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Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against the glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and severe alveolar hemorrhage. The noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, contains the main target autoantigen in this disease. Epitope mapping studies of α3(IV)NC1 have identified several nephritogenic epitopes and critical residues that bind to autoantibodies and trigger anti-GBM disease. The discovery of novel target antigens has revealed the heterogeneous nature of this disease. In addition, both epitope spreading and mimicry have been implicated in the pathogenesis of anti-GBM disease. Epitope spreading refers to the development of autoimmunity to new autoepitopes, thus worsening disease progression, whereas epitope mimicry, which occurs via sharing of critical residues with microbial peptides, can initiate autoimmunity. An understanding of these autoimmune responses may open opportunities to explore potential new therapeutic approaches for this disease. We review how current advances in epitope mapping, identification of novel autoantigens, and the phenomena of epitope spreading and mimicry have heightened the understanding of autoimmunity in the pathogenesis of anti-GBM disease, and we discuss prospects for immunotherapy.

In this study, a novel low molecular weight polysaccharide (named LMW-BSP) was extracted from Bletilla striata at 4 °C. The results of structural characteristics analysis showed that LMW-BSP was a 23 kDa neutral polysaccharide contained glucose and mannose at a molar ratio of 1.00:1.26. Structural investigations of the periodate oxidation studies, Smith-degradation as well as methylation were performed, and combined with 1D and 2D NMR spectroscopy, the main chain residues sequence of LMW-BSP was concluded to be: α-D-Manp-(1 → 3)-β-D-Manp-(1 → [4)-β-D-Glcp-(1]

Background The combination of anti-glomerular basement membrane (GBM) disease and immunoglobulin A nephropathy (IgAN) has been well documented in sporadic cases, lacking overall assessment in large collections. Herein, we investigated the clinical and immunological characteristics and outcome of this entity. Methods 75 consecutive patients with biopsy-proven anti-GBM disease from March 2012 to March 2020 were screened. Among them, patients with concurrent IgAN were identified and enrolled. The control group included biopsied classical anti-GBM patients during the same period, excluding patients with IgAN, other glomerular diseases or tumors, or patients with unavailable blood samples and missing data. Serum IgG and IgA autoantibodies against GBM were detected by enzyme-linked immunosorbent assay, as were circulating IgG subclasses against GBM. Results 15 patients with combined anti-GBM disease and IgAN were identified, accounting for 20% (15/75) of all patients. Among them, nine were male and six were female, with an average age of 46.7±17.3 years. Thirty patients with classical anti-GBM disease were enrolled as controls, with 10 males and 20 females at an average age of 45.4±15.3 years. Patients with combined anti-GBM disease and IgAN had restricted kidney involvement without pulmonary hemorrhage. Compared with classical patients, anti-GBM patients with IgAN presented with significantly lower levels of serum creatinine on diagnosis (6.2±2.9 v.s. 9.5±5.4mg/dl, P = 0.03) and less occurrence of oliguria/anuria (20%, 3/15 v.s. 57%, 17/30, P = 0.02), but more urine protein excretion [2.37(1.48,5.63) v.s. 1.11(0.63,3.90) g/24h, P = 0.01]. They showed better kidney outcome during follow-up (ESKD: 47%, 7/15 v.s. 80%, 24/30, P = 0.03). The autoantigen and epitope spectrum were comparable between the two groups, but the prevalence of circulating anti-α3(IV)NC1 IgG1(67% v.s. 97%, P = 0.01) and IgG3(67% v.s. 97%, P = 0.01) were lower in patients with IgAN. Conclusions Concurrent IgAN was not rare in anti-GBM disease. Patients showed milder kidney lesions and better recovery after immunosuppressive therapies. It might be partly explained by lower prevalence of anti-GBM IgG1 and IgG3 in these patients.

Background Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. Methods A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. Results Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. Conclusions Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.

In the modeling approach of Jupiter’s radiation belt, the accurate calculation of magnetic coordinates from geographic coordinates is the basis. In the previous studies, the L-shell parameters are always calculated based on the assumption of a dipole field though the accuracy of this method is low. We present a new L-shell calculation method based on the magnetic field lines tracing method and ANN (Artificial Neural Network). In this method, a compromise between calculation accuracy and speed is achieved. This method consists of a classifier and a predictor. The Classifier is a BP (Back Propagation) ANN based on AdaBoost algorithm and the Predictor is a BP ANN optimized by GA (Genetic Algorithm). The Classifier is used to identify whether the coordinates are within Jupiter’s inner magnetosphere. If so, the Predictor is used to calculate the L-shell parameters. The error rates of the Classifier and the Predictor are 3 and 7%, relatively. In an example of the Juno’s orbit, the calculation speed of this ANN-based method is about 3 orders higher than that based on the magnetic field lines tracing method.

In this study, to develop new advanced corrosion inhibitors with high corrosion inhibition efficiency at low concentration, a simple but effective strategy that is the adjustment of bridge heteroatoms in a mixed corrosion inhibitor named 2-(n-hexylamino)-4-(3-N,N-dimethylaminopropyl)amino-6-(2-aminobenzimidazol)-1,3,5-s-triazine (BDCT) was used to improve the anti-corrosive properties. Two series of new compounds were designed by adjusting three bridge N atoms in BDCT by different number of O and S atoms at three different positions. The molecular structures and different kinds of anti-corrosive properties of 14 designed compounds were investigated by the DFT and MD methods. The results showed that when compared to BDCT, the molecular area, electrophilicity, electronegativity, strength of feed-back bonding, softness, chemical reactivity and binding energy on the Fe(110) surface were improved obviously by the introduced bridge O and S atoms, leading to higher corrosion inhibition efficiency. This effect could be further enhanced with the increased number of them, and S atoms were found to better than O atoms obviously. The introduction positions of O and S atoms also made effects on anti-corrosive properties, introducing them at the R1 position was more helpful for improving anti-corrosive properties than R2 than R3. As a result, the compound with three bridge S atoms (B7) has the best anti-corrosive properties. The adsorption sites, type of bonding with metals and corrosion inhibition mechanism of BDCT were also changed completely by O and S atoms.

Transformer is one of the most important pieces of equipment in power system. The insulation aging and lifespan of transformer are significantly affected by hot spot distributions of internal components inside. In the present paper, the electromagnetic losses of different components and heat transfer process in a three-phase forced oil circulation transformer (400 kVA-15 kV/400 V) are numerically studied with finite element method. The leakage magnetic flux and eddy current loss density for metal components and oil tank are carefully analyzed, and the effect of metal components’ electromagnetic loss on hot spot temperature of different components and oil flow in transformer is also studied. It is found that the surface current of metal components is generated by leakage magnetic flux, and surface current density is large when leakage magnetic flux concentrates. The effect caused by relative magnetic permeability of metal components is remarkable on electromagnetic loss of metal components and oil tank, while the effect caused by relative magnetic permeability of transformer tank is relatively small. Due to the mixing of metal components on oil flow, the heat transfer of core is enhanced, its hot spot temperature is lowered, and the hot spot locations of coil and core also change. These results are meaningful for further understanding of heat transfer process in transformer and important for the optimal design of transformer.

Background Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. Methods To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. Results On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice. Conclusions Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.

Background: Ovarian cancer (OC) is the most pathogenic gynecological malignant tumor in the world. Due to the difficulty of early diagnosis, most of patients developed chemo-resistance and recurrence during/after the chemotherapy. Cylindromatosis (CYLD) is one member of lysine 63 deubiquitinases, and the regulatory mechanism of CYLD in mediating cisplatin (DDP) resistance need to be elucidated.Methods: Database analysis indicated that CYLD was associated with tumor development and prognosis; Patient tumor samples and clinicopathological characteristics were used to study the clinical significance of CYLD. Molecular biological methods were used to verify the function of CYLD in chemo-resistance with the parental and drug resistant cell lines (A2780/ A2780-DDP, OVCAR3/OVCAR3-DDP). Then flow cytometry analysis, co-IP and ChIP analysis were conducted to identify the upstream regulators and downstream effectors of CYLD; The drug combination method was used to investigate the drug synergistic effect of cisplatin combination with ABCB1 inhibitor or HER3 inhibitor. Animal models were further used to verify the role of CYLD in cancer chemo-resistance.Results: The expression levels of CYLD were downregulated in pan-cancer, especially in ovarian cancer, leading to acceleration of tumor progression and cisplatin resistance. CYLD knockdown in the parental cells was sufficient to induce DDP resistance through inhibiting cell apoptosis and promoting the drug efflux via inducing the expression of ABCB1. HER3 expression levels were much higher in the resistant cells, and HER3 was the upstream mediator for CYLD suppression through STAT3 signaling. Moreover, overexpression of CYLD in the resistant cells was sufficient to promote sensitivity to platinum-based treatment both in vitro and in vivo. ABCB1 was a functional downstream target of CYLD to regulate tumor growth and drug resistance both in vitro and in vivo.Conclusions: In this study, the results demonstrated that higher HER3 expression rendered CYLD suppression, consequently, increased cisplatin resistance and induced poor prognosis by inhibiting cell apoptosis and promoting the drug efflux in OC. Our findings showed that HER3/CYLD/ABCB1 is a new signaling pathway to regulate tumor growth and DDP resistance, which are potential new therapeutic targets to overcome DDP resistance.

Ovarian cancer (OC) is a malignant tumor that seriously threatens women's health. Due to the difficulty of early diagnosis, most patients exhibit advanced disease or peritoneal metastasis at diagnosis. We discovered that IFFO1 is a novel tumor suppressor, but its role in tumorigenesis, development and chemoresistance is unknown. In this study, IFFO1 levels were downregulated across cancers, leading to the acceleration of tumor development, metastasis and/or cisplatin resistance. Overexpression of IFFO1 inhibited the translocation of β-catenin to the nucleus and decreased tumor metastasis and cisplatin resistance. Furthermore, we demonstrated that IFFO1 was regulated at both the transcriptional and posttranscriptional levels. At the transcriptional level, the recruitment of HDAC5 inhibited IFFO1 expression, which is mediated by the transcription factor YY1, and the METTL3/YTHDF2 axis regulated the mRNA stability of IFFO1 in an m6A-dependent manner. Mice injected with IFFO1-overexpressing cells had lower ascites volumes and tumor weights throughout the peritoneal cavity than those injected with parental cells expressing the vector control. In conclusion, we demonstrated that IFFO1 is a novel tumor suppressor that inhibits tumor metastasis and reverses drug resistance in ovarian cancer. IFFO1 was downregulated at both the transcriptional level and posttranscriptional level by histone deacetylase and RNA methylation, respectively, and the IFFO1 signaling pathway was identified as a potential therapeutic target for cancer.

Introduction: Anti-glomerular basement membrane (GBM) disease is a rare but the most aggressive form of glomerulonephritis. To dissect the prognostic factors, we retrospectively analyzed the clinical features of a large cohort and compared the clinical features and prognosis during decades. Methods: Data on clinical manifestation, treatment, and prognosis were collected. Cox models and receiver operating characteristic (ROC) curve were used to investigate the predictors for outcomes. The Kaplan-Meier curve and log-rank test were used to compare kidney and patient survival. Results: A total of 448 patients were enrolled. Patient survival and kidney survival at 1 year was 69.4% and 37.7%, respectively. During the past 3 decades, mortality at 3 months and 1 year significantly dropped from 37.5% and 57.1% in 1991–2000 to 2.8% and 6.9% in 2011–2020 (p < 0.001), respectively; kidney prognosis showed a tendency of improvement as well. Serum creatinine (Scr) on diagnosis (HR, 1.16; 95% CI, 1.05–1.29) and crescent percentage (HR, 1.73; 95% CI, 1.34–2.24) were independent predictors for end-stage kidney disease. ROC curve showed that the optimal cutoff point of Scr on diagnosis for prediction of dialysis dependency at 1 year was 536.4 μmol/L (sensitivity 88.3% and specificity 80.8%). Antineutrophil cytoplasmic antibodies (ANCAs) positivity (HR, 4.43; 95% CI, 1.72–11.38) was a predictor for mortality. Plasma exchange was associated with a better patient prognosis (HR, 0.40; 95% CI 0.16–0.95). Conclusion: Scr on diagnosis and percentage of crescents were predictors for kidney outcomes. Positive ANCA was a predictor for mortality. Overall patient prognosis of anti-GBM disease was improved during the past 3 decades.

A new solar electron event model is developed based on Virtual Timeline Method (VTM). We study events individually by analyzing the 17-year data of 3DP instrument on WIND spacecraft. This model is established in different solar cycle phases and is based on statistics of duration, fluence, and waiting time of solar electron events. The fluences follow a log-normal distribution and logarithmic durations fit well with logarithmic fluences linearly. We prove that waiting times of events significantly deviates from the Poisson process by investigating the stationary and event independence property of Poisson distribution. After a comparison study on waiting times, we choose the Levy distribution in solar minimum and maximum years. During solar minimum, the event frequency is much lower than that of solar maximum, but the event magnitude is independent of solar cycle period. Large events also happen in solar minimum years. In different solar cycle phases, this model can output a spectrum with confidence level and mission duration by generating many series of virtual timelines composed of many pseudo-events based on Monte Carlo method. On the other hand, spectra in solar minimum years are softer than that in solar maximum years. The fluences in solar maximum years are about one order of magnitude higher than that in solar minimum years in a given mission period. We also compare this model with Interplanetary Electron Model (IEM) quantitatively and prove that this model is advanced.

The major epitopes recognized by autoantibodies in anti-glomerular basement membrane (GBM) disease are found in the α3-subunit non-collagenous domain of type IV collagen [α3(IV)NC1], which is present in the glomerular and alveolar basement membranes. These epitopes are structurally cryptic, owing to the hexamer formation of the non-collagenous domain of α3, α4, and α5 subunits and are expressed by the dissociation of the hexamer. Anti-GBM disease usually manifests as a single attack (SA), and we rarely see patients who repeatedly relapse. We recently treated a patient with anti-GBM disease who exhibited repeated relapse (RR). Here, we conducted immunohistochemistry of formalin-fixed paraffin-embedded normal kidney sections and immunoblotting using recombinant human α3(IV)NC1 to compare the epitopes recognized by anti-GBM antibodies in the RR patient and SA patients. Although a clear staining of GBM especially in the connecting basement membrane of Bowman's capsule was observed when IgGs of SA patients were used as primary antibodies, such staining was not obtained when IgG of the RR patient was employed. In immunoblotting of α3(IV)NC1 using the IgG of the RR patient as a primary antibody, an 18-kDa band was detected besides the 56.8-kDa band corresponding to the whole-size α3(IV)NC1. Whereas the 56.8-kDa band disappeared after digestion of the recombinant α3(IV)NC1 by protease, the 18-kDa band remained. Furthermore, the 18-kDa band was not detected by a commercially available anti-α3(IV)NC1 monoclonal antibody. These findings suggest that the IgG of the RR patient recognizes the epitope distinct from that recognized by the anti-α3(IV)NC1 monoclonal antibody.

BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3(127–148) as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. METHODS: To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. RESULTS: On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3(127–148). Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3(127–148). B7 induced T cell activation from human α3(127–148)-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7’s pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3(135–145)-immunized mice. CONCLUSIONS: Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.

An improved model for device proton SEU cross section simulation is established totally based on heavy ion test data. The model is deduced from the assumption that an injecting heavy ion with a certain LET value will just generate a SEU cross section value corresponding to the LET value at the heavy ion test data. Based on the assumption, the model has special sub-volume collection efficiency, which makes the SEU cross section simulation result through the model independent of critical charge (Qcrit). The modeling method is verified by heavy ion and proton test data of Xilinx XC2V1000 and XC4VSX55 FPGA. The difference of proton SEU cross section between simulation result and test data is less than 69% above 40 MeV of proton.

AIM Anti-glomerular basement membrane (GBM) disease is an autoimmune disorder with rapidly progressive glomerulonephritis and alveolar haemorrhage. Fever symptoms and prodromal infections have been reported in many cases, but still not been elucidated. METHODS Our study enrolled 140 consecutive patients with anti-GBM disease and retrospectively analyzed the characteristics of fever symptoms and the possible reasons. RESULTS Among the 140 patients, 94 (67.1%) patients presented with fever (over 37.5°C) prior to admission or within 48 h of hospitalization. Among those with fever, 74 (78.7%) patients had infections, 15 (16.0%) patients had positive serum anti-neutrophil cytoplasmic antibodies, all towards myeloperoxidase, which was comparable to the patients without fever (17.4%, P = 0.830). There were 93/140 patients suffered from infections, with 47.3% in lungs and 31.2% on upper respiratory tract. In some cases, we identified the microbes of infections, including Candida albicans, Escherichia coli, Acinetobacter baumannii, Enterococcus faecalis, Klebsiella pneumoniae, Hemolytic staphylococci, Pseudomonas aeruginosa and Citrobacter braakii. Patients with fever had higher levels of serum anti-GBM antibodies (154.9 ± 58.4 vs. 106.0 ± 63.2 IU/mL, P < 0.001), higher serum creatinine (733.4 ± 402.5 vs. 580.6 ± 368.1 μmol/L, P = 0.032), higher percentage of crescents (87.0 ± 15.6 vs. 67.4 ± 37.6%, P = 0.021), and higher frequency of progression to end stage renal disease (ESRD) (80.9% vs. 60.9%, P = 0.011). CONCLUSION We concluded that fever is a common symptom in anti-GBM disease and associates with more severe glomerulonephritis. The majority of patients at presentation had fever with respiratory tract infections, which needs further investigation to reveal their role in the pathogenesis of anti-GBM disease.