Blockade of TRPM7 Channel Activity and Cell Death by Inhibitors of 5-Lipoxygenase

TRPM7 is a ubiquitous divalent-selective ion channel with its own kinase domain. Recent studies have shown that suppression of TRPM7 protein expression by RNA interference increases resistance to ischemia-induced neuronal cell death in vivo and in vitro, making the channel a potentially attractive pharmacological target for molecular intervention. Here, we report the identification of the 5-lipoxygenase inhibitors, NDGA, AA861, and MK886, as potent blockers of the TRPM7 channel. Using a cell-based assay, application of these compounds prevented cell rounding caused by overexpression of TRPM7 in HEK-293 cells, whereas inhibitors of 12-lipoxygenase and 15-lipoxygenase did not prevent the change in cell morphology. Application of the 5-lipoxygenase inhibitors blocked heterologously expressed TRPM7 whole-cell currents without affecting the protein's expression level or its cell surface concentration. All three inhibitors were also effective in blocking the native TRPM7 current in HEK-293 cells. However, two other 5-lipoxygenase specific inhibitors, 5,6-dehydro-arachidonic acid and zileuton, were ineffective in suppressing TRPM7 channel activity. Targeted knockdown of 5-lipoxygenase did not reduce TRPM7 whole-cell currents. In addition, application of 5-hydroperoxyeicosatetraenoic acid (5-HPETE), the product of 5-lipoxygenase, or 5-HPETE's downstream metabolites, leukotriene B4 and leukotriene D4, did not stimulate TRPM7 channel activity. These data suggested that NDGA, AA861, and MK886 reduced the TRPM7 channel activity independent of their effect on 5-lipoxygenase activity. Application of AA861 and NDGA reduced cell death for cells overexpressing TRPM7 cultured in low extracellular divalent cations. Moreover, treatment of HEK-293 cells with AA861 increased cell resistance to apoptotic stimuli to a level similar to that obtained for cells in which TRPM7 was knocked down by RNA interference. In conclusion, NDGA, AA861, and MK886 are potent blockers of the TRPM7 channel capable of attenuating TRPM7's function during cell stress, making them effective tools for the biophysical characterization and suppression of TRPM7 channel conductance in vivo

Chapter 7 : Use of Assessments to Inform Educational Policies in French-Speaking Belgium

In French-speaking Belgium, the national assessments developed only lately, and there are not yet national assessments developed by professionals that can be used to evaluate trends. Therefore, the only tools available to rigorously evaluate trends are international assessments. French-speaking Belgium has participated in international assessments since the early 1970s and their results are highly valued by policy-makers. Their level of awareness of the strengths and weaknesses of the education system can be considered as good. However, until recently, the impact of international assessments on education policies has been limited. Only scattered initiatives have been taken. From 2014, an extremely ambitious plan called Pacte pour un enseignement d’excellence has been launched. The Pact tackles most of the systemic weaknesses of the education system in FS Belgium and addresses at the same time structural change (lowering grade repetition, moving to a comprehensive lower secondary education), curricular changes and governance in a long-term perspective. A significant reform of the system of national assessments is currently under discussion

The alpha-kinase family: an exceptional branch on the protein kinase tree

The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in the context of an alpha-helix. Although recent studies show that some members of this family can also phosphorylate residues in non-helical regions, the name alpha-kinase has remained. During evolution, the alpha-kinase domains combined with many different functional subdomains such as von Willebrand factor-like motifs (vWKa) and even cation channels (TRPM6 and TRPM7). As a result, these kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. Here, we review the current state of knowledge on different members of this kinase family and discuss the potential use of alpha-kinases as drug targets in diseases such as cancer

Mobilité des élèves dans le système éducatif belge francophone

International audienceCette communication a pour objectif de présenter une première étude des parcours scolaires qui sont accomplis à travers le système éducatif belge francophone entre deux années consécutives, notamment en tenant compte de certaines caractéristiques des établissements scolaires, comme leur identification ou non en discrimination positive et des caractéristiques individuelles des élèves (sexe, nationalité, retard scolaire, passage de classe ou redoublement). Elle vise notamment à prédire la mobilité des élèves, c'est-à-dire les changements éventuels d'établissement ou, au contraire, la stabilité de ceux-ci, en fonction des paramètres mentionnés, pour chacune des années d'étude de l'enseignement maternel, primaire et secondaire