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Acute-on-chronic liver failure (ACLF) is a group of clinical syndromes related to severe acute liver function impairment and multiple-organ failure caused by various acute triggering factors on the basis of chronic liver disease. Due to its severe condition, rapid progression, and high mortality, it has received increasing attention. Recent studies have shown that the pathogenesis of ACLF mainly includes direct injury and immune injury. In immune injury, cytotoxic T lymphocytes (CTLs), dendritic cells (DCs), and CD4 + T cells accumulate in the liver tissue, secrete a variety of proinflammatory cytokines and chemokines, and recruit more immune cells to the liver, resulting in immune damage to the liver tissue, massive hepatocyte necrosis, and liver failure, but the key molecules and signaling pathways remain unclear. The “danger hypothesis” holds that in addition to the need for antigens, damage-associated molecular patterns (DAMPs) also play a very important role in the occurrence of the immune response, and this hypothesis is related to the pathogenesis of ACLF. Here, the research status and development trend of ACLF, as well as the mechanism of action and research progress on various DAMPs in ACLF, are summarized to identify biomarkers that can predict the occurrence and development of diseases or the prognosis of patients at an early stage.

MSN8C, an analog of mansonone E, has been identified as a novel catalytic inhibitor of human DNA topoisomerase II that induces tumor regression and differs from VP-16(etoposide). Treatment with MSN8C showed significant antiproliferative activity against eleven human tumor cell lines in vitro. It was particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. The resistance factor (RF) of MSN8C for Topo II in HL-60/MX2 versus HL-60 was 1.7, much lower than that of traditional Topo II poisons. Furthermore, in light of its potent antitumor efficacy and low toxicity, as demonstrated in the A549 tumor xenograft model, MSN8C has been identified as a promising candidate for antitumor applications.

Mucosal immunity plays an important role in the pathogenesis of IgA nephropathy (IgAN). This study aimed to investigate if infection of Helicobacter pylori (H. pylori), a common bacteria in the gastrointestinal tract, associated with IgAN. This study included 261 patients with IgAN and 46 healthy controls. Clinical information and plasma samples were collected from patients and healthy controls. H. pylori infection was confirmed by western blot. Plasma IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were detected by specific enzyme-linked immunosorbent assay. Total H. pylori infection rates showed no statistical differences between IgAN patients and healthy controls, but the infection rates of type I H. pylori in IgAN patients were significantly higher than those in healthy controls (44.4 vs. 28.3%, p = 0.040). Compared with uninfected patients, the systolic blood pressure, 24-h proteinuria, and blood urea nitrogen levels were significantly higher in patients with H. pylori infection (126.0 ± 15.5 vs. 119.6 ± 14.5 mmHg, p = 0.010; 1.8 ± 2.7 vs. 1.2 ± 1.4 g/24h, p = 0.013; 7.9 ± 5.4 vs. 6.7 ± 3.9 μmol/L, p = 0.042), especially in patients with type I infection (126.5 ± 15.4 vs. 119.6 ± 14.5 mmHg, p = 0.002; 1.9 ± 2.9 vs. 1.2 ± 1.4 g/24 h, p = 0.033; 8.1 ± 5.6 vs. 6.7 ± 3.9 μmol/L, p = 0.041). Similarly, patients with IgAN and type I H. pylori infection showed higher plasma Gd-IgA1 levels than uninfected patients (5.5 ± 2.2 vs. 4.5 ± 2.2 μg/mL, p = 0.037). Virulent type I H. pylori infection is more common in patients with IgAN. Patients with IgAN and type I H. pylori infection showed lower renal function and higher underglycosylation of plasma IgA1.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1 . Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3′-UTR of Nf-κb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3′-UTR fragments can be recognized by Rig-I. The 3′-UTR binding with Rig-I plays a critical role in normal translation of Nf-κb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-κb1 and 3′-UTR–mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κB signaling and is involved in multiple biological processes in addition to host antivirus immunity.

C-C chemokine receptor 6 ( CCR6 ) is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN). In this study, we aimed to identify the functional variants. First, we analyzed the associations of CCR6 common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region. Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15, P = 2.00 × 10 −2 ) and the expression quantitative trait loci (eQTL) effect ( P = 1.45 × 10 −3 ). It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10 −3 ) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10 −7 ). Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP , the alleles of rs3093023 (G>A) rather than of CCR6DNP were shown differential nuclear protein binding effect by electrophoretic mobility shift assay. The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated with CCR6 mRNA ( r = −0.60, P = 3.94 × 10 −9 ). At the mRNA level, the eQTL effect of CCR6 was validated ( P = 4.39 × 10 −2 ), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG . At the protein level, a higher CCR6 + cell ratio was observed in a risk allele dose-dependent manner in lymphocytes ( P = 3.57 × 10 −2 ), CD3 + T cells ( P = 4.54 × 10 −2 ), and CD4 + T cells ( P = 1.32 × 10 −2 ), but not in CD8 + T cells. Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis. Overall, the rs3093023 was prioritized as the function variant in CCR6 , which may contribute to IgAN susceptibility by regulating Th17 cells.

RIG-I (retinoid acid-inducible gene-I), a putative RNA helicase with a cytoplasmic caspase-recruitment domain (CARD), was identified as a pattern-recognition receptor (PRR) that mediates antiviral immunity by inducing type I interferon production. To further study the biological function of RIG-I, we generated Rig-I −/− mice through homologous recombination, taking a different strategy to the previously reported strategy. Our Rig-I −/− mice are viable and fertile. Histological analysis shows that Rig-I −/− mice develop a colitis-like phenotype and increased susceptibility to dextran sulfate sodium-induced colitis. Accordingly, the size and number of Peyer's patches dramatically decreased in mutant mice. The peripheral T-cell subsets in mutant mice are characterized by an increase in effector T cells and a decrease in naïve T cells, indicating an important role for Rig-I in the regulation of T-cell activation. It was further found that Rig-I deficiency leads to the downregulation of G protein αi2 subunit (Gαi2) in various tissues, including T and B lymphocytes. By contrast, upregulation of Rig-I in NB4 cells that are treated with ATRA is accompanied by elevated G α i2 expression. Moreover, G α i2 promoter activity is increased in co-transfected NIH3T3 cells in a Rig-I dose-dependent manner. All these findings suggest that Rig-I has crucial roles in the regulation of G α i2 expression and T-cell activation. The development of colitis may be, at least in part, associated with downregulation of G α i2 and disturbed T-cell homeostasis.

Compared with the transmission transformer condition assessment, less data is one of the major problems that limit distribution transformer condition assessment work. This paper intends to solve this problem through reducing state variables dimensionality. First, through analyzing the principle of every state variables of distribution transformer by use of the maximum Eigen-value approach, the core state collection of assessing the distribution transformer is formed and the state variables dimensionality is reducing. Then, the initial results of distribution transformer condition assessment are obtained by using core state variables. Thirdly, the sensitivity of the non-core state variables to the evaluation results is calculated. Finally, the initial assessment result is modified considering the non-core state variables change and the sensitivity to get the final result. Through the above proposed method, the evaluation process need only consider the core state variables and the change of non-core state variables. This method not only reduces the demand for data, but also ensures accuracy of the results using the sensitivity correction. The results of a condition assessment instance of distribution transformer verify the validity of the method.

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-Kb1. Rig-I is required for NF-KB activity via regulating Nf-Kb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-Kb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-Kb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-Kb1 and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-KB signaling and is involved in multiple biological processes in addition to host antivirus immunity. [PUBLICATION ABSTRACT]