Purinergic P2X7 receptors (P2X7R) are fundamental to innate immune response. In macrophages, transient stimulation of P2X7R activates several transport mechanisms and induces the scrambling of phospholipids with subsequent membrane blebbing and apoptosis. These processes support phagocytosis and subsequent killing of phagocytosed bacteria. Here we demonstrate that the stimulation of P2X7 receptors activates anoctamin 6 (ANO6, TMEM16F), a protein that functions as Ca(2+) dependent phospholipid scramblase and Ca(2+)-activated Cl(-) channel. Inhibition or knockdown of ANO6 attenuates ATP-induced cell shrinkage, cell migration and phospholipid scrambling. In mouse macrophages, Ano6 produces large ion currents by stimulation of P2X7 receptors and contributes to ATP-induced membrane blebbing and apoptosis, which is largely reduced in macrophages from Ano6-/- mice. ANO6 supports bacterial phagocytosis and killing by mouse and human THP-1 macrophages. Our data demonstrate that anoctamin 6 is an essential component of the immune defense by macrophages.

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. Here we show that the glycolytic enzyme pyruvate kinase M2 (PKM2) limits glucose oxidation, and maintains the growth and epigenetic state of ECs. We find that loss of PKM2 alters mitochondrial substrate utilization and impairs EC proliferation and migration in vivo. Mechanistically, we show that the NF-κB transcription factor RELB is responsive to PKM2 loss, limiting EC growth through the regulation of P53. Furthermore, S-adenosylmethionine synthesis is impaired in the absence of PKM2, resulting in DNA hypomethylation, de-repression of endogenous retroviral elements (ERVs) and activation of antiviral innate immune signalling. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs.

The role of calcium-activated chloride channels for renal function is unknown. By immunohistochemistry we demonstrate dominant expression of the recently identified calcium-activated chloride channels, Anoctamin 1 (Ano1, TMEM16A) in human and mouse proximal tubular epithelial (PTE) cells, with some expression in podocytes and other tubular segments. Ano1-null mice had proteinuria and numerous large reabsorption vesicles in PTE cells. Selective knockout of Ano1 in podocytes (Ano1-/-/Nphs2-Cre) did not impair renal function, whereas tubular knockout in Ano1-/-/Ksp-Cre mice increased urine protein excretion and decreased urine electrolyte concentrations. Purinergic stimulation activated calcium-dependent chloride currents in isolated proximal tubule epithelial cells from wild-type but not from Ano1-/-/Ksp-Cre mice. Ano1 currents were activated by acidic pH, suggesting parallel stimulation of Ano1 chloride secretion with activation of the proton-ATPase. Lack of calcium-dependent chloride secretion in cells from Ano1-/-/Ksp-Cre mice was paralleled by attenuated proton secretion and reduced endosomal acidification, which compromised proximal tubular albumin uptake. Tubular knockout of Ano1 enhanced serum renin and aldosterone concentrations, probably leading to enhanced compensatory distal tubular reabsorption, thus maintaining normal blood pressure levels. Thus, Ano1 has a role in proximal tubular proton secretion and protein reabsorption. The results correspond to regulation of the proton-ATPase by the Ano1-homolog Ist2 in yeast.

The aim of this article is to present some contributions to the understanding of social inequality in Europe today. We analyse the distributional inequalities of economic and educational resources as well as the categorical inequalities between nation states and between social classes. The source of the empirical data was the European Social Survey 2012. We were able to calculate European income deciles, build a matrix of class-country segments, and analyse the intersections of this structural matrix with the distributions of income and schooling. The results reveal high degrees of distributional inequality in Europe. They also show the structural configurations assumed in Europe by the intersection of distributive and categorical inequalities.Keywords inequality, Europe, income, education, class.Resumo O objetivo deste artigo é apresentar alguns contributos para a compreensão das desigualdades sociais na Europa atual. Analisam-se as desigualdades distributivas de recursos económicos e educativos assim como as desigualdades categoriais entre estados nacionais e entre classes sociais. A fonte de informação empírica foi o European Social Survey 2012. Foi possível calcular decis europeus de rendimentos, construir uma matriz de segmentos classe-país, e analisar as interseções dessa matriz estrutural com as distribuições de rendimentos e escolaridades. Os resultados revelam graus elevados de desigualdade distributiva na Europa. Mostram também as configurações estruturais assumidas na Europa pelas interseções de desigualdades distributivas e categoriais.Palavras-chave desigualdades, Europa, rendimento, educação, classe.Résumé L'objectif de cet article est de présenter quelques contributions pour la compréhension des inégalités sociales observées aujourd'hui en Europe. L'analyse porte sur les inégalités distributives de ressources économiques et éducatives ainsi que sur les inégalités catégorielles entre États nationaux et entre classes sociales. La source d'information empirique a été l'Enquête sociale européenne (ESS) 2012. Il a été possible de calculer les déciles européens de revenus, de construire une matrice de segments classe-pays et d'analyser les intersections de cette matrice structurelle avec les distributions de revenus et de scolarités. Les résultats révèlent des niveaux élevés d'inégalité distributive en Europe. Ils montrent aussi les configurations structurelles que prennent en Europe les intersections d'inégalités distributives et catégorielles.Mots-clés inégalités, Europe, revenu, éducation, classe.SOCIOLOGIA, PROBLEMAS E PRÁTICAS, n.º 81, 2016, pp. 75-93.

CFFT-004 is a dual-acting small molecule with independent corrector and potentiator activities that partially rescues F508del-CFTR in recombinant cells and native airway epithelia. The limited efficacy and potency of CFFT-004 suggests that combinations of small molecules targeting different defects in F508del-CFTR might be a more effective therapeutic strategy than a single agent.