Multidimensional Scaling Reveals the Main Evolutionary Pathways of Class A G-Protein-Coupled Receptors

Class A G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors in the human genome. Understanding the mechanisms which drove the evolution of such a large family would help understand the specificity of each GPCR sub-family with applications to drug design. To gain evolutionary information on class A GPCRs, we explored their sequence space by metric multidimensional scaling analysis (MDS). Three-dimensional mapping of human sequences shows a non-uniform distribution of GPCRs, organized in clusters that lay along four privileged directions. To interpret these directions, we projected supplementary sequences from different species onto the human space used as a reference. With this technique, we can easily monitor the evolutionary drift of several GPCR sub-families from cnidarians to humans. Results support a model of radiative evolution of class A GPCRs from a central node formed by peptide receptors. The privileged directions obtained from the MDS analysis are interpretable in terms of three main evolutionary pathways related to specific sequence determinants. The first pathway was initiated by a deletion in transmembrane helix 2 (TM2) and led to three sub-families by divergent evolution. The second pathway corresponds to the differentiation of the amine receptors. The third pathway corresponds to parallel evolution of several sub-families in relation with a covarion process involving proline residues in TM2 and TM5. As exemplified with GPCRs, the MDS projection technique is an important tool to compare orthologous sequence sets and to help decipher the mutational events that drove the evolution of protein families

Völkisch und sozial? : Neonazistische Agitation gegen die neue EU-Freizügigkeit für Arbeitnehmerinnen

Wnt/β-catenin signalling pathway is crucial for the formation of many tissues and organs during development. In recent years, this pathway has also been found to regulate the biology of stem cells in the intestine and probably in other organs in adult life. Abnormal activation of Wnt/β-catenin signalling, which controls the expression of a high number of genes, is critical for the initiation and progression of most colorectal cancers. In line with this, the gene expression signature induced by activation of the Wnt/β-catenin pathway defines the intestinal stem cells present at the bottom of the crypts and also colon cancer stem cells. This supports the importance of inhibitors of the Wnt/β-catenin pathway as potential agents in colorectal cancer therapy. However, the complexity, wide activity in the organism modulating the biology of several cell types, and characteristics of this pathway have delayed the identification of suitable targets and so, the development of such inhibitors that are only now reaching the clinic.Peer reviewe

Supporting immigrant language learning on smartphones: A field trial

The challenge of supporting immigrant language learning and social integration has increased recently, leading to initiatives and projects that aim to provide assistance, including using smartphones in the course of daily activities. However, much of the Mobile Assisted Language Learning (MALL) literature focuses on classroom based learning, leaving a gap in understanding learning in informal settings. This paper discusses a UK field trial of the European funded MASELTOV project, which developed a suite of smartphone tools and services (the ‘MApp’) to help immigrants’ language learning and social inclusion in four European cities. MApp tools and services include language lessons designed to assist informal learning in everyday life, focusing on situational language needs and a social forum for peer support, cultural information, comments and practice. The paper reports on interview data and social forum use. Our findings suggest that the MApp helps immigrants with their confidence; with relevant, practical language learning and practice of different language skills, and supports social learning. Studying and practising language skills in locations and at times that learners choose, along with access to a social forum for socio-emotional support and feedback, is a powerful combination for informal mobile language learning