Dislocation response of ECC-RC composite supporting structures of tunnels passing through active fault.

To address the problems of the conventional composite supporting structures (CCSSs) such as insufficient anti-dislocation performance and deformation capacity, this study used Engineered Cementitious Composite (ECC) lining sections instead of the traditional lining sections and optimized support design parameters, resulting in the development of novel ECC-RC composite supporting structures (ECSSs) of tunnels passing through active fault. The dislocation response characteristics and their parameter sensitivity of the ECSS was revealed by way of 1/25-scale fault dislocation model tests and finite element analysis. The test results show that the mechanical response characteristics and the failure modes of the CCSS and the ECSS are similar under reverse fault dislocation. Compared with the CCSS, the anti-dislocation performance of the ECSS is significantly improved by introducing of the ECC lining and optimizing the design parameters. The vertical deformation of the ECSS and the range of influence under the same dislocation are significantly decreased, and the strain are reduced to different degrees. This phenomenon shows that by improving the material properties, shortening the spacing of aseismatic joints and optimising the thickness of the shock absorption layer, the stress conditions and applicability under deformation of the structure are improved. The ECSS benefits from the crack resistance and toughening effect of fibres, the degree and scope of cracking of the ECSS are significantly reduced compared with those of the CCSS, and internal and external through cracks and local spalling are absent. The results of finite element analysis show that the overall damage degree of the ECSS is decreased and the damage range is increased by decreasing the strength of the surrounding rock in the fault zone. The fault dislocation response pattern of the ECSS varies depending on the fault type. The damage degree caused by different fault types follows the order of normal fault, strike-slip fault, and reverse fault from large to small. However, the damage range caused by the strike-slip fault is significantly larger compared to normal fault and reverse fault. In the design of fault resistance, the surrounding rock conditions of the fault zone and the form of fault dislocation should be considered.

Possible opportunities and challenges for traditional Chinese medicine research in 2035.

The drug development process is poised for significant transformation due to the rapid advancement of modern biological and information technologies, such as artificial intelligence (AI). As these new technologies and concepts infiltrate every stage of drug development, the efficiency and success rate of research and development are expected to improve substantially. Traditional Chinese medicine (TCM), a time-honored therapeutic system encompassing herbal medicine, acupuncture, and qigong, will also be profoundly impacted by these advancements. Over the next decade, Traditional Chinese medicine research will encounter both opportunities and challenges as it integrates with modern technologies and concepts. By 2035, TCM is anticipated to merge with modern medicine through a more contemporary and open research and development model, providing substantial support for treating a broader spectrum of diseases.

PRRSV NSP1α degrades TRIM25 through proteasome system to inhibit host antiviral immune response.

Porcine reproductive and respiratory syndrome (PRRS) is the most economically significant disease caused by porcine reproductive and respiratory syndrome virus (PRRSV). Type I interferon (IFN) induces a large number of interferon-stimulated genes (ISGs) expression to inhibit PRRSV infection. To survive in the host, PRRSV has evolved multiple strategies to antagonize host innate immune response. Previous studies have reported that PRRSV N protein decreases the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress IFN-ß production. However, whether other PRRSV proteins inhibit the antiviral function of TRIM25 is less well understood. In this study, we first found that PRRSV NSP1α decreased ISGylation of TRIM25. Meanwhile, NSP1α significantly suppressed TRIM25-mediated IFN-ß production to promote PRRSV replication. Further studies demonstrated that PRRSV NSP1α reduced the protein level of TRIM25 in proteasome system but did not regulate the transcription level of TRIM25. In addition, the function of NSP1α in TRIM25 degradation did not rely on its papain-like cysteine protease activity. Taken together, PRRSV NSP1α antagonizes the antiviral response of TRIM25 by mediating TRIM25 degradation to promote PRRSV replication. Our data identify TRIM25 as a natural target of PRRSV NSP1α and reveal a novel mechanism that PRRSV induces TRIM25 degradation and inhibits host antiviral immune response.

RH20, a phase-separated RNA helicase protein, facilitates plant resistance to viruses.

RNA silencing, a conserved gene regulatory mechanism, is critical for host resistance to viruses. Liquid-liquid phase separation (LLPS) is an important mechanism in regulating various biological processes. Emerging studies suggest RNA helicases play important roles in microRNA (miRNA) production through LLPS. In this study, we investigated the functional role of RNA helicase 20 (RH20), a DDX5 homolog in Arabidopsis thaliana, in RNA silencing and plant resistance to viruses. Our findings reveal that RH20 localizes in both the cytoplasm and nucleus, with puncta formation in the cytoplasm exhibiting liquid-liquid phase separation behavior. We demonstrate that RH20 plays positive roles in plant immunity against viruses. Further study showed that RH20 interacts with Argonaute 2 (AGO2), a key component of the RNA silencing pathway. Moreover, RH20 promotes the accumulation of both endogenous and exogenous small RNAs (sRNAs). Overall, our study identifies RH20 as a novel phase separation protein that interacting with AGO2, influencing sRNAs accumulation, and enhancing plant resistance to viruses.

Modified basalt fiber filled in constructed wetland-microbial fuel cell: Comparison of performance and microbial impacts under PFASs exposure.

Basalt fiber (BF) with modification of iron (Fe-MBF) and calcium (Ca-MBF) were filled into constructed wetland-microbial fuel cell (CW-MFC) for innovative comparison of improved performance under perfluorooctanoic acid (PFOA) exposure. More enhancement on nitrogen and phosphorus removal was observed by Fe-MBF than Ca-MBF, with significant increase of ammonium (NH4+-N) removal by 3.36-5.66 % (p < 0.05) compared to control, even under PFOA stress. Markedly higher removal efficiency of PFOA by 4.76-8.75 % (p < 0.05) resulted from Fe-MBF, compared to Ca-MBF and control BF groups. Besides, superior electrochemical performance was found in Fe-MBF group, with maximum power density 28.65 % higher than control. Fe-MBF caused higher abundance of dominant microbes on electrodes ranged from phylum to family. Meanwhile, ammonia oxidizing bacteria like Nitrosomonas was more abundant in Fe-MBF group, which was positively correlated to NH4+-N and total nitrogen removal. Some other functional genera involved in denitrification and phosphorus-accumulation were enriched by Fe-MBF on electrodes and MBF carrier, including Dechloromonas, Candidatus_Competibacter, and Pseudomonas. Additionally, there were more biomarkers in Fe-MBF group, like Pseudarcobacter and Acidovorax, conducive to nitrogen and iron cycling. Most functional genes of nitrogen, carbon, and sulfur metabolisms were up-regulated with Fe-MBF filling, causing improvement on nitrogen removal.

Stapled hemorrhoidopexy for hemorrhoids: A overview of systematic reviews and meta-analysis.

Stapled hemorrhoidopexy has been used for years to treat hemorrhoids. Despite numerous systematic reviews and meta-analyses on the topic, inconsistent conclusions have left people uncertain about its effectiveness and raised doubts about the quality of these reviews.In order to provide reliable evidence for clinical practice, it is crucial to conduct an overview to assess the quality of MAs/SRs regarding the efficacy and complications of SH.A comprehensive search was performed across seven databases to identify MAs/SRs on the efficacy and complications of SH from inception to October 2023. The selected MAs/SRs were then assessed using three well-established tools: AMSTAR-2, PRISMA 2020and GRADE. These assessments provide a robust evaluation of the quality and reliability of the included MAs/SRs.We removed overlapping randomized controlled trials (RCTs) and conducted a new meta-analysis of the outcomes. The overview included 23 meta-analyses.In AMSTAR-2, three reviews were deemed moderate quality, nine reviews were classified as low quality, and eleven reviews were evaluated as critically low quality.In PRISMA 2020,certain deficiencies were exhibited, such as abstracts (0/23:0 %),final retrieval date (0/23:0 %), sensitivity analysis (6/23:26.09 %),publication bias assessment (11/23:47.83 %), the quality of evidence (2/23:8.70 %) and so on.In GRADE,twenty-six items were rated as moderate quality (27.96 %),forty-one items were rated as low quality (44.09 %) and twenty-six items were rated as critically low quality (27.96 %).SH has been found to be an effective intervention for reducing postoperative pain, shortening procedure time, and promoting wound healing. The re-analysis indicated that SH can reduce postoperative pain in hemorrhoid patients (odds ratio = 0.28, 95 % confidence interval [0.15,0.55], p = 0.0002; I2 = 74 %, p < 0.00001). But SH is associated with a higher risk of postoperative bleeding and recurrence of prolapse.Given that the reviews included in this overview were rated as low quality, caution should be exercised when interpreting the findings.

The precise function of alphaherpesvirus tegument proteins and their interactions during the viral life cycle.

Alphaherpesvirus is a widespread pathogen that causes diverse diseases in humans and animals and can severely damage host health. Alphaherpesvirus particles comprise a DNA core, capsid, tegument and envelope; the tegument is located between the nuclear capsid and envelope. According to biochemical and proteomic analyses of alphaherpesvirus particles, the tegument contains at least 24 viral proteins and plays an important role in the alphaherpesvirus life cycle. This article reviews the important role of tegument proteins and their interactions during the viral life cycle to provide a reference and inspiration for understanding alphaherpesvirus infection pathogenesis and identifying new antiviral strategies.

Rhein alleviates MPTP-induced Parkinson's disease by suppressing neuroinflammation via MAPK/IκB pathway.

Background: Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons in vitro by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear. Methods: PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein. Results: Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and M1 polarization markers of microglia in vivo. In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition. Conclusion: Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.

Rhein inhibits M1 polarization of BV2 microglia through MAPK/IκB signalling pathway and reduces neurotoxicity caused by neuroinflammation.

BACKGROUND: Rhein is an anthraquinone compound with anti-inflammatory pharmacological activity. It has been found to play a neuroprotective role in neurological diseases, but the neuroprotective mechanism of rhein remains unclear. METHODS: SH-SY5Y cells serving as neuron-like cells and BV2 microglia were used. The toxicity of rhein on BV2 microglia and the viability of SH-SY5Y cells were measured by CCK-8 assay. The mRNA expression and secretion of pro-inflammatory cytokines were detected by qPCR and ELISA. Iba1, CD86 and pathway signalling protein in BV2 microglia were assessed by Western blot and immunofluorescence. Apoptosis of SH-SY5Y cells exposed to neuroinflammation was analysed through flow cytometry. RESULTS: Rhein inhibited MAPK/IκB signalling pathways. Further studies revealed that rhein inhibited the production of pro-inflammatory cytokines TNF-α, IL-6, IL-1ß and iNOS in BV2 cells and also inhibited the expression of M1 polarization markers Iba1 and CD86 in BV2 cells. Furthermore, rhein reduced the apoptotic rate and restored cell viability of SH-SY5Y cells exposed to neuroinflammation. CONCLUSIONS: Our study demonstrated that rhein inhibited microglia M1 polarization via MAPK/IκB signalling pathway and protected nerve cells through suppressing neuroinflammation.

Ultrasensitive detection of dopamine using Au microelectrodes integrated with mesoporous silica thin films.

An electrochemical method was developed for ultrasensitive and selective detection of dopamine in human serum using mesoporous silica thin film modified gold microelectrodes. Vertically aligned mesoporous silica thin films were deposited onto Au microelectrodes by electrochemically assisted self-assembly (EASA). The mesochannels have uniform pore sizes of 2.1 nm in diameter and a negatively charged wall surface. Cyclic voltammetry reveals effective charge permselectivity through the negatively charged mesoporous channels. By using differential pulse voltammetry, the mesoporous silica thin film modified Au microelectrode can be employed for the ultrasensitive detection of dopamine with a detection limit as low as 0.084 µM. In addition, thanks to the electrostatic and steric effects of the silica mesochannels, excellent anti-interference and anti-fouling properties of the electrochemical sensors are demonstrated.

Genetic Effects of Grain Quality Enhancement in Indica Hybrid Rice: Insights for Molecular Design Breeding.

Improving rice quality remains a crucial breeding objective, second only to enhancing yield, yet progress in quality improvement lags behind yield. The high temperature and ripening conditions in Southern China often result in poor rice quality, impacting hybrid rice production and utilization. Therefore, to address this challenge, analyzing the molecular basis of high-quality traits is essential for molecular design breeding of high-quality hybrid rice varieties. In this study, we investigated the molecular basis of grain shape, amylose content, gel consistency, gelatinization temperature, and aroma, which influence rice quality. We discovered that quality related alleles gs3, GW7TFA, gw8, chalk5, Wxb, ALKTT, and fgr can enhance rice quality when applied in breeding programs. Polymerization of gs3, GW7TFA, gw8, and chalk5 genes improves rice appearance quality. The gs3 and GW7TFA allele polymerization increasing the grain's length-width ratio, adding the aggregation of gw8 allele can further reducing grain width. The chalk5 gene regulates low chalkiness, but low correlation to chalkiness was exhibited with grain widths below 2.0 mm, with minimal differences between Chalk5 and chalk5 alleles. Enhancing rice cooking and eating quality is achieved through Wxb and ALKTT gene polymerization, while introducing the fgr(E7) gene significantly improved rice aroma. Using molecular marker-assisted technology, we aggregated these genes to develop a batch of indica hybrid rice parents with improved rice quality are obtained. Cross-combining these enhanced parents can generate new, high-quality hybrid rice varieties suitable for cultivation in Southern China. Therefore, our findings contribute to a molecular breeding model for grain quality improvement in high-quality indica hybrid rice. This study, along with others, highlights the potential of molecular design breeding for enhancing complex traits, particularly rice grain quality.

Tailoring the peroxidase-like properties of Mo atom nanoclusters/N-MXene nanozymes for sensitive colorimetric detection of glutathione.

Although nanozyme engineering has made tremendous progress, there is a huge gap between them and natural enzymes due to the enormous challenge of precisely adjusting the geometric and electronic structure of active sites. Considering that intentionally adjusting the metal-carrier interactions may bring the promising catalytic activity, in this work, a novel Mo atom nanocluster is successfully synthesized using nitrogen-doped Mxene (MoACs/N-MXene) nanozymes as carriers. The constructed MoACs/N-MXene displays excellent peroxidase-like catalytic activity and kinetics, outweighing its N-MXene and Mo nanoparticles (NPs)-MXene references and natural horse radish peroxidase. This work not only reports a successful example of MoACs/N-MXene nanozyme as a guide for achieving peroxidase-mimic performance of nanozymes for colorimetric glutathione sensing at 0.29 µM, but also expands the application prospects of two-dimensional MXene nanosheets by reasonably introducing metal atomic clusters and nonmetal atom doping and exploring related nanozyme properties.

Inoculation with Funneliformis mosseae promotes selenium accumulation and transformation in pepper (Capsicum annuum L.).

Selenium (Se) is one of the fifteen essential nutrients required by the human body. Mycorrhizal microorganisms play a crucial role in enhancing selenium availability in plants. However, limited research exists on the impact of arbuscular mycorrhizal fungi (AMF) on selenium accumulation and transport in pepper plants. This study employed a pot experiment to investigate the changes in pepper plant growth, selenium accumulation, and transformation following inoculation with AMF and varying concentrations of exogenous selenium. The results indicate that exogenous selenium application in pepper has dual effects. At low concentrations (≤8 mg L⁻1), it promotes growth and nutrient accumulation, whereas high concentrations (>16 mg L⁻1) inhibit these processes. AMF inoculation positively influences selenium accumulation and transport in peppers, significantly increasing yield per plant by 17.89%, vitamin C content by 67.36%, flavonoid content by 43.26%, capsaicin content by 14.82%, DPPH radical scavenging rate by 18.18%, and ABTS radical scavenging rate by 27.81%. Additionally, it significantly reduces selenocysteine methyltransferase (SMT) enzyme activity, while minimally affecting ATP sulfurylase (ATPS) and adenosyl sulfate reductase (APR) enzyme activities. The combined treatment of AMF and 8 mg L⁻1 exogenous selenium has been proven to be the most effective for selenium enrichment in peppers, offering new insights into utilizing exogenous selenium and AMF inoculation to enhance selenium content in peppers.

Duck STING mediates antiviral autophagy directing the interferon signaling pathway to inhibit duck plague virus infection.

Migratory birds are important vectors for virus transmission, how migratory birds recognize viruses and viruses are sustained in birds is still enigmatic. As an animal model for waterfowl among migratory birds, studying and dissecting the antiviral immunity and viral evasion in duck cells may pave a path to deciphering these puzzles. Here, we studied the mechanism of antiviral autophagy mediated by duck STING in DEF cells. The results collaborated that duck STING could significantly enhance LC3B-II/I turnover, LC3B-EGFP puncta formation, and mCherry/EGFP ratio, indicating that duck STING could induce autophagy. The autophagy induced by duck STING is not affected by shRNA knockdown of ATG5 expression, deletion of the C-terminal tail of STING, or TBK1 inhibitor BX795 treatment, indicating that duck STING activated non-classical selective autophagy is independent of interaction with TBK1, TBK1 phosphorylation, and interferon (IFN) signaling. The STING R235A mutant and Sar1A/B kinase mutant abolished duck STING induced autophagy, suggesting binding with cGAMP and COPII complex mediated transport are the critical prerequisite. Duck STING interacted with LC3B through LIR motifs to induce autophagy, the LIR 4/7 motif mutants of duck STING abolished the interaction with LC3B, and neither activated autophagy nor IFN expression, indicating that duck STING associates with LC3B directed autophagy and dictated innate immunity activation. Finally, we found that duck STING mediated autophagy significantly inhibited duck plague virus (DPV) infection via ubiquitously degraded viral proteins. Our study may shed light on one scenario about the control and evasion of diseases transmitted by migratory birds.

Rapid improvement of grain appearance in three-line hybrid rice via CRISPR/Cas9 editing of grain size genes.

KEY MESSAGE: Genetic editing of grain size genes quickly improves three-line hybrid rice parents to increase the appearance quality and yield of hybrid rice. Grain size affects rice yield and quality. In this study, we used CRISPR/Cas9 to edit the grain size gene GW8 in the maintainer line WaitaiB (WTB) and restorer line Guanghui998 (GH998). The new slender sterile line WTEA (gw8) was obtained in the BC2F1 generation by transferring the grain mutation of the maintainer plant to the corresponding sterile line WantaiA (WTA, GW8) in the T1 generation. Two slender restorer lines, GH998E1 (gw8(II)) and GH998E2 (gw8(I)), were obtained in T1 generation. In the early stage, new sterile and restorer lines in grain mutations were created by targeted editing of GS3, TGW3, and GW8 genes. These parental lines were mated to detect the impact of grain-type mutations on hybrid rice yield and quality. Mutations in gs3, gw8, and tgw3 had a minimal impact on agronomic traits except the grain size and thousand-grain weight. The decrease in grain width in the combination mainly came from gw8/gw8, gs3/gs3 increased the grain length, gs3/gs3-gw8/gw8 had a more significant effect on the grain length, and gs3/gs3-gw8/gw8(I) contributed more to grain length than gs3/gs3-gw8/gw8(II). The heterozygous TGW3/tgw3 may not significantly increase grain length. Electron microscopy revealed that the low-chalky slender-grain variety had a cylindrical grain shape, a uniform distribution of endosperm cells, and tightly arranged starch grains. Quantitative fluorescence analysis of endospermdevelopment-related genes showed that the combination of slender grain hybrid rice caused by gs3 and gw8 mutations promoted endosperm development and improved appearance quality. An appropriate grain size mutation resulted in hybrid rice varieties with high yield and quality.

Bioinformatic analysis combined with immune infiltration to explore osteoarthritis biomarkers and drug prediction.

Along with global aging, osteoarthritis (OA) appears to have a high incidence and disability rate, which seriously affects the quality of life of patients, making age a major risk factor. However, the pathology of OA is under-researched, and there is no obvious and effective treatment. Research has demonstrated the importance of aging, inflammation, and immunology in the onset and course of OA. This study aims to anticipate therapeutic drugs based on critical genes associated with OA and to elucidate the roles of genes and possible biomarkers associated with inflammation, immunology, and cellular senescence in OA. The OA gene expression matrix was first obtained from the Gene Expression Omnibus database. Screening for OA significant differentially expressed genes by bioinformatics identification. Specific biological processes and related signaling pathways of the differential genes were enriched. Then elucidate the status of immune cell involvement in OA based on immune infiltration analysis. Finally predict therapeutic agents based on pivotal genes. A total of 198 differentially expressed genes were identified in OA, and TP53, EGFR, TGFB1, LEP, CD4, MAPK8, SCARB1, ADIPOQ, JAK2, and SERPINE1 were further identified as important hub genes. The enrichment results showed that the development of arthritis was mainly related to immune cell differentiation, amino acid metabolism and cellular senescence process. The validation of immune infiltration results indicated that NK_cells, CD4_Tcells, Macrophages, Monocytic_lineage, Dendritic_cells, Basophils, CD8+_naive_T-cells may play an important role in the immune process of OA. Key Drug Prediction of Hub Genes found that Halicin, Ruxolitinib, Tofacitinib, Clenoliximab, Baricitinib may be a key drug or component in the treatment of OA.

Innovative application of basalt fibers as biological carrier in constructed wetland-microbial fuel cell for improvement of performance under perfluorooctanoic acid exposure.

Basalt fiber (BF) was filled in constructed wetland-microbial fuel cell (CW-MFC) as bio-carrier for enhancement of operation performance under perfluorooctanoic acid (PFOA) exposure. In this study, although PFOA caused significant decline of ammonium removal by 7.5-7.7 %, slight promotion on nitrogen and phosphorus removal was observed with BF filling, compared to control. PFOA removal also increased by 1.7-3.4 % in BF filling group. Besides, improved electrochemical performance was discovered with BF filling, in which the highest power density increased by 86.6 % than control, even under PFOA stress. Enhanced stability and performance of CW-MFC resulted from stimulation of functional bacteria on electrodes like Dechloromonas, Thauera, Zoogloea, Gemmobacter, and Pseudomonas, which were further enriched on BF carrier. Higher abundance of nitrogen metabolism and related genes on electrodes and BF carrier was also discovered with BF filling. This study offered new findings on application of BF in CW-MFC systems with PFOA exposure.

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D.

Introduction: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing ß cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear. Objectives: This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset. Methods: The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development. Results: B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9 fl/fl Cd19-Cre+ mice showed delayed diabetes onset, indicating microbiota's impact. Conclusion: B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.

Activation of Nrf2 inhibits atherosclerosis in ApoE-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.

BACKGROUND: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. METHODS: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE-/- mice. RESULTS: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. CONCLUSIONS: Upon HCD feeding in ApoE-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.