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Background: To make early prediction of immunoglobulin A nephropathy (IgAN) before renal biopsy, we developed and validated a new non-invasive nomogram for the early prediction of IgAN in primary glomerulonephritis (GN) in south China. Methods: A total of 431 patients were included in this study and additional 113 patients were included as the independent test cohorts to validate our results. A stepwise regression model was used for features selection. Multivariate logistic regression analysis with 5-fold cross validation was used to validate the result of the stepwise selection. Performance of the logistic regression model was assessed with respect to its calibration, discrimination, and clinical usefulness. Independent test was assessed. Results: We developed a model incorporating age of patients and four clinical chemistry signatures, including serum IgA, serum albumin (ALB), serum phosphorus (P) and 24-hour urinary protein (24hUpro) and presented with a nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) reached 0.89 (95% CI: 0.86–0.92) and 0.88 (95%: 0.85-0.92) in the training set and validation set, respectively. The model also had good performance in independent test cohorts (AUC of 0.82, 95% CI: 0.75–0.90). The DCA and calibration plot of the model also shows good performance. Conclusions: The logistic regression model presented in this study incorporates age of patients, IgA, ALB, P and 24hUpro and can be conveniently used to facilitate the individualized prediction of IgAN.

Objectives Genetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. Methods The present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages. Results The Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy‐associated protein LC3‐II production in Mtb‐infected macrophages. circTRAPPC6B‐enhanced autophagy aggregation or sequestration was also observed in fluorescence in situ hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR‐874‐3p, as shown by bioinformatics, dual‐luciferase reporter gene analysis and pull‐down assay, respectively. Notably, miR‐874‐3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3′‐untranslated region (UTR) in Mtb‐infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb‐infected macrophages by blocking the ability of miR‐874‐3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of miR‐874‐3p to suppress ATG16L1 expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages. Conclusion The current findings suggested that both circTRAPPC6B and miR‐874‐3p mechanisms can be explored as potential therapeutics against Mtb infection.

IL-35 is an anti-inflammatory cytokine and is thought to be produced by regulatory T (Treg) cells. A previous study found that IL-35 was upregulated in the serum of patients with active tuberculosis (ATB), and IL-35-producing B cells infiltrated to tuberculous granuloma of patients with ATB. Purified B cells from such patients generated more IL-35 after stimulation by antigens of Mycobacterium tuberculosis and secreted more IL-10. However, the function and the underlying mechanisms of IL-35-producing B cells in TB progression have not been investigated. The present study found that the expression of mRNA of IL-35 subsets Ebi3 and p35 was elevated in mononuclear cells from peripheral blood, spleen, bone marrow, and lung tissue in a mouse model infected with Mycobacterium bovis BCG, as tested by real-time polymerase chain reaction. Accordingly, the flow cytometry analysis showed that the counts of a subset of IL-35+ B cells were elevated in the circulating blood and in the spleen, bone marrow, and lung tissue in BCG-infected mice, whereas anti-TB therapy reduced IL-35-producing B cells. Interestingly, BCG infection could drive the infiltration of IL-35-producing B cells into the lung tissue, and the elevated counts of IL-35-producing B cells positively correlated with the bacterial load in the lungs. Importantly, the injection of exogenous IL-35 stimulated the elevation in the counts of IL-35-producing B cells and was associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg.The study showed that a subset of IL-35-producing B cells might take part in the downregulation of immune response in mycobacterial infection.

Objectives Genetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. Methods The present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages. Results The Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy‐associated protein LC3‐II production in Mtb‐infected macrophages. circTRAPPC6B‐enhanced autophagy aggregation or sequestration was also observed in fluorescence in situ hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR‐874‐3p, as shown by bioinformatics, dual‐luciferase reporter gene analysis and pull‐down assay, respectively. Notably, miR‐874‐3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3′‐untranslated region (UTR) in Mtb‐infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb‐infected macrophages by blocking the ability of miR‐874‐3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of miR‐874‐3p to suppress ATG16L1 expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages. Conclusion The current findings suggested that both circTRAPPC6B and miR‐874‐3p mechanisms can be explored as potential therapeutics against Mtb infection., In this study, we found that circTRAPPC6B could inhibit intracellular Mycobacterium tuberculosis (Mtb) growth by inducing autophagy in Mtb‐infected macrophages through abolishing the suppression of miR‐874‐3p on ATG16L1 expression. This study highlights circTRAPPC6B as a potential therapeutic agent for tuberculosis control.

Background: Genetic and epigenetic mechanisms appear to regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. Methods: We assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms whereby circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages. Findings: While Mtb infection of monocytes/macrophages resulted in a significantly decreased circTRAPPC6B level, circTRAPPC6B inhibited intracellular Mtb growth in macrophages. Whereas, circTRAPPC6B expression enhanced autophagy or autophagy-associated protein LC3-II production in Mtb-infected macrophages. The circTRAPPC6B-enhanced autophagy aggregation or sequestration was also observed in FISH analysis and confocal imaging. Mechanistically, circTRAPPC6B could target an inhibiting element miR-874-3p, as evidenced by bioinformatics, dual-luciferase reporter gene analysis, and pull-down assay, respectively. Notably, miR-874-3p prohibited autophagy via suppression of autophagy protein ATG16L1 expression by binding to its 3’-UTRin Mtb-infected macrophages and thus promoted intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtb-infected macrophage by blocking the ability of miR-874-3p to inhibit ATG16L1. Thus, circTRAPPC6B can antagonize the ability of miR-874-3p to suppress ATG16L1 expression, and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages. Interpretation: Our findings suggest that both circTRAPPC6B and miR-874 mechanisms can be explored as potential therapeutics against Mtb infection. Funding: This work was supported by the National Natural Science Foundation of China (881870016, 1570009 and 81273237), the Natural Science Foundation of Guangdong Province (2015A030313513 and 2020A1515010283), and the Science and Technology Innovation Fund of Guangdong Medical University (STIF201110, B2012078). Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: The protocol of using human blood samples in vitro was approved by the Institutional Review Boards for Human Donors’ Research and Institutional Biosafety Committees at Institut Pasteur of Shanghai, Guangdong Medical University, and Dongguan 6th Hospital (China). The protocols of using macaque spleen tissue samples and mycobacterium H37Rv strain were approved by the Institutional Review Boards for Biosafety Committee at the University of Illinois–Chicago College of Medicine (IL, USA). All studies complied with the guidelines of the Office for Human Research Protections. All patients and healthy controls provided written informed consent before initiation of study.

IL-35 is an anti-inflammatory cytokine and is thought to be produced by regulatory T (Treg) cells. A previous study found that IL-35 was upregulated in the serum of patients with active tuberculosis (ATB), and IL-35-producing B cells infiltrated to tuberculous granuloma of patients with ATB. Purified B cells from such patients generated more IL-35 after stimulation by antigens of Mycobacterium tuberculosis and secreted more IL-10. However, the function and the underlying mechanisms of IL-35-producing B cells in TB progression have not been investigated. The present study found that the expression of mRNA of IL-35 subsets Ebi3 and p35 was elevated in mononuclear cells from peripheral blood, spleen, bone marrow, and lung tissue in a mouse model infected with Mycobacterium bovis BCG, as tested by real-time polymerase chain reaction. Accordingly, the flow cytometry analysis showed that the counts of a subset of IL-35+ B cells were elevated in the circulating blood and in the spleen, bone marrow, and lung tissue in BCG-infected mice, whereas anti-TB therapy reduced IL-35-producing B cells. Interestingly, BCG infection could drive the infiltration of IL-35-producing B cells into the lung tissue, and the elevated counts of IL-35-producing B cells positively correlated with the bacterial load in the lungs. Importantly, the injection of exogenous IL-35 stimulated the elevation in the counts of IL-35-producing B cells and was associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg.The study showed that a subset of IL-35-producing B cells might take part in the downregulation of immune response in mycobacterial infection.

Numerous studies have suggested that circular RNAs (circRNAs), a type of non-coding RNA lacking 5′-caps and 3′-poly(A) tails, are involved in the biological processes of various human diseases. However, little is known about their functions and diagnostic value in active pulmonary tuberculosis (APTB). The aim of the present study was to examine whether hsa_circ_0001380 is able to serve as a diagnostic biomarker for patients with APTB. The expression level of hsa_circ_0001380 was detected in the peripheral blood of 32 patients with APTB and 31 healthy volunteers by reverse transcription-quantitative PCR. The functional prediction of hsa_circ_0001380 was performed in silico. RNase R was used to detect the stability of hsa_circ_0001380. Finally, the diagnostic value of hsa_circ_0001380 was evaluated by receiver operating characteristic (ROC) curve analysis. The results showed that hsa_circ_0001380 was significantly downregulated in the peripheral blood of patients with APTB. In addition, hsa_circ_0001380 was found to be resistant to RNase R treatment. Moreover, four N6-adenosine methylation modification sites and two potential microRNA binding sites were predicted in silico. Importantly, the area under the ROC curve was 0.9502, which suggested that hsa_circ_0001380 may act as a diagnostic biomarker for APTB. Taken together, the results indicated that circRNA hsa_circ_0001380 was downregulated in the peripheral blood of patients with APTB, and could serve as a diagnostic biomarker.

Regulatory B cells (Bregs) have critical roles as a negative regulator of immunity, mainly due to the fact that it secrets high a level of interleukin 10 (IL-10). Recently, a new subset of Bregs was identified as a key source of IL-35, which is an immunosuppressive cytokine and conventionally thought to be secreted by regulatory T cells (Tregs). Our previous study showed that the level of IL-35 in serum was elevated in the patients with active tuberculosis (ATB). However, none of the studies reported that IL-35 is secreted by B cells in ATB patients. In the current study, we found that the mRNA expressions of the both subunits (p35 and Ebi3) of IL-35 by circulating B cells were increased in ATB patients. By using immunohistochemistry and immunofluorescence staining, we found a subset of B cells infiltrated into the tuberculous granuloma of ATB patients also expressed IL-35. Moreover, Mycobacterium tuberculosis (MTB) lysate stimulation assay also demonstrated higher levels of IL-35 were exerted by MTB lysate within purified B cells from healthy control group (HC). Flow cytometry analysis further showed that the IL-35-producing B cells from ATB patients produced a higher level of IL-10. Taken together, IL-35-producing B cells may play a regulatory role during MTB infection by producing IL-10.

INTRODUCTION Low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels are associated with incidence of cardiovascular disease (CVD). Alirocumab has been considered as an efficacious, safe and promising therapeutic modality for hypercholesterolemia. The purpose of this study is to compare the differences of the three different doses of alirocumab in patients with hypercholesterolemia. EVIDENCE ACQUISITION Randomized controlled trials were identified from PubMed, EMBASE, PMC and Cochrane-library databases. The inter-comparison of different doses were performed by subgroups analysis. Meta-analyses were performed by the Review Manager 5.3 and STATA 13.0 software. EVIDENCE SYNTHESIS A total of nine studies involving 3870 patients were included in this meta-analysis. Alirocumab administered at 75-150 mg every 2 weeks (Q2W) resulted in a greater percent change from baseline in LDL-C concentrations (MD, -55.17; 95% CI: -64.35 to -45.99; P

B cell activating factor (BAFF), a member of the tumor necrosis factor family, is a key cytokine for B cell survival, a function that is essential for B cell maturation and memory. The expression levels of BAFF and its potential contribution to B cell maturation remain elusive in patients with tuberculous pleural effusion (TPE). The present study enrolled 40 healthy controls (HC) and 45 TPE patients, and investigated the levels of BAFF in the plasma and pleural effusion. Concomitantly, B cell subsets including naive B cell (CD19+IgD+CD27‑), unswitched B cell (CD19+IgD+CD27+), switched B cell (CD19+IgD‑CD27+), total memory B cell (CD19+CD27+), plasma B cell (CD19+IgD‑CD38+CD27+) and transitional B cell (CD19+IgDdim CD38+) in peripheral blood mononuclear cells (PBMCs) and pleural fluid mononuclear cells (PFMCs) were assessed using multicolor flow cytometry. Finally, the associations between BAFF and each sub‑group of B cells in TPE patients were analyzed. Compared with HC cases, an increased BAFF level and elevated frequency of switched B cell were observed in the blood and pleural effusion from patients with TPE. The proportions of naive B cell, plasma B cell and transitional B cell were lower in the PFMCs of TPE patients. Furthermore, a significant correlation was observed between the level of BAFF, and the proportion of switched B cell in the peripheral blood and pleural effusion of TPE patients. These findings indicated that the B cell profile may be different in the pleural effusion, and BAFF may activate switched B cells to enhance the humoral immune responses in patients with TPE. Further studies are required to elucidate the underlying mechanisms and determine the potential immunotherapy of the BAFF‑switched B cell axis.

It has been reported that circular RNA (circRNA) is associated with human cancer. However, few studies have been reported in active pulmonary tuberculosis (APTB). The global circRNA expression was detected in the peripheral blood mononuclear cells (PBMCs) of APTB patients (n=5) and health controls (HC) (n=5) by using high-throughput sequencing. According to the systematical bioinformatics analysis, the basic content of circRNAs and their fold changes in the two groups were calculated. We selected 6 significant differentially expressed circRNAs, hsa_circ_0005836, hsa_circ_0009128, hsa_circ_0003519, hsa_circ_0023956, hsa_circ_0078768, and hsa_circ_0088452 and validated the expression in PBMCs from APTB (n=10) and HC (n=10) by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Further, the verification of these specific circRNAs (hsa_circ_0005836 and hsa_circ_0009128) between APTB (n=34) and HC (n=30) in PBMCs was also conducted by qRT-PCRs. The RNA-seq data showed the significant differential expression of the 523 circRNAs between the APTB and HC groups (199 circRNAs were significantly up-regulated and 324 circRNAs were down-regulated). Hsa_circ_0005836 and hsa_circ_0009128 expression was significantly down-regulated in the PBMCs of APTB (P