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关键词： Necrotizing Enterocolitis   Cytomegalovirus   TLR4 Signaling   3' -NT   3'-nitrotyrosine   ATCC   American Type Culture Collection   ATP   adenosine triphosphate   CMV   cytomegalovirus   DHE   dihydroethidium   GSEA   gene set enrichment analysis   H&E   hematoxylin-eosin   IEC-6   intestinal epithelial cells   Ifng   interferon gamma   LPS   lipopolysaccharide   mCMV   murine cytomegalovirus   mtDNA   mitochondrial DNA   NEC   necrotizing enterocolitis   NECA   5'-N-ethylcarboxamido adenosine   NF-κB   nuclear factor kappa B   qRT-PCR   quantitative reverse transcription polymerase chain reaction   ROS   reactive oxygen species   scRNA-seq   single-cell RNA sequencing   TLR4   toll-like receptor 4   Tnf   tumor necrosis factor  

摘要： BACKGROUND AND AIMS: Necrotizing enterocolitis (NEC) is life-threatening condition in premature infants, marked acute intestinal necrosis. NEC develops in part after activation of the lipopolysaccharide receptor toll-like receptor 4 (TLR4) by intestinal microbes in the intestinal epithelium. Previous authors have shown an increased risk of NEC in human infants after cytomegalovirus (CMV) infection, which can affect mitochondrial function. We now seek to explore the impact and the mechanisms of CMV infection on NEC severity and its relationship with TLR4 signaling and mitochondria function. METHODS: NEC was induced in newborn mice with and without CMV infection. RNA sequencing and gene set enrichment analysis were performed to identify effects on inflammatory and metabolic pathways. The role of TLR4 signaling and mitochondrial function were investigated in wild-type and Tlr4-deficient mice. The adenosine receptor agonist 5'-N-ethylcarboxamido adenosine was tested for its ability to reduce C MV-induced effects on NEC severity. RESULTS: CMV infection significantly increased NEC severity in wild-type mice. Mechanistically, CMV infection triggered proinflammatory pathways, disrupted cellular metabolism, and upregulated Tlr4 expression, leading to mitochondrial dysfunction and nuclear factor-kB translocat ion. These effects were notably absent in Tlr4deficient mice. 5'-N-ethylcarboxamido adenosine treatment reversed CMV-induced NEC severity by reducing mitochondrial dysfunction and TLR4-driven nuclear factorkB activation. CONCLUSIONS: CMV infection worsens NEC severity in mice by amplifying TLR4 signaling, inflammation, and mitochondrial dysfunction. Targeting CMV and its influence on TLR4 may offer novel therapeutic approaches for NEC

关键词： Type 2 diabetes (T2D)   Bifidobacterium longum   Lactiplantibacillus rhamnosus   Insulin sensitivity   IL-22  

摘要： Type 2 diabetes (T2D) is known as adult-onset diabetes, but recently, T2D has increased in the number of younger people, becoming a major clinical burden in human society. The objective of this study was to determine the effects of Bifidobacterium and Lactiplantibacillus strains derived from the feces of 20 healthy humans on T2D development and to understand the mechanism underlying any positive effects of probiotics. We found that Bifidobacterium longum NBM7-1 (Chong Kun Dang strain 1;CKD1) and Lactiplantibacillus rhamnosus NBM17-4 (Chong Kun Dang strain 2;CKD2) isolated from the feces of healthy Korean adults (n = 20) have anti-diabetic effects based on the insulin sensitivity. During the oral gavage for 8 weeks, T2D mice were supplemented with anti-diabetic drugs (1.0-10 mg/kg body weight) to four positive and negative control groups or four probiotics (200 uL;1 x 10(9) CFU/mL) to groups separately or combined to the four treatment groups (n = 6 per group). While acknowledging the relatively small sample size, this study provides valuable insights into the potential benefits of B. longum NBM7-1 and L. rhamnosus NBM17-4 in mitigating T2D development. The animal gene expression was assessed using a qRT-PCR, and metabolic parameters were assessed using an ELISA assay. We demonstrated that B. longum NBM7-1 in the CKD1 group and L. rhamnosus NBM17-4 in the CKD2 group alleviate T2D development through the upregulation of IL-22, which enhances insulin sensitivity and pancreatic functions while reducing liver steatosis. These findings suggest that B. longum NBM7-1 and L. rhamnosus NBM17-4 could be the candidate probiotics for the therapeutic treatments of T2D patients as well as the prevention of type 2 diabetes.

关键词： HLA   HLA-C*03:86   recombination   sequence-based typing   Taiwanese  

摘要： Recombination between C*03:03:01:01 and C*01:02:01:01 results in the novel allele, HLA-C*03:86.

关键词： TNF   MUC4   Triple negative breast cancer   Immunotherapy   Metastasis  

摘要： Purpose: Triple-negative breast cancer (TNBC) has the worst prognosis among breast cancers. Immunotherapy is a therapeutic option, but there is no biomarker to guide promising combination treatments. Mucin 4 (MUC4) favors metastasis in preclinical cancer models. This study evaluates the efficacy of soluble TNF (sTNF) neutralization to tackle MUC4 expression preventing metastasis in combination with immunotherapy, and the potential use of MUC4 as a prognostic and predictive biomarker in TNBC patients. Experimental Design: To explore TNF modulation of MUC4 expression, a panel of TNBC cell lines was used. To assess the effect of sTNF blockade with a dominant negative molecule in combination with anti-PD-1 antibody on lung metastasis and overall survival (OS), 4T1 and LMM3 tumors were used. MUC4, PD-L1 and Ki-67 expression was evaluated by immunohistochemistry, and tumor infiltrating lymphocytes (TILs) were assessed by H&E staining, in a cohort of 49 early TNBC patients treated with chemotherapy. Results: TNF neutralization reduces MUC4 expression in TNBC cell lines. Only the combination of sTNF blockade with anti-PD-1 antibody prevents metastasis and increases mice survival. In early TNBC patients MUC4 expression is inversely associated with TILs presence and PD-L1 and Ki-67 expression. Finally, MUC4 is associated with metastasis and is an independent biomarker of poor OS. Conclusions: We proved the existence of a sTNF/MUC4 axis in TNBC that can be actionable by sTNF neutralization, preventing metastasis. We suggest that MUC4 is a suitable biomarker to guide immunotherapy in TNBC, together with the administration of sTNF blocking drugs to improve outcome.

关键词： Key words Illicit drug trade   Gun violence   Drug control   Homicides   Health disparate   minority and vulnerable populations  

摘要： The article maps relationships between armed violence (AV) and the illicit drug trade through an integrative review focused on empirical research. The sample included 20 articles, categorized to year of publication and fieldwork, objectives, methods, study location and results. The results were based on thematic content analysis and showed that the relationship between IDT and AV occurs Organized Armed Violence. However, this violence spreads, affecting society, especially residents of peripheral The following stood out: Availability of Firearms (AF), with a broad presence in the IDT environment;violence, highlighting the need to use FA for the IDT due to its illegality and militarized perspective State action, thematizes the absence of preventive public security in peripheral areas and the violent, ineffective action of the State;Armed territorial dominance, shows the strength of the organized IDT effects on the population;Young black people: primary victims and perpetrators, highlights the vulnerability young people to AV and also Health impacts.

关键词： Staphylococcus aureus   Baimao-Longdan-Congrong-Fang   alpha-hemolysin   Sortase A   Mice pneumonia model  

摘要： Background: Baimao-Longdan-Congrong-Fang (BLCF), a traditional Chinese herbal formula described in the Taiping Shenghui Fang (998 AD), consists of medicinal plants with heat-clearing and tonifying properties. BLCF has a promise as a treatment for Staphylococcus aureus (S. aureus) pneumonia, according to its historical use and current pharmacological research. Purpose: In this study, the inhibitory effects of BLCF on S. aureus virulence factors were evaluated in vitro, and its mechanisms of action were investigated in a methicillin-resistant S. aureus (MRSA) pneumonia mouse model. Methods: The inhibitory effect of BLCF on S. aureus virulence factors, including sortase A (SrtA) and alpha-hemolysin (Hla), was investigated by fluorescence resonance energy transfer (FRET) and hemolysis assays. A C57BL/6J mouse model of MRSA pneumonia was employed to evaluate its therapeutic efficacy. Accordingly, an integrated strategy of medicinal chemistry, network pharmacology analysis, GEO database analysis, bioinformatics, molecular docking, molecular dynamics simulation, GeneMANIA-based functional association (GMFA), and GSEA was used to identify and illustrate potential therapeutic targets and mechanisms. Subsequently, the mechanistic results were confirmed by Western blot analysis and RT-qPCR. Results: While BLCF exhibited weak inhibitory activity against S. aureus USA300, Newman, and SA37 strains, it significantly suppressed SrtA-related virulence functions without affecting bacterial growth. FRET and hemolysis assays confirmed that BLCF inhibited SrtA activity (IC50 = 1.25 mg/mL) while decreasing hemolytic activity. Furthermore, BLCF protected mice from MRSA infection, increasing their survival rates. Bioinformatics analysis identified 26 active compounds and 2 hub genes (Tnf and Mmp9) that were associated with 5 types of immune cell, including activated CD4 T cells, myeloid-derived suppressor cells, activated dendritic cells, macrophages, and mast cells. Molecular docking reve

关键词： Platelet transfusion   Hla antigens   Antibody formation   Systematic Review   Meta-Analysis  

摘要： Platelet refractoriness caused by alloimmunization to anti-HLA antibodies remains present in daily hemotherapy: the frequent need for platelet transfusions may influence the longterm survival of treated patients. This study aimed to perform a systematic review with meta-analysis to investigate the chances of anti-HLA antibody formation triggering immune-induced platelet refractoriness in platelet transfused individuals. By adopting Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, a search was conducted of publications in online databases between 1976 and July 2022. The risk of bias in the studies was assessed according to the data quality assessment proposed by the 'A MeaSurement Tool to Assess systematic Reviews' (AMSTAR-2) tool. Meta-analysis was performed by evaluating the Forest and Funnel Plots. From 832 published articles, 50 were read in full with 14 studies being included in this systematic review. The forest plot showed a likely low heterogeneity (I2: 12.3%;p-value = 0.32), and high odds ratio (174.57;confidence interval: 73.23-416.16) showing platelet refractoriness is triggered by anti-HLA alloantibodies. In this study, anti-HLA antibody formation contributed to an approximate 175-fold higher chance of triggering immune-induced platelet refractoriness. Some explanations about why some statistical differences were observed are offered by studies. This study demonstrates the need for developing policies to identify and monitor anti-HLA antibodies in patients, as well as for HLA matching, and makes some suggestions for future research to promote the prevention of patient sensitization due to platelet transfusions including the development of platelet refractoriness. (c) 2025 Associa & ccedil;& atilde;o Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Espa & ntilde;a, S.L.U. This is an open access article under the CC BY license (http://***/licenses/by/4.0/).