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关键词： alleles   breast neoplasms   high-throughput nucleotide sequencing   HLA-DP antigens   point mutation  

摘要： Identification of the novel alleles HLA-DPA1*02:142 and HLA-DPA1*01:03:01:92.

摘要： Inflammation is critical for controlling infections but can cause disease when unchecked. During Mycobacterium tuberculosis (Mtb) infection, neutrophil-dominated inflammation is associated with exacerbated disease. ATG5 expression by neutrophils mediates autophagy-independent control of infection but mechanistic understanding of how this regulates protective neutrophil function is lacking. Using genetic mouse models along with in vivo and in vitro infection systems, we report herein that ATG5 is required in neutrophils to suppress type I interferon-induced PAD4-mediated histone citrullination and neutrophil extracellular trap (NET) release. In addition, ATG5 suppresses type I interferon-induced CXCL2 secretion and neutrophil swarming during Mtb infection. Elevated type I IFN signalling and NET release contribute to the early susceptibility of Atg5fl/fl-LysM-Cre mice during infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during infection, revealing a potential target for host-directed therapies.

关键词： Plasmablast   Il-21   Cytokine   B cell   iGB  

摘要： Antibodies of the IgE and IgG1 isotypes are relevant for type 2 immunity. In vivo, the production of both is elevated by IL-4, but differentially affected by IL-21, with IgE suppressed and IgG1 production enhanced by IL- 21. However, whether the cytokines drive these outcomes primarily by impacting antibody-secreting, proliferating plasmablasts (PB), or their germinal center B cell precursors, is challenging to unravel. In vitro analyses using Nojima cultures, wherein na & iuml;ve B cells are activated on fibroblasts co-expressing CD40L and BAFF, allows for evaluation of this problem. Here, we explore how IL-4 and IL-21 alone and in combination affect Nojimacultured B cell proliferation and fate, asking what is unique or redundant about exposure to each. In secondary culture, as expected, IL-21 amplified replicative expansion. IL-21 also selectively promoted the differentiation of IgG1+ B cells into PB. The effect was countermanded by synchronous exposure to IL-4, suggesting competing signaling pathways are triggered by the two cytokines independently. Secondary culture with IL-4 alone promoted IgE+ B cell genesis without increasing replicative expansion. Combined exposure to IL-21 and IL-4 led to increased IgE class-switching and proliferative expansion, suggesting that once B cells are switched to IgE, IL-21 can promote IgE+ B cell proliferation. Thus, in culture IL-21 operates to promote proliferation and also drives differentiation of IgG1+ B cells into PB whereas IL-4 has an ongoing role in IgE B cell genesis. The balance of IL-4 and IL-21 thus impacts the fate of in vitro-generated germinal center B cells and highlights how the notable IgE-suppressing effects of IL-21 in vivo likely precede the class-switch step, after which IL-21 may amplify IgE production by virtue of its pro-proliferative effects.

关键词： biological DMARD   Observational studies/registry  

关键词： Lipopolysaccharide   Minocycline   Memantine   Neuroinflammation   Medial prefrontal cortex (mPFC)  

摘要： Minocycline has been shown to ameliorate neuroinflammation that was encountered in many neurodegenerative diseases. This study aims to investigate the expression of inflammatory mediators in the rat medial prefrontal cortex (mPFC) after minocycline treatment in a lipopolysaccharide (LPS)- induced neuroinflammation rat model. Adult male Sprague Dawley (SD) rats (N = 50) were divided into 5 groups: (1) control, (2) LPS (5 mg/kg), (3) LPS + minocycline (25 mg/kg), (4) LPS + minocycline (50 mg/kg) and (5) LPS + memantine (10 mg/kg). Intraperitoneal minocycline and memantine were given daily for 14 days, while LPS injection was given once on the 5th day. Western blot and immunohistochemistry were used to assess density and expression of toll-like receptor-4 (TLR-4), nuclear factor kappa-B (NF-kB), tumor necrosis factor (TNF)-alpha and cyclooxygenase (COX)-2 in the medial prefrontal cortex (mPFC) of rats. Findings displayed that minocycline significantly decreased expression and density of TLR-4, NF-kB, TNF-alpha and COX-2 proteins that were comparable to memantine in mPFC of SD rat injected with single intraperitoneal LPS. Interestingly, the anti-inflammatory effects of minocycline 50 mg/kg were significantly more than minocycline 25 mg/kg. This study suggested that minocycline can modulate LPS-induced neuroinflammation in dose-dependent manner in the mPFC area. Thus, it is suggested that minocycline can be used as potential preventive-therapeutic drug for neuroinflammatory diseases such as depression and anxiety.

关键词： Knee osteoarthritis   IL-16 polymorphisms meta-analysis   Protective effect   Genetic variations   Ethnic differences  

摘要： Background: Knee osteoarthritis (KOA) is a multifactorial condition affected by genetic and environmental factors. Studies have explored the relationship between IL-16 genetic polymorphisms and KOA risk, but findings have been inconclusive. This meta-analysis seeks to assess the association between IL-16 polymorphisms and KOA risk. Methods: A systematic literature search was conducted in several databases, including PubMed, Web of Science, EMBASE, SciELO, and CNKI, for studies published until June 1, 2024. Two independent researchers identified peer-reviewed articles in English, Portuguese, and Chinese using keywords related to "Knee Osteoarthritis" and "Interleukin 16." Relevant references were also manually reviewed for additional studies. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to assess the association strength. Additionally, minor allele frequencies (MAFs), Hardy-Weinberg equilibrium (HWE) data, heterogeneity, publication bias, and Newcastle-Ottawa scores (NOS) were evaluated. Results: This analysis included 15 case-control studies, encompassing 1747 individuals with KOA and 1627 healthy controls. Within these studies, five investigated the genetic variations rs11556218 (584 cases, 542 controls), rs4778889 (583 cases, 543 controls), and rs4072111 (580 cases, 542 controls). The findings suggest that the IL-16 variants rs11556218 and rs4072111 may offer protection against KOA development, while no link exists between the rs4778889 variant and KOA susceptibility. The variability in IL-16 polymorphisms, particularly in Asian and Chinese populations, indicates different genetic associations with KOA risk. Strong results, supported by sensitivity analyses and the absence of significant publication bias, emphasize the influence of study methods on the relationship between these polymorphisms and KOA risk. Conclusions: The analysis of three polymorphisms-rs11556218, rs4778889, and rs4072111-shows varying associations with KOA. Rs115

关键词： IL-1 beta inhibition   Atherosclerotic plaque stability   Fibroblast-like cells   CHIP   Prg4  

摘要： Targeting interleukin-1 beta (IL-1 beta) to mitigate inflammation is known to stabilize atherosclerotic plaques, thereby lowering the risk of acute cardiovascular events. The precise mechanisms are not yet known. Fideler et al. examined the effects of IL-1 beta on exaggerated atherosclerosis following clonal hematopoiesis of indeterminate potential (CHIP). Unexpectedly, they showed an effect of IL-1 beta blockage on fibroblast-like cells and their role in the progression of atherosclerosis in the presence of CHIP. Here, we discuss these findings and place them in context of current insights on plaque fibroblast identity and function. While single cell sequencing studies had observed the presence of plaque fibroblasts in atherosclerotic plaques, their function has yet to be unraveled. By focusing on both in vitro and ex vivo models, the research explored how IL-1 beta stimulation drives functional and molecular changes in fibroblast-like cells, such as increased cytokine production and enhanced matrix degradation, which replicate the inflammatory microenvironment commonly seen in atherosclerotic lesions. Furthermore, the study suggests that inhibiting IL-1 beta might encourage the accumulation of fibroblast-like cells within the fibrous cap, a process that could improve plaque stability by reducing inflammatory activity and strengthening the structural integrity of the plaque. Depletion of proteoglycan 4 (Prg4) -positive cells, that represent fibroblasts amongst other cell types, reduced cap thickness in atherosclerosis with clonal hematopoiesis of indeterminate potential. The findings suggest that IL-1 beta not only plays a critical role in promoting inflammation, but also in altering the phenotype of fibroblast-like cells, contributing to the destabilization of atherosclerotic plaques. This study is the first to show a function of plaque fibroblast-like cells in exaggerated atherosclerosis following clonal hematopoiesis of indeterminate potential. Future studies sh

关键词： HLA   HLA-DPB1   next-generation sequencing   novel allele  

摘要： HLA-DPB1*1469:01 shows a non-synonymous mutation in codon 205 within Exon 4 compared with HLA-DPB1*25:01.

关键词： TNF   fibrinolysis   proximity extension assay   renal fibrosis   urinary extracellular vesicles   vitronectin  

摘要： Vitronectin (VTN) is a potential non-invasive biomarker for renal fibrosis, originally described in urinary extracellular vesicles (uEV) from kidney transplant patients (KTx). However, VTN's specific role in renal fibrosis is unclear, as it is involved in various physiological processes. This study aims to identify other uEV-associated proteins linked to renal fibrosis to clarify which pathways involve VTN. uEV were isolated from 33 KTx patients and five healthy controls. uEV proteins were analysed using proximity extension assay (PEA), and data were normalized and compared using Welch's two-sided -test to identify differentially expressed proteins between fibrotic ( = 31) and non-fibrotic patients ( = 7). Urinary VTN levels and monocyte chemoattractant protein-1 (MCP-1) were measured by ELISA. PEA analysis identified 33 proteins overexpressed in the fibrotic group. These proteins clustered in STRING analysis, primarily associating with coagulation, fibrinolysis and TNF-inflammation involving macrophages. ELISA detection of MCP-1 further validated the results. High levels of VTN in the fibrotic group were accompanied by the upregulation of fibrinolytic pathway components (PAI-1, tPA and uPAR), which are well-known to interact with VTN. This study highlights TNF-induced inflammation involving macrophages and fibrinolysis as key mechanisms underlying renal fibrosis with direct implications of VTN, which support VTN's potential as a biomarker for this pathological process.

关键词： canine mammary carcinoma   Newcastle disease virus   NF-kappa B pathway   oncolysis   pyroptosis  

摘要： Mammary tumours are the most common type of neoplasm in female dogs, with nearly half being malignant. Oncolytic Newcastle disease virus (NDV) therapy has emerged as a novel cancer treatment option;however, its precise oncolytic mechanism in canine mammary tumours (CMT) remain unclear. Ultrastructural analysis of NDV-infected CMT-U27 cells with locally damaged cell membranes and swollen and ruptured mitochondria revealed the occurrence of pyroptosis. Transcriptome sequencing further identified a significant upregulation of pyroptosis-related genes, including NLRP1, NOD2, caspase-1, and GSDMD. Subsequent examination of RNA and protein expression levels of pyroptosis-related molecules in vitro indicated that NDV induces pyroptosis in CMT-U27 cells via the caspase-1/GSDMD pathway. Additionally, inhibition of the TNF alpha/NF-kappa B pathway and knockdown of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) using small interfering RNA demonstrated that the TNF alpha/NF-kappa B pathway can regulate NDV-induced pyroptosis through the NLRP3 inflammasome. In a xenograft model, intravenous administration of NDV significantly inhibited tumour growth, and prolonged the survival time in nude mice bearing CMT-U27 cells. NDV treatment enhances intratumoural pyrotosis in tumour bearing mice. In conclusion, these findings suggest that NDV induces pyroptosis in CMT-U27 cells through the TNF alpha/NF-kappa B/NLRP3 pathway, providing a foundation for future research into NDV's therapeutic potential in canine mammary cancer.