TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans.Trex1−/−
...mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation ofcGasinTrex1−/−
mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele ofcGaslargely rescued the phenotypes ofTrex1−/−
mice. Similarly, deletion ofcGasin mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of theDNaseII−/−
mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases inTrex1−/−
andDNaseII−/−
mice and suggest that inhibition of cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Recent achievement in genetics and epigenetics has led to the exploration of the pathogenesis of systemic lupus erythematosus (SLE). Identification of differentially expressed genes and their ...regulatory mechanism(s) at whole-genome level will provide a comprehensive understanding of the development of SLE and its devastating complications, lupus nephritis (LN).
We performed whole-genome transcription and DNA methylation analysis in PBMC of 30 SLE patients, including 15 with LN (SLE LN(+)) and 15 without LN (SLE LN(-)), and 25 normal controls (NC) using HumanHT-12 Beadchips and Illumina Human Methy450 chips. The serum proinflammatory cytokines were quantified using Bio-plex Human Cytokine 27-plex assay. Differentially expressed genes and differentially methylated CpG were analyzed with GenomeStudio, R, and SAM software. The association between DNA methylation and gene expression were tested. Gene interaction pathways of the differentially expressed genes were analyzed by IPA software.
We identified 552 upregulated genes and 550 downregulated genes in PBMC of SLE. Integration of DNA methylation and gene expression profiling showed that 334 upregulated genes were hypomethylated, and 479 downregulated genes were hypermethylated. Pathway analysis on the differential genes in SLE revealed significant enrichment in interferon (IFN) signaling and toll-like receptor (TLR) signaling pathways. Nine IFN- and seven TLR-related genes were identified and displayed step-wise increase in SLE LN(-) and SLE LN(+). Hypomethylated CpG sites were detected on these genes. The gene expressions for MX1, GPR84, and E2F2 were increased in SLE LN(+) as compared to SLE LN(-) patients. The serum levels of inflammatory cytokines, including IL17A, IP-10, bFGF, TNF-α, IL-6, IL-15, GM-CSF, IL-1RA, IL-5, and IL-12p70, were significantly elevated in SLE compared with NC. The levels of IL-15 and IL1RA correlated with their mRNA expression. The upregulation of IL-15 may be regulated by hypomethylated CpG sites in the promotor region of the gene.
Our study has demonstrated that significant number of differential genes in SLE were involved in IFN, TLR signaling pathways, and inflammatory cytokines. The enrichment of differential genes has been associated with aberrant DNA methylation, which may be relevant to the pathogenesis of SLE. Our observations have laid the groundwork for further diagnostic and mechanistic studies of SLE and LN.
Objective
Systemic lupus erythematosus (SLE) is characterized by the production of antibodies against self antigens. However, the events underlying autoantibody formation in SLE remain unclear. This ...study was undertaken to investigate the role of plasma autoantibody levels, microbial translocation, and the microbiome in SLE.
Methods
Plasma samples from 2 cohorts, one with 18 unrelated healthy controls and 18 first‐degree relatives and the other with 19 healthy controls and 21 SLE patients, were assessed for autoantibody levels by autoantigen microarray analysis, measurement of lipopolysaccharide (LPS) levels by Limulus amebocyte assay, and determination of microbiome composition by microbial 16S ribosomal DNA sequencing.
Results
First‐degree relatives and SLE patients exhibited increased plasma autoantibody levels compared to their control groups. Parents and children of lupus patients exhibited elevated plasma LPS levels compared to controls (P = 0.02). Plasma LPS levels positively correlated with plasma anti–double‐stranded DNA IgG levels in first‐degree relatives (r = 0.51, P = 0.03), but not in SLE patients. Circulating microbiome analysis revealed that first‐degree relatives had significantly reduced microbiome diversity compared to their controls (observed species, P = 0.004; Chao1 index, P = 0.005), but this reduction was not observed in SLE patients. The majority of bacteria that were differentially abundant between unrelated healthy controls and first‐degree relatives were in the Firmicutes phylum, while differences in bacteria from several phyla were identified between healthy controls and SLE patients. Bacteria in the Paenibacillus genus were the only overlapping differentially abundant bacteria in both cohorts, and were reduced in first‐degree relatives (adjusted P Padj = 2.13 × 10−12) and SLE patients (Padj = 0.008) but elevated in controls.
Conclusions
These results indicate a possible role of plasma microbial translocation and microbiome composition in influencing autoantibody development in SLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Superhydrophobic surfaces have great potential for application in self-cleaning and oil/water separation. However, the large-scale practical applications of superhydrophobic coating surfaces are ...impeded by many factors, such as complicated fabrication processes, the use of fluorinated reagents and noxious organic solvents and poor mechanical stability. Herein, we describe the successful preparation of a fluorine-free multifunctional coating without noxious organic solvents that was brushed, dipped or sprayed onto glass slides and stainless-steel meshes as substrates. The obtained multifunctional superhydrophobic and superoleophilic surfaces (MSHOs) demonstrated self-cleaning abilities even when contaminated with or immersed in oil. The superhydrophobic surfaces were robust and maintained their water repellency after being scratched with a knife or abraded with sandpaper for 50 cycles. In addition, stainless-steel meshes sprayed with the coating quickly separated various oil/water mixtures with a high separation efficiency (>93%). Furthermore, the coated mesh maintained a high separation efficiency above 95% over 20 cycles of separation. This simple and effective strategy will inspire the large-scale fabrication of multifunctional surfaces for practical applications in self-cleaning and oil/water separation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Autoimmunity has emerged as a characteristic of the post-COVID syndrome (PCS), which may be related to sex. In order to further investigate the relationship between SARS-CoV-2 and autoimmunity in ...PCS, a clinical and serological assessment on 100 patients was done. Serum antibody profiles against self-antigens and infectious agents were evaluated by an antigen array chip for 116 IgG and 104 IgM antibodies. Thirty pre-pandemic healthy individuals were included as a control group. The median age of patients was 49 years (IQR: 37.8 to 55.3). There were 47 males. The median post-COVID time was 219 (IQR: 143 to 258) days. Latent autoimmunity and polyautoimmunity were found in 83% and 62% of patients, respectively. Three patients developed an overt autoimmune disease. IgG antibodies against IL-2, CD8B, and thyroglobulin were found in more than 10% of the patients. Other IgG autoantibodies, such as anti-interferons, were positive in 5-10% of patients. Anti-SARS-CoV-2 IgG antibodies were found in > 85% of patients and were positively correlated with autoantibodies, age, and body mass index (BMI). Few autoantibodies were influenced by age and BMI. There was no effect of gender on the over- or under-expression of autoantibodies. IgG anti-IFN-λ antibodies were associated with the persistence of respiratory symptoms. In summary, autoimmunity is characteristic of PCS, and latent autoimmunity correlates with humoral response to SARS-CoV-2.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
In this study, pre‐gelatinized highland barley flour (PHBF), pre‐gelatinized sweet potato starch (PSPS), wheat gluten (WG), and egg white protein (EWP) were used to develop highland barley ...noodles. Their effects on noodle quality were analysed, and then noodle formula optimization was carried out based on them. Changes in quality characteristics and intermolecular structure were analysed to explore the underlying mechanism. PHBF, PSPS, WG, and EWP influence the quality characteristics of HB noodles from diverse angles. After formula optimization, noodles with improved cooking and textural properties were obtained, in which HBF accounts for 93.0% of the composite flour and can be categorised as low expected glycemic index (eGI) foods. The viscosity and elasticity of the dough both improved; a more stable protein structure and enhanced starch structure were formed; and increased intermolecular forces were observed, which would contribute to the enhanced protein cross‐linking, structural order, and textural properties of noodles.
Development of noodles with high highland barley flour incorporation level with proteins and pre‐gelatinized flour/starch.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of ...transforming growth factor beta 1 (TGF-β1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-β1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.
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•Treg cell-derived TGF-β1 regulates mast cell and IgE responses•Treg cell-derived TGF-β1 drives the differentiation of ROR-γt+ Treg cells during weaning•Haploinsufficiency of Tgfb1 in Treg cells dysregulates the allergic response•Biallelic deletion of Tgfb1 in Treg cells precipitates lethal autoimmunity
The cytokine TGFβ-1 is implicated in controlling allergic and autoimmune responses; however, the specific role of regulatory T (Treg) cell-derived TGF-β1 in governing these responses has been unclear. Turner et al. demonstrate that Treg cell-derived TGF-β1 is critical for restraining allergic and autoimmune diseases in a gene dose-dependent manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation ...profiling, a LASSO model to develop a five-CpG-based assay for ccRCC prognosis that can be used with formalin-fixed paraffin-embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96-4.82; P=3.9 × 10(-6)-2.2 × 10(-9)), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual 'stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system.
•The N,Cl-CDs show high sensitivity and selectivity towards curcumin sensing.•The sensing mechanism was based on a synergistic effect dynamic quenching and IFE.•The fluorescence method was used for ...curcumin detection in food samples.
In this work, a novel simple, fast, selective and inexpensive fluorescence method for the determination of curcumin based on the fluorescence quenching of nitrogen and chlorine dual-doped carbon nanodots (N,Cl-CDs) was for the first time presented. The N,Cl-CDs were fastly and greenly produced by simply mixing glucose, 1,2-ethylenediamine (EDA) and hydrochloric acid (HCl). The fluorescence of N,Cl-CDs was significantly quenched by curcumin via a synergistic effect of dynamic quenching and inner filter effect (IFE). The N,Cl-CDs shows high selectivity and sensitivity towards curcumin sensing, achieving a linear range of 0.1–35 μM and a limit of detection (LOD) as low as 38 nM. The proposed fluorescence method was successfully utilized for curcumin detection in food samples with recoveries in a range of 96.8–106.1%. The findings of this study suggest the feasibility and usefulness of N,Cl-CDs as an effective fluorescence probe for the determination of curcumin in complex food matrix.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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