

bioRxiv2025

Molecular Insights into Cell Wall Architecture and Xylan-Bound Cellulose Fibrils in the Wheat Straw

The plant cell wall, a highly abundant renewable resource, remains insufficiently understood in terms of its structure, particularly the architecture of cellulose microfibrils and their interactions with hemicellulose and lignin, which impede the development of efficient downstream conversion. Here we present an alternative model of xylan-bound cellulose microfibril architecture in the cell wall of intact wheat straw, using solid-state nuclear magnetic resonance (ssNMR) coupled with X-ray scattering techniques. We show that the spectroscopic and scattering data can be fit to a simple elementary microfibril consisting of 18 glucan chains, with additional contributions from 0 to 4 tightly bound flat-ribbon xylan chains across the cellulose fibril axis. These xylan-bound cellulose microfibrils are found to serve as the secondary interaction site with lignin, following the non-flat xylan domains. The loose packing of these xylan-bound cellulose fibrils results in a heterogenous hydration landscape within the cell wall, allowing water penetration while maintaining structural integrity through numerous physical contacts between the polymers. This study provides a potential framework to reconcile the mounting biochemical evidence supporting the 18-chain elementary cellulose microfibril model and cellulose synthase complex with the oversized observations from characterization techniques, which report averaged structures influenced by microfibril coalescence and hemicellulose binding. The structural insights also offer valuable information regarding recalcitrance and the potential applications of biomass in biorefinery operations.

biochemistry↗

bioRxiv2025

Emergence of Lignin-Carbohydrate Interactions During Plant Stem Maturation Visualized by Solid-State NMR

Lignification waterproofs and strengthens the secondary plant cell wall, while increasing the energy cost associated with releasing sugars for biofuel production. The physical association between lignin and the carbohydrate scaffold that accommodates lignin polymerization, as well as the temporally distinct roles of different lignin units and carbohydrate partners during lignification, remain largely unclear. Here we map the lignin-carbohydrate interactions by solid-state NMR in 13C-labeled Arabidopsis inflorescence stems as secondary cell walls are formed. Analysis includes wild-type and two mutants that either selectively or globally disrupt lignin biosynthesis. Mature cell walls in the basal regions of older stems are enriched in S-lignin and carbohydrate-lignin interactions. Acetylated xylan is the dominant mediator of interactions with S-lignin, while methylated pectin unexpectedly interacts with G-lignin during early-stage lignification. The critical role of S-lignin in stabilizing carbohydrate-lignin interface is emphasized by the weak lignin-carbohydrate interactions and compromised mechanical properties of a low-S fah1 mutant, whereas the ref3 mutant, with low overall lignin content but a higher S/G ratio, remained unaffected. These findings demonstrate that the molecular mixing pattern, rather than lignin content, is a key determinant of the structure and properties of lignocellulosic materials.

biophysics↗

bioRxiv2024

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. PET-CT imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.

bioengineering↗

bioRxiv2024

Five-layered robot (F-robot) based on functionally graded multilayer foam antiviral low-carbon (F-MAX) system for Pathogenic Microorganism Elimination

In this study, a revolutionary air filtration technology, the F-MAX multilayer composite plate, is introduced, offering high efficiency and environmental sustainability. This innovative system is designed to capture a wide range of pollutants, including harmful viruses and bacteria, enhancing air quality significantly. The F-MAX combines multiple layers, each tailored to target specific particles, with features like an electrostatically charged melt-blown fabric and eco-friendly materials like lithium brine by-product magnesia. Its durability, antiviral, and antibacterial properties make it a sustainable choice for air purification, suitable for both commercial and residential use. This system represents healthier living environments, effectively removing airborne contaminants, and demonstrating a commitment to a sustainable future. Additionally, the study introduces the F-robot specifically designed for laboratory environments to ensure pristine air quality. One-Sentence SummaryT-robot air filter, which use F-MAX, a multilayer composite consisted of self-healing cellular coating, Desert Rose (DR) coating, melt-blown cloth, and BMSC with high-efficiency, environmentally sustainable filtration, and antiviral properties, suitable for diverse environments.

microbiology↗

bioRxiv2023

Soil intake modifies the gut microbiota and alleviates ovalbumin-induced mice asthma inflammation

BackgroundLow cleanliness living environment (LCLE) can increase gut microbial diversity and prevent allergic diseases, whereas gut microbial dysbiosis is closely related to the pathogenesis of asthma. Our previous studies suggested that soil in the LCLE is a key factor in shaping intestinal microbiota. ObjectiveWe aimed to explore if sterilized soil intake as prebiotics while being incubated with microbes in the air can attenuate mice asthma symptoms by modifying gut microbiota. Methods16S rRNA gene sequencing was used to analyze the gut microbial composition, in combination with immune parameters measured in the lung and serum samples. Results16S rRNA gene sequencing results showed significant differences in the fecal microbiota composition between the test and control mice, with a higher abundance of Allobaculum, Alistipes, and Lachnospiraceae_UCG-001, which produce short-chain fatty acids and are beneficial for health in the test mice. Soil intake downregulated the concentrations of IL-6, IL-4, IL-17F, TNF-, and IL-22 in serum and increased the expression of IFN-{gamma}, which regulated the Th1/Th2 balance in lung by polarizing the immune system toward Th1, strongly alleviating ovalbumin-induced asthma inflammation. The effect of sensitization on gut microbiota was greater than that of air microbes and age together, but weaker than that of soil. ConclusionSoil intake had a significant therapeutic effect on mouse asthma, possibly by promoting the growth of multiple beneficial bacteria. The results indicated that the development of soil-based prebiotic products might be used for allergic asthma management and our study provides further evidence for the hygiene hypothesis. ImportanceExposure to a low cleanliness living environment (LCLE), of which soil is an important component, can shape the gut microbiota and support immune tolerance, preventing allergic diseases such as eczema and asthma. However, with the rapid progress of urbanization, it is impossible to return to farm-like living and we are becoming disconnected from the soil. Here, our study found that ingesting sterilized soil and living in an LCLE have the same protective effects on asthma inflammation. Ingestion of sterilized soil significantly altered the gut microbial composition and exerted significant therapeutic effects on asthmatic mice. However, edible sterilized soil possesses more advantages than LCLE exposure, such as the absence of pathogenic bacteria, safer, and convenience. The results indicate that the development of soil-based prebiotic products might be used for allergic asthma management and our study further supports the hygiene hypothesis. NotificationThe article is currently undergoing peer review in the World Allergy Organization Journal.

microbiology↗

bioRxiv2023

Sterile Soil as Prebiotics Mitigate Intergenerational Loss of Gut Microbial Diversity and Anxiety-Like Behavior Induced by Antibiotics in mice

The decline in gut microbial diversity of modern human is closely associated with the rising prevalence of various diseases. It is imperative to investigate the underlying causes of gut microbial loss and the rescue measures. Although the impact of non-perinatal antibiotic use on gut microbiota has been recognized, its intergenerational effects remain unexplored. Our previous research has highlighted soil in the farm environment as a key prebiotic for gut microbiome health by restoring gut microbial diversity and balance. In this study, we investigated the intergenerational consequences of antibiotic exposure and the therapeutic potential of soil prebiotics. We treated mice with vancomycin and streptomycin for 2 weeks continuously, followed by 4-8 weeks of withdrawal period before breeding. The process was repeated across 3 generations. Half of the mice in each generation received an oral soil prebiotic intervention. We assessed gut microbial diversity, anxiety behavior, microglia reactivity, and gut barrier integrity across generations. The antibiotics exposure led to a decrease in gut microbial diversity over generations, along with aggravated anxiety behavior, microglia abnormalityies, and altered intestinal tight junction protein expression. Notably, the third generation of male mice exhibited impaired reproductive capacity. Oral sterile soil intervention restored gut microbial diversity in adult mice across generations, concomitantly rescuing abnormalities in behavior, microglia activity, and intestinal barrier integrity. In conclusion, this study simulated an important process of the progressive loss gut microbiota diversity in modern human and demonstrated the potential of sterile soil as a prebiotic to reverse this process. The study provides a theoretical and experimental basis for the research and therapeutic interventions targeting multiple modern chronic diseases related to intestinal microorganisms.

microbiology↗

bioRxiv2022

A Mesenchymal Cell Niche in Skin for Acute Myeloid Leukemia

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML post-transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4-/- mouse skin post-cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse. A 40-word summary Sandhow et al have in transplantation-induced AML mouse models demonstrated the leukemia-regenerating capacity of AML cells infiltrated in the skin and the role of skin mesenchymal niches in maintaining/protecting AML cells, providing new insight into the pathology of leukemia cutis.

cancer biology↗

bioRxiv2022

Salicin modifies osteoarthritis progression by binding on IRE1α and inhibiting IRE1α mediated endoplasmic reticulum stress

ObjectivesTo investigate the effect and mechanisms of salicin (SA) on osteoarthritis (OA) progression. MethodsPrimary rat chondrocytes were stimulated with TNF- and treated with or without SA. CCK-8 was utilized to determine the cytotoxicity of SA. RT-qPCR, Western Blotting and immunofluorescence staining were used to detect inflammatory factors, cartilage matrix degeneration markers, cell proliferation and apoptosis markers expression at mRNA and protein levels respectively. EdU assay and flow cytometer analysis were utilized for evaluating cell proliferation and apoptosis. RNA-sequencing, molecular docking, drug affinity responsive target stability and WB were applied to clarify mechanisms. Rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. ResultsNo obvious cytotoxicity was found with the treatment of 10 M SA. SA rescued TNF- induced degeneration of cartilage matrix, inhibition of chondrocytes proliferation, and promotion of chondrocytes apoptosis. In mechanism, we clarified SA could directly bind on IRE1 and occupy IRE1 phosphorylation site, followed with inhibiting IRE1 phosphorylation and regulating IRE1 mediated endoplasmic reticulum (ER) stress by IRE1-I{kappa}B-p65 signaling. Finally, intra-articular injection of SA loaded PLGA could ameliorate OA progression by inhibiting IRE1 mediated ER stress in OA model. ConclusionsSA alleviates OA by directly binding on ER stress regulator IRE1 and inhibits IRE1 mediated ER stress by IRE1-I{kappa}B-p65 signaling. Topical use of small molecular drug SA holds the potential of modifying OA progression.

cell biology↗

bioRxiv2021

Soil causes gut microbiota to flourish and total serum IgE levels to decrease in mice

Traditional farm environments induce protection from allergic diseases. In this study, farm environmental factors were classified into three categories, environmental microbes, soil, and organic matter. To explore the impact of soil and environmental microorganisms on gut microbiota and immune function, mice were fed sterilized soil, soil microbes (in lieu of environmental microbes), or non-sterilized soil. Metagenomic sequencing results showed the intake of sterile soil i.e. inhaling a small amount of soil microbes in the air increased gut microbial diversity and the abundance of type III secretion system (T3SS) genes, and decreased serum immune globulin E (IgE) levels induced by 2-4-dinitrofluorobenzene(DNFB). The intake of soil microbes increased the abundance of genes involved in the metabolism of short chain fatty acids and amino acid biosynthesis. Meanwhile, the intake of soil increased gut microbial diversity, the abundance of T3SS genes and related infectious elements, and genes associated with the metabolism of short chain fatty acids and amino acid biosynthesis, and decreased serum IgE levels. Therefore, soil may be useful as a potential "prebiotic" promoting the reproduction and growth of some intestinal microorganisms that harbor bacterial secretion system genes, especially those of T3SS, whose abundance was positively and significantly correlated with innate immune function of mice.

ecology↗

bioRxiv2020

Age-specific gene signatures underlying the transcriptomes and functional connectomes of human cerebral cortex

The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method TCA (Transcriptome-connectome Correlation Analysis), which integrates the brain functional MR magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood, and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets.

neuroscience↗