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摘要： Introduction The development of neurological disorders following trypanosome brain infection has been recognised for over a century. However, an ongoing endeavour persists to comprehensively understand the neurocognitive and neuropathological changes accompanying such infection and the disease progression. Efforts are ongoing to screen for effective new trypanocidal compounds. Therapies now favor activating M2 macrophages via IL-4 or IL-13 anti-inflammatory cytokines. This study aims to investigate whether prostacyclin analogue (Iloprost) treatment against CNS Trypanosoma brucei infection would beneficially affect cognitive and anxiety-like behaviours in IL-4/IL-13-expressing mice, and to determine if trypanosome-induced neurocognitive alterations can be therapeutically reversed and to elucidate the underlying molecular and epigenetic mechanisms. Methods Sixty-four male albino Swiss mice (8-10 weeks old) were used, divided into two groups (n=32 per group): IL-4Rα-/- and wild-type (WT) littermates. At day 4 post-infection with Trypanosoma brucei brucei, both groups received intraperitoneal Iloprost (200µg/kg) for 3 days. The mice were assessed for locomotion and anxiety-like behavior. Blood samples were collected for parasitaemia and hemogram tests. Target gene transcripts in the prefrontal cortices (PFC) and hippocampal (HPC) tissues were quantified using RT-PCR. Cytokine expression and methylation profiling were assessed using ELISA and EZ DNA methylation kits. Results IL-4R inhibition induced systemic inflammation in IL-4R-/- mice, whereas Diminazine treatment reversed decreased vertical exploration in the open field and revealed reduced anxiety-like behaviour in these animals. Molecular analysis shows IL-13 gene downregulation in both PFC and HPC. IL-4 and IL-4R genes are only downregulated in the HPC of IL-4R-/- infected mice, indicating different responses to infection in distinct brain regions. Furthermore, Iloprost and Diminazine treatments not only reversed

关键词： Asthma   Bispecific antibody   IL-23   TNF-alpha   Airway hyperresponsiveness   Pulmonary inflammation  

摘要： Asthma, a chronic multi-factorial pulmonary inflammatory condition with a high morbidity rate, is characterized by airway hyperresponsiveness and persistent pulmonary inflammation. There is a need to develop more effective treatment(s) for the management of asthma. In this study, we have investigated the therapeutic potential of BiSpekDAb (an engineered bispecific antibody comprising an anti-IL-23 domain antibody and an antiTNF-alpha domain antibody fused together via flexible linkers to a half-life extension partner) in asthma. Asthma was established by sensitization and challenge of female Wistar rats with the combination of ovalbumin and lipopolysaccharide and the efficacy of BiSpekDAb was investigated by its subcutaneous administration for 11 days on each alternative day (6 doses) during the challenge phase. Significant deterioration of pulmonary functions, enhanced airway hyperresponsiveness, increase in the number of immune cells such as lymphocytes, eosinophils, neutrophils in blood circulation as well as in lungs, enhanced production of inflammatory cytokines (IL-23, TNF alpha, IL-1 beta, IL-6, IL-22), allergic IgE antibodies, oxidative stress markers, and histopathological changes (thickening of epithelial lining, infiltration of immune cells, mast cell degranulation, and overproduction of mucus) were observed in asthma animals, and administration of BiSpekDAb attenuated airway hyperresponsiveness (AHR), pulmonary inflammation and other pathological changes. BiSpekDAb significantly inhibited IL-23 and TNF-alpha levels in the lungs of asthmatic rats. Our results suggest that targeting IL-23 and TNF-alpha simultaneously opens a new therapeutic window for biologics development aimed at mitigating pulmonary inflammation such as asthma.

关键词： HLA-DQB1*06:01:01:09 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DQB1*06:01:01:09 allele differs from HLA-DQB1*06:01:01:01 by a single nucleotide substitution in intron 2.

关键词： HLA   HLA-DQA1   nanotype sequencing   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DQA1*05:89 differs from HLA-DQA1*05:05:01:01 by one non-synonymous nucleotide substitution in exon 2.

摘要： Nuclear factor-kappa B (NF-kappa B)/p65, a vital signaling molecule in the NF-kappa B pathway, participates in diverse physiological functions and host-virus interactions. However, the involvement of NF-kappa B/p65 in fish virus infection remains poorly understood. In this study, we explored the role of the p65 in virus infection and its impact on IL- 18 regulation in largemouth bass ( Micropterus salmoides). Bioinformatics analysis showed that the ORF sequence of Msp65 spanned 1941 bp, encoding 646 amino acids with two conserved functional domains, including RHD and IPT domain. Msp65 mRNA was presented in various tissues, with higher levels detected in the liver and gill. After exposure to largemouth bass virus (LMBV), red grouper nervous necrosis virus, lipopolysaccharide and poly (I:C), Msp65 expression was activated in vivo. In addition, the antiviral role of Msp65 were explored. In vitro, Msp65 overexpression hindered LMBV replication and formation of viral assembly site. In vivo, we found that disruption of Msp65 by using maslinic acid (MA) notably promoted the infectivity of LMBV, indicating its antiviral capabilities in largemouth bass. Besides, the downregulation of Msp65 suppressed the expression of inflammatory and interferon signaling molecules. Conversely, Msp65 overexpression boosted the activities of IFN-I, IFN-III and ISRE promoters, suggesting the positive regulation of Msp65 on interferon immune pathway. Furthermore, to unveil the regulatory role of Msp65 on MsIL-18, a promoter investigation was conducted. The luciferase reporter assay demonstrated that Msp65 positively influenced the expression of MsIL18. Subsequent analysis suggested that the putative binding sites for MsIL-18 could potentially reside within the-228 to-203 bp of the MsIL-18 promoter. These findings illustrated that Msp65 involved in LMBV infection by modulating immune responses, presenting a novel insight into the antiviral mechanisms of p65 in bony fish.

关键词： ADRA (amino acid derivative reactivity assay)   BR (borderline range)   EpiSensA (epidermal sensitization assay)   IL-8 Luc (interleukin-8 reporter gene assay)   MAD (median absolute deviation)   MADp (pooled median absolute deviation)   NAC (N-(2-(1-naphthyl)acetyl)-L-cysteine)   NAL (alpha-N-(2-(1-naphthyl)acetyl)-L-lysine)  

摘要： Most predictive models that use alternatives to animal experiments divide judgements into two classes with a cutoff value for each model. However, if the results of alternative methods are close to the cutoff values, the true result may be ambiguous because of variability in the data. Therefore, the OECD GL497 uses a judgement method that establishes a borderline range (BR) around a cutoff value using a statistical method. However, because there is no detailed description of how the BR is calculated, we clarified two specific points. The scale-constant correction method was used to calculate the median absolute deviation (MAD) around the median. In addition, the bottom-raised transformation method was used when the data were "0" because calculation of the BR requires that all data are logarithmic. Indeed, the BRs for the amino acid derivative reactivity assay (ADRA), interleukin-8 reporter gene assay (IL-8 Luc), and epidermal sensitization assay (EpiSensA) were calculated using data from each validation study. The results showed that the BR for ADRA and IL-8 Luc ranged from 4.1 to 5.9 and 1.25 to 1.57, respectively. Furthermore, the BRs of four genes (ATF3, GCLM, DNAJB4, and IL-8) evaluated using EpiSensA ranged from 10.71 to 21.02, 1.64 to 2.45, 1.61 to 2.52, and 3.11 to 5.16, respectively. The difference (deviation) between the lower and upper BR limits and cutoff value for each alternative method were comparable to those of the alternative methods listed in the guidelines (DPRA, KerarinoSens, and h-CLAT) and thus were considered as adequate.

关键词： Kimura disease   Nocardiosis   Primary immune deficiency  

摘要： A 12-year-old boy who had been diagnosed with Kimura disease was brought with a history suggestive of acute pyelonephritis. There was a family history of a first-degree relative with a diagnosis of Mendelian Susceptibility to Mycobacterial disease. Investigations revealed a left renal abscess. Aspirate culture grew Nocardia otitidiscaviarum. Targeted gene sequencing revealed a novel mutation in the IL12RB1 gene. Based on the above information a diagnosis of an underlying primary immune deficiency disorder was made. He was managed with appropriate antibiotics, showing steady improvement and eventually a complete recovery.

关键词： HLA   HLA-C*15:02:01:69Q   NGS   novel allele   questionable expression  

摘要： HLA-C*15:02:01:69Q differs from HLA-C*15:02:01:01 by a single substitution at the genomic nucleotide position 2727 in intron 7.

关键词： Immune checkpoints   Colorectal cancer   B7family   TNF family  

摘要： Soluble immune checkpoints (sIC) are crucial factors in the immune system. They regulate immune responses by transforming intercellular signals via binding to their membrane-bound receptor or ligand. Moreover, soluble ICs are vital in immune regulation, cancer development, and prognosis. They can be identified and measured in various tumor microenvironments. Recently, sICs have become increasingly important in clinically assessing malignancies like colorectal cancer (CRC) patients. This review explores the evolving role of the soluble B7 family and soluble tumor necrosis factor (TNF) superfamily members in predicting disease progression, treatment response, and overall patient outcomes in CRC. We comprehensively analyze the diagnostic and prognostic potential of soluble immune checkpoints in CRC. Understanding the role of these soluble immune checkpoints in CRC management and their potential as targets for precision medicine approaches can be critical for improving outcomes for patients with colorectal cancer.

关键词： Systemic lupus erythematosus   bone marrow mesenchymal stem cells   autophagy   senescence   IL-6   lupus mice  

摘要： BackgroundSystemic lupus erythematosus is a common autoimmune disease. Studies have suggested that defective stem cells could be involved in the pathogenesis of systemic lupus erythematosus, which leads to changes in the function of immune cells. By observing the cell morphology, autophagy, and senescence of bone marrow mesenchymal stem cells (BMSCs) from lupus mice and normal controls, this study investigated the role of IL-6 in autophagy and senescence of BMSCs and explored relevant *** MRL/lpr and C57 mice with similar weights and sizes at 20-22 weeks old were selected. BMSCs were isolated using the whole bone marrow adherent method. Quantitative real-time polymerase chain reaction, beta-galactosidase staining, western blotting, and ELISA were used to detect autophagy and *** with BMSCs from normal mice, BMSCs from lupus mice exhibited low autophagy and premature senescence with a senescence-associated secretory phenotype. The addition of exogenous IL-6 increased the protein levels of p-STAT3 and Bcl-2, and in the IL-6-treated group, the premature senescence of cells increased and autophagy *** biological functions of BMSCs from MRL/lpr lupus mice were impaired. IL-6 prevents autophagy and subsequently promotes the senescence of BMSCs by activating the IL-6/STAT3 pathway.