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关键词： egg layer chickens   Marek's disease   MHC   genetic resistance  

摘要： Mortality from Marek's disease virus (MDV) infection results in economic loss for the poultry industry. It is controlled by vaccination, but the virus mutates and becomes more virulent. Variation within the MHC is well known to impact the outcomes following MDV infection from research performed utilizing the White Leghorn breed, with laboratory strains of the virus. The effect of the MHC haplotype following MDV challenge was determined from six lines of commercial elite (White Plymouth Rock (two), White Leghorn (three), and Rhode Island Red (one)) egg layer lines, challenged with vv+ virus. Mortality was recorded as sire daughter averages at 16-18 weeks of age from 19 generations of data. Sires were genotyped using a set of MHC-specific SNPs, encompassing 210,000 bp. Across all lines, there was a total of 23 unique MHC haplotypes, of which 15 were found at a frequency greater than 5% and used for further analysis. A significant impact on mortality was found for 16 of the haplotypes, with 9 haplotypes associated with decreased mortality and 7 haplotypes with increased mortality. There were three haplotypes identified in more than one line, allowing cross-line comparisons. The effect of these common haplotypes was consistent (either negative, positive or neutral) between lines.

关键词： anti-TNF failure   biological therapy   sequential therapy   ulcerative colitis   inflammatory bowel diseases  

摘要： Background: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy. Research design and methods: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated. Results: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib (p = 0.05;p = 0.001) and vedolizumab (p = 0.02;p = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs (p < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence (p = 0.05) and colectomy-free survival rates (p = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia (p = 0.002) and shorter disease duration at second-line initiation (p = 0.03) increased, while concomitant immunomodulators (p = 0.05) reduced the risk for colectomy. Shorter disease duration (p = 0.01) and primary non-response to the previously used anti-TNF (p < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents. Conclusion: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.

关键词： 细胞因子   流式细胞术   D-二聚体   病例报告  

摘要： 2024年2—11月该中心对3例细胞因子初检异常升高患者采用二步法进行了复测，3例患者初检时细胞因子均异常升高，复测后细胞因子水平显著降低。分析患者各项检测结果，发现3例患者体内D-二聚体水平均升高，疑似D-二聚体导致细胞因子检测假阳性，提示二者存在关联。

关键词： Herbicides   RAW 264.7   TNF   immunomodulatory activity   mitochondria   oxidative stress   clomazone   sulfentrazone   glyphosate  

摘要： Weeds are a concern in agriculture and the use of herbicides constitutes an effective, efficient, and economical way to control their growth. Recent discoveries of herbicides are promising for the management of resistant weeds. However, there is a gap in the knowledge of the toxic effects of some herbicides previously reported on immune cells. The present study aimed to examine cellular immunotoxicity of three herbicides (clomazone, glyphosate, and sulfentrazone) after 96 hr incubation utilizing RAW 264.7 BALB/c mouse monocyte/macrophage-like cell line to elucidate the role of some toxicological pathways. Data demonstrated the herbicides clomazone, glyphosate, and sulfentrazone initiated a cytotoxic effect as evidenced by EC50 values of 429.2;53.7;866.6 mg/L, respectively. Clomazone and sulfentrazone, at all concentrations, induced excess production of reactive oxygen (ROS) and reactive nitrogen (RNS) free radicals. An immunosuppression was observed in RAW 264.7 cells after incubation with 50 or 100 mg/L glyphosate and 500 or 1000 mg/L sulfentrazone. In addition, all herbicides produced mitochondrial depolarization and decreased tumor necrosis factor-alpha (TNF-alpha) levels. This constitutes the first report of the effects of clomazone and sulfentrazone on RAW 264.7 cells, including reduced TNF-alpha levels, indicating the adverse influence of herbicides on the immune system.

摘要： Dysregulations in protein kinases significantly contribute to the initiation, progression, and drug resistance in non-small cell lung cancer (NSCLC). Identification of novel oncogenic drivers within the human kinome is crucial for targeted therapy. In this study, we conducted a comprehensive analysis of the TCGA database and literature, pinpointing 16 candidate genes in lung cancer exhibiting frequent dysregulation and limited research. Our functional analysis revealed Serine/threonine kinase 31 (STK31) as a key player in driving tumor growth, in immune-competent mice, with minimal impact in nude mice. Further investigations unveiled upregulation of STK31 led to CD8+ T cell exhaustion. Mechanistically, STK31 induced CD8+ T cell exhaustion through the signal transducer and activator of transcription 3 (STAT3) - interleukin 6 (IL-6) signaling pathway. Direct interaction between STK31 and STAT3 activated the transcription of downstream oncogenic targets, such as IL-6, facilitating immune escape. Moreover, STK31 exhibited elevated expression levels in lung cancer tissues compared to adjacent tissues and displayed a significant correlation with poor prognosis in lung cancer patients. This study defines a critical role of STK31 in promoting immune escape through STAT3 activation, positioning it as a promising therapeutic target for lung cancer.

关键词： Glycosylation   Autoimmune disorder   Homology modeling   Molecular docking   Molecular dynamics simulation  

摘要： Interleukin-1 receptor antagonist (IL-1ra) is a vital anti-inflammatory molecule, acting as a decoy protein that competitively binds to Interleukin-1 receptors (IL-1RI and IL-1RII). The deregulation of IL-1 activity has been linked to autoimmune disorders, impaired wound healing, and the occurrence of cytokine storms in the context of infections. At present, *** expressed IL-1ra isoform was used as a therapeutic drug for the treatment of IL-1 mediated inflammatory diseases;however, daily dosing raises concerns about allergens and infection. Notably, the drug lacks glycosylation, an important post-translational modification for protein stability and pharmacodynamics. The present study utilizes computational molecular dynamics simulations to investigate the influence of glycosylation on the stability and binding efficacy of IL-1ra. To study the impact, we introduced mammalian bi-antennary hybrid glycan with terminal sialic acid/ N-Acetylneuraminic acid (Neu5Ac) added to the respective Asparagine (Asn) residue of 3D modeled IL-1ra structure. The molecular dynamics simulations demonstrated that glycosylated IL-1ra increased the structural stability and exhibited a sustained level of binding stability with 24 hydrogen bonds and 8 salt bridges in comparison to non-glycosylated IL-1ra protein with 20 hydrogen bonds and 6 salt bridges as the result of post simulation. This finding underscores the possibility of glycosylation as it means to augment the effectiveness of therapeutic medications that specifically target immune regulation. These understandings help to translate the concept to the complete expression of proteins. Our study addressed the mechanism of how the N-glycan regulates cytokine, which will provide insight into the design of novel anti-inflammatory drugs and specifically glycan play a role in RA.

关键词： Tripterygium wilfordii polyglycoside tablets   Hepatocellular carcinoma   therapeutic drug   IL-6   PI3K/MAPK/STAT3 signaling pathway  

摘要： Tripterygium wilfordii polyglycoside tablets (TWPT) have traditionally been used to treat certain inflammatory diseases. This study validated TWPT as a novel application in hepatocellular carcinoma treatment through multiple targets, thereby expanding its clinical medication scope. TWPT exhibited a low toxicity and a significantly antihepatoma effects in vitro and in vivo. Through network pharmacology analysis, we found TWPT attenuated the progression of hepatocellular carcinoma by multi-targeting, including IL-6, MMP9, TNF-alpha and VEGFA. Additionally, TWPT targeted IL-6 to regulate downstream pathways, including the PI3K/Akt, JAK2/STAT3, and MAPK signaling pathways. Thus, TWPT could be developed as a potential therapeutic drug for hepatocellular carcinoma.

关键词： human leukocyte antigen   tuberculosis   local ancestry   admixture   KhoeSan  

摘要： Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 x 10(-6), OR = 0.437, SE = 0.182) in the HLA-DPB1 gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.

关键词： Adipose tissue   Cell biology   Glucose metabolism   Metabolism   Obesity  

摘要： Type 2 innate lymphoid cells (ILC2s) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We used cell systems and genetic models to examine the mechanism through which IL-13, an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drove beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPAR gamma-related pathways. The latter was mediated by increased expression and activity of PPAR gamma through the IL-13 receptor 1 (IL-13R1) downstream effectors STAT6 and p38 MAPK, respectively. Il13-KO or preadipocyte Il13ra1-KO mice were refractory to cold-or beta 3-adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4-KO mice showed no defects in beige adipogenesis. Il13-KO and Il13ra1-KO mouse models exhibited increased body weight and fat mass and dysregulated glucose metabolism but had a mild cold-intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also found that genetic variants of human IL13RA1 were associated with BMI and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.

关键词： Disease severity system   Hierarchical intervention   IgA vasculitis nephritis   Immune function   Inflammatory factors  

摘要： The objective of this study is to study the effects of a disease severity-based nursing intervention in children with immunoglobulin A (IgA) vasculitis nephritis, including recombinant human interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). A sample of 104 children treated at the Nephrology Department from May 2021 to May 2023 was selected for this study. The division into groups depended on distinct nursing approaches: the control group (n = 52) received conventional intervention, including basic skin care, dietary advice, and parental communication, without disease severity stratification. The research group (n = 52) received a three-level intervention (grade I, nurse-patient ratio 1:6, 12-hourly rounds, UV irradiation once daily;grade II, nurse-patient ratio 1:3, 9-hourly rounds, protein-restricted diet;grade III, nurse-patient ratio 1:1, 6-hourly rounds, liquid diet and continuous UV) based on severity. Both groups received standardized medications. Comparative analysis was conducted before intervention, 2 weeks, and 4 weeks to evaluate immune function, inflammatory factors, and renal function indicators. Initially, no statistically significant differences in immune indicators, inflammatory factors, or renal function indicators were observed in both groups (p > 0.05). After receiving care for 2 and 4 weeks, the research group displayed notably higher levels of CD3(+) and CD4(+) T cells in differentiated clusters (p < 0.05). Additionally, the research group demonstrated lower levels of natural killer cells, IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM) (p < 0.05). Furthermore, IFN-gamma, IL-6, and TNF-alpha levels were notably lower in the research group (p < 0.05). Key renal function indicators, including erythrocyte count, microalbuminuria (mALB), 24-h urine protein quantity, and serum beta(2)-microglobulin (beta(2)-MG), were significantly reduced in the research group (p < 0.05). Systematic hierarchical