Background Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more ...likely to persist into adulthood and more often occurs with other allergic diseases. Objective We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to-severe AD with allergic sensitization. Methods Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks. Results SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance ( P < 2.0 × 10−8 ). These associated SNPs are more than 1 Mb from the closest gene, protocadherin ( PCDH )9. SNPs at 4 additional loci had P values of less than 1 × 10−6 , including SNPs at or near the neuroblastoma amplified sequence ( NBAS ; 2p24.3), thymus-expressed molecule involved in selection ( THEMIS ; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER ( SCAPER ; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 ( PSTPIP1 ), in immune cells. Conclusion Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background The incidence of food allergies has increased dramatically during the last decade. Recently, probiotics have been studied for the prevention and treatment of allergic disease. Objective We ...examined whether Bifidobacterium longum KACC 91563 and Enterococcus faecalis KACC 91532 have the capacity to suppress food allergies. Methods B longum KACC 91563 and E faecalis KACC 91532 were administered to BALB/c wild-type mice, in which food allergy was induced by using ovalbumin and alum. Food allergy symptoms and various immune responses were assessed. Results B longum KACC 91563, but not E faecalis KACC 91532, alleviated food allergy symptoms. Extracellular vesicles of B longum KACC 91563 bound specifically to mast cells and induced apoptosis without affecting T-cell immune responses. Furthermore, injection of family 5 extracellular solute-binding protein, a main component of extracellular vesicles, into mice markedly reduced the occurrence of diarrhea in a mouse food allergy model. Conclusion B longum KACC 91563 induces apoptosis of mast cells specifically and alleviates food allergy symptoms. Accordingly, B longum KACC 91563 and family 5 extracellular solute-binding protein exhibit potential as therapeutic approaches for food allergies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Notably, there was a recent case report on abatacept treatment in an adult with idiopathic autoimmune enteropathy.7 To investigate the molecular effect of the drug, we sampled the patient's blood at ...the trough level (ie, 0 day) and at 1, 4, 6, and 8 days (among these, samples from the trough level and days 4 and 8 were subjected to the fluorescence-activated cell sorting analysis) after the administration of the drug (Fig 2, A-D; for drug treatment details, see the Methods section in this article's Online Repository at www.jacionline.org). Here we report a direct effect of CTLA-4 dysfunction in human; enhancing the CTLA-4-mediated signal with CTLA-4-Ig toned down immune responses in a patient with severe autoimmune features, eventually achieving substantial clinical improvements. ...it would be worthwhile to investigate patients with idiopathic autoimmune features for additional CTLA-4 mutations that may affect proper protein function and use CTLA-4-Ig as a potential therapeutic solution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Recent evidence suggests that prenatal maternal distress increases the risk of allergic diseases in offspring. However, the effect of prenatal maternal depression and anxiety on atopic ...dermatitis (AD) risk remains poorly understood. Objective We investigated whether prenatal maternal distress is associated with AD risk in offspring and whether the mechanism is mediated by reactive oxygen species. Methods Two general population-based birth cohorts formed the study. One cohort (Cohort for Childhood Origin of Asthma and Allergic Diseases COCOA) consisted of 973 mother-baby dyads, and the other (Panel Study on Korean Children PSKC) consisted of 1531 mother-baby dyads. The association between prenatal distress and AD was assessed by using Cox proportional hazards and logistic regression models. In COCOA placental 11β-hydroxysteroid dehydrogenase type 2 and glutathione levels and serum IgE levels in 1-year-old children were measured. Results In COCOA and PSKC AD occurred in 30.6% (lifetime prevalence) and 11.6% (1 year prevalence) of offspring, respectively. Prenatal maternal distress increased the risk of AD in offspring, both in COCOA (hazard ratio for depression, 1.31 95% CI, 1.02-1.69; hazard ratio for anxiety, 1.41 95% CI, 1.06-1.89) and PSKC (odds ratio for distress, 1.85 95% CI, 1.06-3.25). In COCOA both prenatal maternal depression and anxiety scores were positively related to the predicted probability of AD ( P < .001 in both). Prenatal distress decreased placental glutathione to glutathione disulfide ratios ( P = .037) and, especially in those who later had AD, decreased placental 11β-hydroxysteroid dehydrogenase type 2 levels ( P = .010) and increased IgE levels at 1 year of age ( P = .005). Conclusion Prenatal maternal depression and anxiety promote risk of AD in offspring. Maternal distress increases the predicted probability of AD. The mechanism might involve chronic stress, abnormal steroid levels, and reactive oxygen species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to inhibit platelet aggregation. Individual variability of platelet inhibition by ...clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness. In this study, we sought to determine the relation of genetic polymorphisms of CYP genes to clopidogrel resistance in Koreans. Four hundred fifty patients who underwent successful percutaneous coronary intervention with drug-eluting stents were randomly assigned to treatment with dual antiplatelet regimen (aspirin plus clopidogrel) or triple antiplatelet regimen (aspirin plus clopidogrel plus cilostazol). Clopidogrel resistance using VerifyNow P2Y12 assay and genetic analysis were performed in 387 patients. Clopidogrel resistance was found in 112 patients (28.9%). In the clopidogrel-responsive group, there was a significantly higher proportion of cilostazol use. Because cilostazol showed a significant influence on clopidogrel resistance, we examined the association of single-nucleotide polymorphisms and clopidogrel resistance in the dual and triple antiplatelet therapy groups, respectively. In all subjects, the CYP2C19*3A allele was significantly more prevalent in the clopidogrel-resistant group compared with the clopidogrel-responsive group. Multiple logistic regression analysis demonstrated that CYP2C19*3 is an independent predictor of clopidogrel resistance. In conclusion, CYP2C19*3 single-nucleotide polymorphisms is an independent risk factor of clopidogrel resistance in Korean subjects with coronary artery disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Peroxisomes are essential organelles for maintaining the homeostasis of lipids and reactive oxygen species (ROS). While oxidative stress-induced endoplasmic reticulum (ER) stress plays an important ...role in nonalcoholic fatty liver disease (NAFLD), the role of peroxisomes in ROS-mediated ER stress in the development of NAFLD remains elusive. We investigated whether an impaired peroxisomal redox state accelerates NAFLD by activating ER stress by inhibiting catalase, an antioxidant expressed exclusively in peroxisomes. Wild-type (WT) and catalase knockout (CKO) mice were fed either a normal diet or a high-fat diet (HFD) for 11 weeks. HFD-induced phenotype changes and liver injury accompanied by ER stress and peroxisomal dysfunction were accelerated in CKO mice compared to WT mice. Interestingly, these changes were also significantly increased in CKO mice fed a normal diet. Inhibition of catalase by 3-aminotriazole in hepatocytes resulted in the following effects: (i) increased peroxisomal H2O2 levels as measured by a peroxisome-targeted H2O2 probe (HyPer-P); (ii) elevated intracellular ROS; (iii) decreased peroxisomal biogenesis; (iv) activated ER stress; (v) induced lipogenic genes and neutral lipid accumulation; and (vi) suppressed insulin signaling cascade associated with JNK activation. N-acetylcysteine or 4-phenylbutyric acid effectively prevented those alterations. These results suggest that a redox imbalance in peroxisomes perturbs cellular metabolism through the activation of ER stress in the liver.
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•Catalase deficiency accelerates nonalcoholic fatty liver disease (NAFLD) in mice.•Catalase deficiency impairs redox balance of peroxisomes in NAFLD.•Peroxisomal redox imbalance accelerates ER stress-mediated NAFLD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in ...human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Rubicon is part of a Beclin-1-Vps34-containing autophagy complex. Rubicon induces antimicrobial responses upon Toll-like receptor (TLR) stimulation and functions as a feedback inhibitor to prevent ...unbalanced proinflammatory responses depending on dectin-1 signaling. However, the role played by Rubicon during antiviral immune responses, particularly the type I interferon (IFN) responses, remains largely unknown. Here, we report that Rubicon acts as a negative regulator for virus-triggered IFN signaling. Knockdown of Rubicon promoted type I interferon signaling and inhibited virus replication, while overexpression of Rubicon had the opposite effect. Rubicon specifically interacts with the interferon regulatory factor (IRF) association domain (IAD) of IRF3, and this interaction leads to inhibition of the dimerization of IRF3, which negatively regulates IFN-mediated antiviral response. Thus, our findings suggest the novel additional role of Rubicon as a negative regulator that inhibits the IFN signaling and cellular antiviral responses, providing a novel cellular mechanism of IRF3 inhibition.
The type I IFN system is a critical innate immune response that protects organisms against virus infection. However, type I IFN signaling must be tightly regulated to avoid excessive production of IFNs. Hence, negative regulatory mechanisms for type I IFN signaling are important, and to date, several related molecules have been identified. Here, we show that Rubicon is a major negative regulator of type I IFN signaling, and unlike previous reports of cellular molecules that inhibit IRF3 activation via proteasomal degradation or dephosphorylation of IRF3, we show that Rubicon interacts with IRF3 and that ultimately this interaction leads to inhibition of the dimerization of IRF3. Thus, we identified a novel negative regulator of type I IFN signaling pathways and a novel cellular mechanism of IRF3 inhibition. The results of this study will increase our understanding of the role of negative-feedback mechanisms that regulate type I IFN signaling and maintain immune homeostasis.
...the patient experienced sudden left leg weakness and headache. ...at a baseline level, the mutant STING proteins barely displayed any IFN-β promoter activity, whereas the V147L mutation showed ...increased activity even without cGAMP (Fig 2, B and C). Patient ID Liu et al, 2014E7 Jeremiah et al, 2014E8 Munoz et al, 2015E9 Chia et al, 2016E10 Current study N1 N2 N3 N4 N5 N6 J1 J2 J3 J4 A1 - - Inheritance pattern Unrelated Familial - - - Sex (M/F) M F M F F M M M M F M M M Variant origin De novo NA Inherited De novo - De novo (two) Variant c.439G>C, p.Val147Leu c.461A>G, p.Asn154Ser c.463G>A, p.Val155Met c.463G>A, p.Val155Met c.439G>C, p.Val147Leu c.461A>G, p.Asn154Ser c.304T>C, p.Ser102Pro & c.835T>C, p.Phe279Leu Age of onset Infancy (8 wk) Adulthood Teenager Teenager Infancy Infancy Infancy Childhood (3 years) Status at last follow-up Alive Alive Alive Alive Dead Dead Alive Dead Alive Alive Alive Alive Alive Rash or Tachypnea + + + + + + − + + + + + + Gangrene of finger/toe 4/6 NA + + + Lung disease 5/6 − + + + + + + CNS vessel involvement Not reported Not reported Not reported Not reported + Table E4Primers used in this study Primer name Primer sequences Primer name Primer sequences TMEM173_S102P_F 5′-AGGAGGATGTTCAGTGCCTG-3′ TMEM173_S102P_R 5′-GGGTATCCAACGTGTGTCAC-3′ TMEM173_F279L_F 5′-ATCAACCCCTCACCCTACCA-3′ TMEM173_F279L_R 5′-GTTACAGGCTGAGGGAGTGG-3′ MYO18A_A1729V_F 5′-CTGTCTAGGGTGAAGGGAGC-3′ MYO18A_A1729V_R 5′-TCTTTCCTGTACAGCCCTCC-3′ BBS1_R196W_F 5′-AGAATGATGGAGGAGGGCAG-3′ BBS1_R196W_R 5′-TGGAAGTCACTGCAGCTTTA-3′ MMP13_I165N_F 5′-CCAGGAGTACTTAGCACAGGT-3′ MMP13_I165N_R 5′-GCCTTCAAAGTTTGGTCCGA-3′ BRWD3_G1286Q_F 5′-TTCTCCAGACTCTGCCTGTG-3′ BRWD3_G1286Q_F 5′-TTGTTCTACTTGCTGCTCCA-3′ IFN-β_qPCR_F 5′-AAACTCATGAGCAGTCTGCA-3′ IFN-β_qPCR_R 5′-AGGAGATCTTCAGTTTCGGAGG-3′ References 1 G.N. Barber, STING: infection, inflammation...
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
The ongoing coronavirus disease 2019 (COVID‐19) pandemic has spurred rapid development of vaccines as part of the public health response. However, the general strategy used to construct ...recombinant trimeric severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike (S) proteins in mammalian cells is not completely adaptive to molecular farming. Therefore, we generated several constructs of recombinant S proteins for high expression in Nicotiana benthamiana. Intramuscular injection of N. benthamiana‐expressed Sct vaccine (NSctVac) into Balb/c mice elicited both humoral and cellular immune responses, and booster doses increased neutralizing antibody titres. In human angiotensin‐converting enzyme knock‐in mice, two doses of NSctVac induced anti‐S and neutralizing antibodies, which cross‐neutralized Alpha, Beta, Delta and Omicron variants. Survival rates after lethal challenge with SARS‐CoV‐2 were up to 80%, without significant body weight loss, and viral titres in lung tissue fell rapidly, with no infectious virus detectable at 7‐day post‐infection. Thus, plant‐derived NSctVac could be a candidate COVID‐19 vaccine.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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