Autoinflammation is the standard mechanism seen in systemic autoinflammatory disease (SAID) patients. This study aimed to investigate the effect of a candidate miRNA, miR-30e-3p, which was identified ...in our previous study, on the autoinflammation phenotype seen in SAID patients and to analyze its expression in a larger group of European SAID patients. We examined the potential anti-inflammatory effect of miR-30e-3p, which we had defined as one of the differentially expressed miRNAs in microarray analysis involved in inflammation-related pathways. This study validated our previous microarray results of miR-30e-3p in a cohort involving European SAID patients. We performed cell culture transfection assays for miR-30e-3p. Then, in transfected cells, we analyzed expression levels of pro-inflammatory genes; IL-1β, TNF-α, TGF-β, and MEFV. We also performed functional experiments, caspase-1 activation by fluorometric assay kit, apoptosis assay by flow cytometry, and cell migration assays by wound healing and filter system to understand the possible effect of miR-30e-3p on inflammation. Following these functional assays, 3'UTR luciferase activity assay and western blotting were carried out to identify the target gene of the aforementioned miRNA. MiR-30e-3p was decreased in severe European SAID patients like the Turkish patients. The functional assays associated with inflammation suggested that miR-30e-3p has an anti-inflammatory effect. 3'UTR luciferase activity assay demonstrated that miR-30e-3p directly binds to interleukin-1-beta (IL-1β), one of the critical molecules of inflammatory pathways, and reduces both RNA and protein levels of IL-1β. miR-30e-3p, which has been associated with IL-1β, a principal component of inflammation, might be of potential diagnostic and therapeutic value for SAIDs.
Key Messages
miR-30e-3p, which targets IL-1β, could have a role in the pathogenesis of SAID patients.
miR-30e-3p has a role in regulating inflammatory pathways like migration, caspase-1 activation.
miR-30e-3p has the potential to be used for future diagnostic and therapeutic approaches.
We investigate the influence of articles, authors, journals and institutions in the field of environmental and ecological economics. We depart from studies that investigated the literature until 2001 ...and include a time period that has witnessed an enormous increase of importance in the field. We adjust for the age effect given the huge impact of the year of an article's publication on its influence and we show that this adjustment does make a substantial difference — especially for disaggregated units of analysis with diverse age characteristics such as articles or authors. We analyse 6597 studies on environmental and ecological economics published between 2000 and 2009. We provide rankings of the influential articles, authors, journals and institutions and find that Ecological Economics, Energy Economics and the Journal of Environmental Economics and Management have the most influential articles, they publish very influential authors and their articles are cited most. The University of Maryland, Resources for the Future, the University of East Anglia and the World Bank appear to be the most influential institutions in the field of environmental and ecological economics.
► We investigate the influence of articles, authors, journals and institutions in environmental and ecological economics. ► We analyse 6597 studies published between 2000 and 2009. ► We adjust for the age effect and use various criteria for influence. ► With articles, journals and institutions, there are clear ‘leaders’. ► With authors, influence is very sensitive to the criterion used.
Diagnosis of systemic autoinflammatory diseases (SAIDs) is often difficult to achieve and can delay the start of proper treatments and result in irreversible organ damage. In several patients with ...dominantly inherited SAID, postzygotic mutations have been detected as the disease-causing gene defects. Mutations with allele frequencies <5% have been detected, even in patients with severe phenotypes. Next-generation sequencing techniques are currently used to detect mutations in SAID-associated genes. However, even if the genomic region is highly covered, this approach is usually not able to distinguish low-grade postzygotic variants from background noise. We, therefore, developed a sensitive deep sequencing assay for mosaicism detection in SAID-associated genes using single-molecule molecular inversion probes. Our results show the accurate detection of postzygotic variants with allele frequencies as low as 1%. The probability of calling mutations with allele frequencies ≥3% exceeds 99.9%. To date, we have detected three patients with mosaicism, two carrying likely pathogenic NLRP3 variants and one carrying a likely pathogenic TNFRSF1A variant with an allele frequency of 1.3%, confirming the relevance of the technology. The assay shown herein is a flexible, robust, fast, cost-effective, and highly reliable method for mosaicism detection; therefore, it is well suited for routine diagnostics.
There has been substantial evolution in the treatment of metastatic renal cell carcinoma with notable changes in the first-line setting. Currently, doublet combination therapy with either two immune ...checkpoint inhibitors or a combination of an immune checkpoint and tyrosine kinase inhibitor is considered the standard of care. The doublet combination therapies have demonstrated significantly improved clinical outcomes. A recently conducted trial (COSMIC-313) showed superior efficacy with a triplet combination of cabozantinib, nivolumab, and ipilimumab when compared to a placebo, nivolumab, and ipilimumab but at the cost of additional toxicity. Many other combination treatments, such as pembrolizumab plus lenvatinib plus belzutifan (NCT04976634), are being investigated, possibly leading to more options in the first-line setting in the future.
Learning and processing natural language requires the ability to track syntactic relationships between words and phrases in a sentence, which are often separated by intervening material. These ...nonadjacent dependencies can be studied using artificial grammar learning paradigms and structured sequence processing tasks. These approaches have been used to demonstrate that human adults, infants and some nonhuman animals are able to detect and learn dependencies between nonadjacent elements within a sequence. However, learning nonadjacent dependencies appears to be more cognitively demanding than detecting dependencies between adjacent elements, and only occurs in certain circumstances. In this review, we discuss different types of nonadjacent dependencies in language and in artificial grammar learning experiments, and how these differences might impact learning. We summarize different types of perceptual cues that facilitate learning, by highlighting the relationship between dependent elements bringing them closer together either physically, attentionally, or perceptually. Finally, we review artificial grammar learning experiments in human adults, infants, and nonhuman animals, and discuss how similarities and differences observed across these groups can provide insights into how language is learned across development and how these language‐related abilities might have evolved.
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