27 research outputs found
The Development of Linguistic Competences for Employability: A Training Project for Teachers
AbstractEmployability is a new concept that has just appeared in the Spanish educational system. Its rising importance is due to European Union educational policies which aim to provide young people with training that enables them to take part successfully in the present and future working world.This paper argues for the need to develop employability from the very start of formal education, and within this, we highlight the importance of developing linguistic competence among pre-school and primary pupils as a key element for favouring employability.To be able to do so, the teaching staff must be trained using quality education to enable them to work effectively on this competence. In this paper we present how a training program, with a specific European dimension, has been designed by a state school from the Valencian Community, to serve as a model for other schools concerned about the development of a linguistic competence that helps to improve both teachers’ and pupils’ employability
Corrigendum:TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human
TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human
TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies
Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.
KEYWORDS:
Craniopharyngioma; IL1-β; Inflammasome; MAPK/ERK pathway; Odontogenesis; Paracrine signalling; Trametini
Cell Senescence in Neuropathology: a Focus on Neurodegeneration and Tumours
The study of cell senescence is a burgeoning field. Senescent cells can modify the cellular microenvironment through the secretion of a plethora of biologically active products referred to as the senescence‐associated secretory phenotype (SASP). The consequences of these paracrine signals can be either beneficial for tissue homeostasis, if senescent cells are properly cleared and SASP activation is transient, or result in organ dysfunction, when senescent cells accumulate within the tissues and SASP activation is persistent. Several studies have provided evidence for a role of senescence and SASP in promoting age‐related diseases or driving organismal ageing. The hype about senescence has been further amplified by the fact that a group of drugs, named senolytics, have been used to successfully ameliorate the burden of age‐related diseases and increase health and life span in mice. Ablation of senescent cells in the brain prevents disease progression and improve cognition in murine models of neurodegenerative conditions. The role of senescence in cancer has been more thoroughly investigated, and it is now accepted that senescence is a double‐edged sword that can paradoxically prevent or promote tumourigenesis in a context dependent manner. In addition, senescence induction followed by senolytic treatment is starting to emerge as a novel therapeutic avenue that could improve current anti‐cancer therapies and reduce tumour recurrence. In this review, we discuss recent findings supporting a role of cell senescence in the pathogenesis of neurodegenerative diseases and in brain tumours. A better understanding of senescence is likely to result in the development of novel and efficacious anti‐senescence therapies against these brain pathologies
Evaluation of Reduced Reaction Volumes for Quantifiler® Duo and Quantifiler® Trio
Quantitation of human DNA is a critical but expensive step in forensic DNA analysis. Quantifiler® Duo and Quantifiler® Trio are two commercial kits commonly used. Reduction in reaction volume holds a large potential for cost savings for laboratories. This work evaluated reducing reaction volume to ~25% of manufacturer\u27s protocol. Both kits returned reproducible quantitation results in reduced volumes and provided comparable results between the two reaction volumes. Elevated or IPC undetected IPC CT in reduced Quantifiler® Duo reaction volume does not predict inhibited STR amplification. Degraded samples returned comparable results in reduced and full volume reactions in Quantifiler® Trio
Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors
Sonic hedgehog (SHH) is an essential morphogenetic signal dictating cell fate decisions in several developing organs in mammals. In vitro data suggest that SHH is required to specify LHX3+/LHX4+ Rathke's pouch (RP) progenitor identity. However, in vivo studies have failed to reveal such a function, supporting instead, a critical role for SHH in promoting proliferation of these RP progenitors and for differentiation of pituitary cell types. Here, we have used a genetic approach to demonstrate that activation of the SHH pathway is necessary to induce LHX3+/LHX4+ RP identity in mouse embryos. First, we show that conditional deletion of Shh in the anterior hypothalamus results in a fully penetrant phenotype characterised by a complete arrest of RP development, with lack of Lhx3/Lhx4 expression in RP epithelium at 9.0 dpc (days post coitum) and total loss of pituitary tissue by 12.5 dpc. Conversely, over-activation of the SHH pathway by conditional deletion of Ptch1 in RP progenitors leads to severe hyperplasia and enlargement of the Sox2+ve stem cell compartment by the end of gestation.</jats:p