ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION

Macrophages are cells from the innate branch of immune system with central roles both under physiologic and pathologic conditions. Such complex behaviour relies on extreme functional plasticity of these cells. Cellular activation and plasticity in macrophages are complex phenomena that require tight regulation. In recent years, microRNAs and lncRNAs emerged as important regulators of many cellular processes and have been proposed as key mediators of the plasticity observed in macrophages. In this study we investigate the possible roles of different microRNAs on macrophage activation and functionality, taking advantage of animal models selectively depleted of candidate miRNA in macrophages. We found that selective depletion of miR-125a in macrophages did not affect clinical outcome in different in vivo models of inflammation. Nonetheless it altered macrophage activation and functions, as evidenced by reduced secretion of TNF\u3b1 after endotoxin challenges. Consistently, macrophages deficient in miR-125a displayed reduced killing of extracellular bacteria although they showed increased phagocytic rate as compared to miR-125a competent cells. With a similar approach, we confirmed that miR-9 is induced in macrophages upon inflammatory stimuli. Increased expression of miR-9 mature form in mice was sustained by the synchronous activation of transcription in both pri-miR-9.1 and pri-miR-9.3 loci, in contrast to human. Finally we identified a lncRNA interfering with the processing of a pro-inflammatory miRNA in differentially activated human macrophages, highlighting a new layer of regulation of macrophage activation. The finding of the present project give new insights into the complex mechanism regulating macrophage activation and underscores the need for future studies to thoroughly identify the molecular mechanisms and the involvement of different miRNA in macrophage activation. Moreover, such studies could set the basis for the transition from basic research to new therapeutic options enabling precise regulation of macrophages activation in different immune pathologies

Some practical issues related to migration in the angle domain

The benefits of recasting pre-stack depth migration in the angle domain are such to suggest its application in industrial Kirchhoff PSDM software. Here we examine some practical aspects of the implementation in the angle domain, namely those that mostly impact performances and effectiveness: memory requirements, poor illumination and errors in velocity estimatio

Effect of donepezil on the expression and responsiveness to LPS of CHRNA7 and CHRFAM7A in macrophages : a possible link to the cholinergic anti-inflammatory pathway

The \u3b17 nicotinic acetylcholine receptor (CHRNA7)modulates the inflammatory response by activating the cholinergic anti-inflammatory pathway. CHRFAM7A, the human-restricted duplicated form of CHRNA7, has a negative effect on the functioning of \u3b17 receptors, suggesting that CHRFAM7A expression regulation may be a key step in the modulation of inflammation in the human setting. The analysis of the CHRFAM7A gene's regulatory region reveals some of the mechanisms driving its expression and responsiveness to LPS in human immune cell models. Moreover, given the immunomodulatory potential of donepezil we show that it differently modulates CHRFAM7A and CHRNA7 responsiveness to LPS, thus contributing to its therapeutic potential

Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues

Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression

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