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关键词： fibrinolysis   proximity extension assay   renal fibrosis   TNF   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 t-test to identify differentially expressed proteins between fibrotic (n = 31) and non-fibrotic patients (n = 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： biological DMARD   Observational studies/ registry   Real-world evidence  

关键词： Psoriasis   pustular psoriasis   acute generalized exanthematous pustulosis   dermatology   spesolimab  

摘要： There can be an elegance and great sense of satisfaction associated with understanding the underlying pathogenesis of a complex condition. Diabetes, for example, is an extraordinarily complex condition with diverse implications across multiple org...

关键词： Laryngeal squamous cell carcinoma   Non-coding RNA   circHIPK2   miR-889-3p   MCTS1   IL-6   Tumor microenvironment  

摘要： Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor of the head and neck with a poor prognosis. The role of circRNAs in LSCC remains largely unknown. In this study, quantitative real-time PCR (qRTPCR), Sanger sequencing and fluorescence in situ hybridization were undertaken to detect the expression, localization, and clinical significance of circHIPK2 in LSCC tissues and TU686 and TU212 cells. The functions of circHIPK2 in LSCC were explored through proliferation analysis, EdU staining, colony formation assay, wound healing assay, and Transwell assay. The regulatory mechanisms underpinning circHIPK2, miR-889-3p, and MCTS1 were investigated using luciferase assay, Western blotting, and qRT-PCR. We found that LSCC tissues and cells demonstrated high expression of circHIPK2 that was closely associated with the malignant progression and poor prognosis of LSCC. Knockdown of circHIPK2 inhibited the proliferation and migration of LSCC cells in vitro. Mechanistic studies showed that circHIPK2 competitively bound to miR-889-3p, elevated MCTS1 level, promoted IL-6 secretion, and ultimately accelerated the malignant progression of LSCC. In conclusion, an axis involving circHIPK2, miR-889-3p, MCTS1 and IL-6 regulates the malignant progression of LSCC. circHIPK2 expression may serve as a novel diagnostic and prognostic biomarker for LSCC.

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.

关键词： acetyl CoA   glycolysis   immunometabolism   interferon   STING  

摘要： Interferon gamma (IFN-gamma) is a pleotropic cytokine which is a central mediator of the immune response to pathogen infection, while also playing important roles in tumour suppression and the pathogenesis of various autoimmune diseases. Consequently, there is potential utility in the treatment of a number of pathological conditions via being able to modify IFN-gamma secretion. T cells and natural killer (NK) cells are the primary IFN-gamma sources, with metabolic rewiring prior to their activation and IFN-gamma secretion in both a unifying feature. The mechanisms by which metabolic changes, particularly increased glycolysis, drive enhanced IFN-gamma production are multi-faceted, but are likely focused on epigenetic changes via increased acetyl CoA levels which fuels histone acetylation. Herein, we discuss the mechanisms by which metabolic changes drive altered IFN-gamma synthesis by immune cells.

关键词： DNA sequence analysis   exons   high-throughput nucleotide sequencing   nucleic acid databases   single nucleotide polymorphisms  

摘要： The novel HLA-DRB1*11:341 allele differs from DRB1*11:01:01:01 by change of C -> A in exon 4.

关键词： Language policy   Legitimation analysis   Structured English Immersion   Discourse analysis   Arizona  

摘要： For over two decades, emergent bilingual students in Arizona have languished under the state's English-only Structured English Immersion policies. Using Theo Van Leeuwan's (2007) legitimation in discourse framework, this study longitudinally tracks shifts in legitimation tactics across the four iterations of the policy-its inception with Proposition 203, its strengthening with House Bill 2064, the introduction of a multiple pathways framework-which included a dual language immersion (DLI) model-with Senate Bill 1019, and the reelection of Tom Horne followed by the legal challenge of the newly approved DLI model. Analysis shows how changing policy contexts and the provision of counterevidence-both empirical and anecdotal-have delegitimized initial arguments for the policy. Yet, despite this, English-only education still maintains its grip on emergent bilingual students. The reason for this is found in the words of Tom Horne, "We all have to obey the law." This single form of impersonal authorization renders all counterevidence and delegitimating tactics moot. Constitutional protection allowed policymakers to strengthen a failed English-only policy in 2006 with the passage of HB 2064, and the same protection has seemingly derailed the attempt to implement DLI with the unanimous passage of SB 1019. More empirical counterevidence will not change this failed policy, nor can bipartisan legislative support. I argue that the only path forward is to change the law that single-handedly legitimizes the policy-something that can only be done through another voter-initiated proposal.

关键词： IL-1 beta   Prostaglandin   Myometrium cells   Cervical stromal cells   Labor onset  

摘要： Inflammatory cytokines such as IL-1 beta and prostaglandins (PGs) are pivotal in the initiation of labor. Nevertheless, the synergistic interaction between PGs and IL-1 beta remains to be fully elucidated. Labor is defined as regular and gradually increasing uterine contractions accompanied by progressive dilation of the cervix, and descent of the fetal. This study employed Luminex to monitor alterations in inflammatory cytokine levels within myometrial tissue (n = 10) during labor compared to non-labor (n = 10) conditions. And the synergistic relationship between PGs and IL-1 beta by investigating the primary myometrium cells and cervical stromal cells culture. The results showed that the inflammatory cytokines of IL-1 beta, IL-6, IL-8 and TNF-alpha in the myometrium tissue were increased in labor group. In myometrium cells, PGF2 alpha and IL-1 beta synergistically up-regulated COX-2 mRNA, upregulated the transcription of PRA and PRB, PGF2 alpha alleviated that IL-1 beta up-regulated IL-8 mRNA. In cervical stromal cells, IL-1 beta up-regulated the COX-2 and PRB protein expression. PGE2 abated that IL-1 beta up-regulated IL-8 mRNA. PGE increased the expression of PRs, which is more pronounced with the prolonged duration. Ratio of PRA/PRB show an increased trend with IL-1 beta and PGE2 co-regulated. This study further clarified the synergistic regulatory mechanism of IL-1 beta and PGs, offering a theoretical foundation for the development of strategies aimed at labor induction and the prevention and treatment of preterm birth.

关键词： Vaccines   Bioinformatics   Immunogenic peptides   COVID 19  

摘要： Vaccines stimulate cells of the adaptive immune system, generating a protective and lasting memory, and are the main public health strategy to protect the world population from emerging pathogens such as the SARS-CoV-2 virus, responsible for millions of deaths in the recent COVID-19 pandemic. Several in-silico algorithms have facilitated the selection of antigens as vaccine candidates;however, their predictive capacity remains limited and it is necessary to continue training them, using information obtained in immunological assays. In this work, the SARS-CoV-2 proteome was sampled using a series of concatenated algorithms that allowed us to define a series of candidate viral peptides for a vaccine against SARS-CoV-2 in individuals from Colombian, whose haplotypes for HLA-I and II were incorporated as part of the algorithm. The immunogenicity of the peptides predicted with three tools or with the combination of them was evaluated and found that short peptides predicted and selected as highly immunogenic peptides were capable of expanding memory CD8 T lymphocytes with an activation phenotype. Altogether, our results outline a pipeline that combines a bioinformatic and immunological approach useful to select immunogenic epitopes from emerging pathogens as vaccine candidates tailored to the population's HLA-Haplotypes.