Biology subjects

Gao, S.

Publications and source records attributed to Gao, S..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

Multimodal meta-analysis of fecal metagenomes reveals microbial single nucleotide variants as superior biomarkers for early detection of colorectal cancer

Microbial signatures show remarkable potentials in predicting colorectal cancer (CRC). This study aimed to evaluate the diagnostic powers of multimodal microbial signatures, multi-kingdom species, genes, and single-nucleotide variants (SNVs) for detecting pre-cancerous adenomas. We performed cross-cohort analyses on whole metagenome sequencing data of 750 samples via xMarkerFinder to identify adenoma-associated microbial multimodal signatures. Our data revealed that fungal species outperformed species from other kingdoms with an area under the ROC curve (AUC) of 0.71 in distinguishing adenomas from controls, while classifier based on SNVs of bacterial species displayed the strongest diagnostic capability (AUC=0.89). SNV biomarkers also exhibited outstanding performances in three independent validation cohorts (AUCs = 0.83, 0.82, and 0.76, respectively) and were highly specific to adenoma. In further support of the above results, functional analyses revealed more frequent inter-kingdom associations between bacteria and fungi, and abnormalities in quorum sensing, purine and butanoate metabolism in adenoma, which were further validated in a newly-recruited cohort via qRT-PCR. Therefore, these data extend our understanding of adenoma-associated multimodal alterations in the gut microbiome and provide a rationale of microbial SNVs for the early detection of CRC.

cancer biology↗

bioRxiv2023

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

cancer biology↗

bioRxiv2022

Characterization of fluorescence lifetime of organic fluorophores for molecular imaging in the SWIR window

SignificanceFluorescence lifetime imaging in the short-wave infrared (SWIR) is expected to enable high resolution multiplexed molecular imaging in highly scattering tissue. AimTo characterize the brightness and fluorescence lifetime of commercially available organic SWIR fluorophores and benchmark them against the tail emission of conventional NIR-excited probes. ApproachCharacterization was performed through our established Time-domain Mesoscopic Fluorescence Molecular Tomography (TD-MFMT) system integrated around a TCSPC-SPAD array. Brightness and fluorescence lifetime was measured for NIR and SWIR probes above 1000 nm. Simultaneous probe imaging was then performed to assess their potential for multiplexed studies. ResultsNIR probes outperformed SWIR probes in brightness while the mean fluorescence lifetimes of the SWIR probes were extremely short. The phantom study demonstrated the feasibility of lifetime multiplexing in the SWIR window with both NIR and SWIR probes. ConclusionsLong tail emission of NIR probes outperformed the SWIR probes in brightness beyond 1000 nm. Fluorescence lifetime was readily detectable in the SWIR window, where the SWIR probes showed shorter lifetimes compared to the NIR probes. We demonstrate the feasibility of lifetime multiplexing in the SWIR window, which paves the way for in vivo multiplexed studies of intact tissues at improved resolution.

bioengineering↗

bioRxiv2022

Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicate that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant Yap activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating "indeterminate" states of differentiation and suggesting that aberrant Yap signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap and Taz or Taz alone in AT2 cells stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, inactivation of only Yap in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

developmental biology↗

bioRxiv2022

Mechanical force induces DRP1-dependent asymmetrical mitochondrial fission for quality control

Mitochondria are membrane-bound organelles that perform diverse critical biological functions. They undergo constant fission and fusion, which are important for mitochondrial inheritance, functions, and quality control. While tremendous efforts have identified many factors governing mitochondria dynamics, emerging evidence indicates the involvement of various intracellular or extracellular mechanical cues. However, how mechanical stress directly modulates mitochondrial dynamics remains largely unknown. Here utilizing an optogenetic mitochondria-specific mechanostimulator to apply pulling forces to intracellular mitochondria, we find that mechanostimulation can promote mitochondrial fission, with sustained mechanostimulation triggering fission more effectively than transient one. Asymmetrical fission can occur at different sub-mitochondrial sites after force-induced mitochondrial elongation. Such force-induced fission is dependent on DRP1 and involves the wrapping of ER tubules. Moreover, mechanical force generates mitochondrial fragments without mtDNA which recruit Parkin proteins. Our results prove the mechanosensitivity and mechanoresponsiveness of mitochondria and reveal the role of mechanical cues in directly regulating mitochondrial dynamics.

cell biology↗

bioRxiv2022

The molecular mechanism of chloramphenicol and thiamphenicol resistance mediated by a novel oxidase CmO in Sphingomonadaceae

Antibiotic resistance mediated by bacterial enzyme inactivation plays a mysterious and crucial role for antibiotic degradation and selection pressure reduction in the environment. The enzymatic inactivation of the antibiotic chloramphenicol (CAP) involves nitro reduction, amide bond hydrolysis and acetylation modification. However, the molecular mechanism of enzymatic oxidation of CAP remains unknown. Here, a novel oxidase gene cmO was identified and confirmed biochemically to catalyze the resistance process through the oxidative inactivation at the side chain C-3 position of CAP and thiamphenicol (TAP) in Sphingomonadaceae. The oxidase CmO is highly conservative in Sphingomonadaceae and shares the highest amino acid homology of 41.05% with the biochemically identified glucose methanol choline (GMC) oxidoreductases. Molecular docking and site-directed mutagenesis analyses demonstrated that CAP was anchored inside the protein pocket of CmO with the hydrogen bonding of key residues glycine (G)99, asparagine (N)518, methionine (M)474 and tyrosine (Y)380. CAP sensitivity test demonstrated that the acetyltransferase and CmO showed higher resistance to CAP as compared with the amide bond-hydrolyzing esterase and nitroreductase. This study provides a better theoretical basis and a novel diagnostic gene for understanding and assessing the fate and resistance risk of CAP and TAP in the environment. ImportanceRising levels of antibiotic resistance undermines ecological and human health as a result of indiscriminate usage of antibiotics. Various resistance mechanisms have been revealed, for instance genes encoding proteins that degrade antibiotics, yet requiring further exploration. In this study, we reported a novel gene encoding an oxidase involved in the inactivation of typical amphenicol antibiotics (chloramphenicol and thiamphenicol), and the molecular mechanism was elucidated. The observation provides novel data to understand capabilities of bacteria to tackle antibiotic stress and suggests complex function of enzymes in the context of antibiotic resistance development and antibiotics removal. The reported gene can be further employed as an indicator to monitor amphenicols fate in the environment, benefiting the risk assessment in this era of antibiotic resistance.

microbiology↗

bioRxiv2022

HiCAT: A tool for automatic annotation of centromere structure

Significant improvements in long-read sequencing technologies have unlocked complex genomic areas, such as centromeres, in the genome and introduced the centromere annotation problem. Currently, centromeres are annotated in a semi-manual way. Here, we propose HiCAT, a generalizable automatic centromere annotation tool, based on hierarchical tandem repeat mining and maximization of tandem repeat coverage to facilitate decoding of centromere architecture. We applied HiCAT to human CHM13-T2T and gapless Arabidopsis thaliana genomes. Our results not only were generally consistent with previous inferences but also greatly improved annotation continuity and revealed additional fine structures, demonstrating HiCATs performance and general applicability.

bioinformatics↗

bioRxiv2022

Noninvasive cancer detection by extracting and integrating multi-modal data from whole-methylome sequencing of plasma cell-free DNA

AbstractPlasma cell-free DNA (cfDNA) methylation and fragmentation signatures have been shown to be valid biomarkers for blood-based cancer detection. However, conventional methylation sequencing assays are inapplicable for fragmentomic profiling due to bisulfite-induced DNA damage. Here using enzymatic conversion-based low-pass whole-methylome sequencing (WMS), we developed a novel approach to comprehensively interrogate the genome-wide plasma methylation, fragmentation, and copy number profiles for sensitive and noninvasive multi-cancer detection. With plasma WMS data from a clinical cohort comprising 497 healthy controls and 780 patients with both early- and advanced-stage cancers of the breast, colorectum, esophagus, stomach, liver, lung, or pancreas, genomic features including methylation, fragmentation size, copy number alteration, and fragment end motif were extracted individually and subsequently integrated to develop an ensemble cancer classifier, called THEMIS, using machine learning algorithms. THEMIS outperformed individual biomarkers for differentiating cancer patients of all seven types from healthy individuals and achieved a combined area under the curve value of 0.971 in the independent test cohort, translating to a sensitivity of 86% and early-stage (I and II) sensitivity of 77% at 99% specificity. In addition, we built a cancer signal origin classifier with true-positive cancer samples at 100% specificity based on methylation and fragmentation profiling of tissue-specific accessible regulatory elements, which localized cancer-like signal to a limited number of clinically informative sites with 66% accuracy. Overall, this proof-of-concept work demonstrates the feasibility of extracting and integrating multi-modal biomarkers from a single WMS run for noninvasive detection and localization of common cancers across stages.

cancer biology↗

bioRxiv2022

Metformin Alleviates Arthrofibrosis in Rat via Fibroblast Metabolic Reprogramming and Lactate-Mediated Macrophage Polarization

BackgroundEmerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has the beneficial effect on arthrofibrosis and its underlying mechanism. MethodsArticular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. ResultsWe found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. ConclusionMetformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis. The translational potential of this articleThe finding of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.

cell biology↗

bioRxiv2022

Physiology and structure of pathogenic Escherichia coli pOmpT reveal two substrate-binding sites

The pathogenicity of bacteria can be achieved by cleaving antimicrobial peptides (AMPs) through the outer membrane protease family (Omptins) to evade or resist the hosts innate immune response. The OmpT-like proteins in Escherichia coli are members of Omptins, which have highly conserved proteolytic activity. Here, sequence alignment and physiological studies have determined that pOmpT is a virulence factor with atypical proteolytic activity. Comparing pOmpT with cOmpT in terms of structure, proteolytic activity and target substrates, it is found that Asp267 and Ser276 of cOmpT are substrate-binding sites and help its catalytic center to cleave substrates (protamine,synthetic peptide or RNase 7). However, special structural features and the nature of residues Ser267 and Thr276 of pOmpT caused the inability of cleavage protamine, but allows it to specifically cleave the human AMP RNase 7. It is suggested that two sites are related with the substrate specificity. In short, we found that pOmpT presents a new structural basis for the specific recognition of substrates, and providing new clues for the development of antimicrobial drugs.

microbiology↗

bioRxiv2022

Metabolic control of histone acetylation for precise and timely regulation of minor ZGA in early mammalian embryos

Metabolism feeds into the regulation of epigenetics via metabolic enzymes and metabolites. However, metabolic features, and their impact on epigenetic remodeling during mammalian pre-implantation development, remain poorly understood. In this study, we established the metabolic landscape of mouse pre-implantation embryos from zygote to blastocyst, and quantified some absolute carbohydrate metabolites. We integrated these data with transcriptomic and proteomic data, and discovered the metabolic characteristics of the development process, including the activation of methionine cycle from 8-cell embryo to blastocyst, high glutaminolysis metabolism at blastocyst stage, enhanced TCA cycle activity from the 8-cell embryo stage, and active glycolysis in the blastocyst. We further demonstrated that oxidized nicotinamide adenine dinucleotide (NAD+) synthesis is indispensable for mouse pre-implantation development. Mechanistically, in part, NAD+ is required for the exit of minor zygotic gene activation (ZGA) by cooperating with SIRT1 to remove zygotic H3K27ac. In human, NAD+ supplement can promote the removal of zygotic H3K27ac and benefit pre-implantation development. Our findings demonstrate that precise and timely regulation of minor ZGA is controlled by metabolic dynamics, and enhance our understanding of the metabolism of mammalian early embryos. HighlightsO_LIWe identified the metabolic features of mouse pre-implantation embryo development. C_LIO_LINAD+ synthesis is indispensable for mouse embryo pre-implantation development. C_LIO_LINAD+-mediated erasure of zygotic H3K27ac is required for the exit of minor ZGA. C_LIO_LINAD+ supplement promotes the removal of zygotic H3K27ac and benefits preimplantation development of human embryos. C_LI

developmental biology↗

bioRxiv2022

Zinc binding inhibits cellular uptake and antifungal activity of Histatin-5 in Candida albicans

Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans. Hist-5 has the ability to bind metals in vitro and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.

microbiology↗

bioRxiv2022

Cardiac-Gated Spectroscopic Photoacoustic Imaging for Ablation-Induced Necrotic Lesion Visualization: In Vivo Demonstration in a Beating Heart

Radiofrequency (RF) ablation is a minimally invasive therapy for heart arrhythmia, including atrial fibrillation (A-fib), which creates lesions using an electric current to isolate the heart from abnormal electrical signals. However, conventional RF procedures do not involve intraoperative monitoring of the area and extent of ablation-induced necrosis, making the assessment of the procedure completeness challenging. Previous studies have suggested that spectroscopic photoacoustic (sPA) imaging is capable of differentiating ablated tissue from its non-ablated counterpart based on PA spectrum variation. Here, we aim to demonstrate the applicability of sPA imaging in an in vivo environment, where the cardiac motion presents, and introduce a framework for mapping the necrotic lesion using cardiac-gated sPA imaging. We computed the degree of necrosis, or necrotic extent (NE), by dividing the quantified ablated tissue contrast by the total contrast from both ablated and non-ablated tissues, visualizing it as continuous colormap to highlight the necrotic area and extent. To compensate for tissue motion during the cardiac cycle, we applied the cardiac-gating on sPA data, based on the image similarity. The in vivo validation of the concept was conducted in a swine model. As a result, the ablation-induced necrotic lesion at the surface of the beating heart was successfully depicted throughout the cardiac cycle through cardiac-gated sPA (CG-sPA) imaging. The results suggest that the introduced CG-sPA imaging system has great potential to be incorporated into clinical workflow to guide ablation procedures intraoperatively.

bioengineering↗

bioRxiv2022

Delivery of Circular mRNA via Degradable Lipid Nanoparticles against SARS-COV-2 Delta Variant

mRNA vaccines have emerged as a most promising and potent platform in the fight against various diseases including the COVID-19 pandemic. However, the intrinsic instability, varying side effects associated with the delivery systems, and continuous emergence of virus variants highlight the urgent need for the development of stable, safe and efficacious mRNA vaccines. In this study, by screening a panel of proprietary biodegradable ionizable lipidoids, we reported on a novel mRNA vaccine (cmRNA-1130) formed from a biodegradable lipidoid with eight ester bonds in the branched tail (AX4) and synthetic circular mRNA (cmRNA) encoding the trimeric Delta receptor binding domain (RBD) of SARS-CoV-2 spike protein for the induction of robust immune activation. The AX4-based lipid nanoparticles (AX4-LNP) revealed much faster elimination rate from liver and spleen in comparison with commercialized MC3-based LNP (MC3-LNP) and afforded normal level of alanine transferase (ALT), aspartate aminotransferase (AST), and creatinine (CRE) in BALB/c mice. Following intramuscular (IM) administration in BALB/c mice, cmRNA-1130 elicited potent and sustained neutralizing antibodies, RBD-specific CD4+ and CD8+ T effector memory cells (Tem), and Th1-biased T cell activations. cmRNA-1130 vaccine showed excellent stability against 6-month storage at 4 {degrees}C and freezing-thawing cycles. In brief, our study highlights mRNA vaccines based on cmRNA and biodegradable AX4 lipids hold great potential as superb therapeutic platforms for the treatment of varying diseases.

immunology↗

bioRxiv2022

K2P channel TWK-40 Regulates a Rhythmic Behavior in C. elegans

Leak potassium (K+) currents, conducted by two-pore domain K+ (K2P) channels, are critical for the stabilization of the membrane potential. The effect of K2P channels on motor rhythm remains enigmatic. We show here that the K2P TWK-40 regulates the rhythmic defecation motor program (DMP) in Caenorhabditis elegans. Disrupting TWK-40 suppresses the expulsion defects of nlp-40 and aex-2 mutants. By contrast, a gain-of-function (gf) mutant of twk-40 significantly reduces the expulsion frequency per DMP cycle. In situ whole-cell patch clamping demonstrates that TWK-40 forms an outward current that hyperpolarize the resting membrane potential of DVB neuron. In addition, TWK-40 substantially contributes to the rhythmic activity of DVB. Specifically, DVB Ca2+ oscillations exhibit obvious defects in twk-40 mutants. Expression of TWK-40(gf) in DVB recapitulates the expulsion deficiency of the twk-40(gf) mutant, and inhibits DVB Ca2+ oscillations in both wild-type and twk-40(lf) animals. Moreover, DVB innervated enteric muscles also exhibit rhythmic Ca2+ defects. Taken together, these results demonstrate that TWK-40 is an essential neuronal inhibitor of DMP, thus revealing a cellular mechanism linking leak K2P channels with rhythmic motor activity.

neuroscience↗

bioRxiv2022

A descending interneuron with depolarized resting membrane potential controls C. elegans motor states

Continuity of behaviors requires animals to make smooth transitions between successive and mutually exclusive behavioral states. Neural principles that govern these transitions are not well understood. C. elegans spontaneously switch between two opposite motor states, forward and backward movement, a phenomenon long thought to reflect the reciprocal inhibition between two interneurons that separately gate the forward and backward motor circuits, AVB and AVA. Combining experimental data and mathematical modeling, we report that spontaneous forward and backward locomotion and their corresponding motor circuits are not separately controlled. AVA and AVB are neither functionally equivalent nor strictly reciprocally inhibitory. Instead, while AVA phasically inhibits the forward promoting interneuron AVB at a fast timescale, it maintains a tonic, extrasynaptic excitation on AVB over the longer timescale. AVAs depolarized spontaneous membrane potential is necessary for this tonic excitation. We propose a new, master neuron model for locomotion. AVA, with tonic and phasic activity of opposite polarities on different time scales, acts as a master neuron to break the symmetry between the underlying forward and backward motor circuits. This offers a parsimonious solution for sustained locomotion consisted of mutually exclusive motor states. TeaserA tonically active C. elegans premotor interneuron functions as the master neuron that underlies continuous modulation of forward and backward movement to ensure smooth transitions between the two opposing motor states.

neuroscience↗

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↗

bioRxiv2022

Dynamic nucleosome organization after fertilization reveals regulatory factors for mouse zygotic genome activation

Chromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome position in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 hour after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome depletion regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely connected with histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development.

developmental biology↗