Neural stem cells, inflammation and NF-kappaB: basic principle of maintenance and repair or origin of brain tumours?

Several recent reports suggest that inflammatory signals play a decisive role in the self-renewal, migration and differentiation of multipotent neural stem cells (NSCs). NSCs are believed to be able to ameliorate the symptoms of several brain pathologies through proliferation, migration into the area of the lesion and either differentiation into the appropriate cell type or secretion of anti-inflammatory cytokines. Although NSCs have beneficial roles, current evidence indicates that brain tumours, such as astrogliomas or ependymomas are also caused by tumour-initiating cells with stem-like properties. However, little is known about the cellular and molecular processes potentially generating tumours from NSCs. Most pro-inflammatory conditions are considered to activate the transcription factor NF-kappaB in various cell types. Strong inductive effects of NF-kappaB on proliferation and migration of NSCs have been described. Moreover, NF-kappaB is constitutively active in most tumour cells described so far. Chronic inflammation is also known to initiate cancer. Thus, NF-kappaB might provide a novel mechanistic link between chronic inflammation, stem cells and cancer. This review discusses the apparently ambivalent role of NF-kappaB: physiological maintenance and repair of the brain via NSCs, and a potential role in tumour initiation. Furthermore, it reveals a possible mechanism of brain tumour formation based on inflammation and NF-kappaB activity in NSCs.

Towards a meta-analysis and toolkit for port-related socio-economic impacts: a review of socio-economic impact studies conducted for seaports

Port authorities increasingly need to communicate with a variety of external stakeholders in order to maintain and strengthen the societal acceptance of seaport activities. The availability of socio-economic impact studies on port authority and regional development agency websites has often made this information accessible to the public at large. However, the differences in methodologies adopted, in terms of selecting, defining and measuring various types of socio-economic impacts, sometimes lead to misconceptions as well as misleading comparisons across ports within and between regions. In this paper, we suggest guidelines for the design and application of a potential best practice from an interregional perspective (UK, France and Belgium), based on research in the framework of a European Commission co-funded project, ‘IMPACTE’. The paper also aims to develop guidelines for comparing the socio-economic impacts of ports across regional and national borders and discusses the development of a European port economic impact measurement toolkit. We analyse a sample of 33 recent socio-economic impact assessment reports in terms of methodologies adopted and types of impacts measured. The review shows a great diversity among these studies, leading to important differences between the impacts of port activity communicated to stakeholders.

Activation of glycoprotein VI (GPVI) and C-type lectin-like receptor-2 (CLEC-2) underlies platelet activation by diesel exhaust particles and other charged/hydrophobic ligands

Platelets are activated by a range of stimuli that share little or no resemblance in structure to each other or to recognized ligands, including diesel exhaust particles (DEP), small peptides [4N1-1, Champs (computed helical anti-membrane proteins), LSARLAF (Leu-Ser-Ala-Arg-Leu-Ala-Phe)], proteins (histones) and large polysaccharides (fucoidan, dextran sulfate). This miscellaneous group stimulate aggregation of human and mouse platelets through the glycoprotein VI (GPVI)-FcR γ-chain complex and/or C-type lectin-like receptor-2 (CLEC-2) as shown using platelets from mice deficient in either or both of these receptors. In addition, all of these ligands stimulate tyrosine phosphorylation in GPVI/CLEC-2-double-deficient platelets, indicating that they bind to additional surface receptors, although only in the case of dextran sulfate does this lead to activation. DEP, fucoidan and dextran sulfate, but not the other agonists, activate GPVI and CLEC-2 in transfected cell lines as shown using a sensitive reporter assay confirming a direct interaction with the two receptors. We conclude that this miscellaneous group of ligands bind to multiple proteins on the cell surface including GPVI and/or CLEC-2, inducing activation. These results have pathophysiological significance in a variety of conditions that involve exposure to activating charged/hydrophobic agents.

Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart.

We investigated the ability of phenylephrine (PE), an alpha-adrenergic agonist and promoter of hypertrophic growth in the ventricular myocyte, to activate the three best-characterized mitogen-activated protein kinase (MAPK) subfamilies, namely p38-MAPKs, SAPKs/JNKs (i.e. stress-activated protein kinases/c-Jun N-terminal kinases) and ERKs (extracellularly responsive kinases), in perfused contracting rat hearts. Perfusion of hearts with 100 microM PE caused a rapid (maximal at 10 min) 12-fold activation of two p38-MAPK isoforms, as measured by subsequent phosphorylation of a p38-MAPK substrate, recombinant MAPK-activated protein kinase 2 (MAPKAPK2). This activation coincided with phosphorylation of p38-MAPK. Endogenous MAPKAPK2 was activated 4-5-fold in these perfusions and this was inhibited completely by the p38-MAPK inhibitor, SB203580 (10 microM). Activation of p38-MAPK and MAPKAPK2 was also detected in non-contracting hearts perfused with PE, indicating that the effects were not dependent on the positive inotropic/chronotropic properties of the agonist. Although SAPKs/JNKs were also rapidly activated, the activation (2-3-fold) was less than that of p38-MAPK. The ERKs were activated by perfusion with PE and the activation was at least 50% of that seen with 1 microM PMA, the most powerful activator of the ERKs yet identified in cardiac myocytes. These results indicate that, in addition to the ERKs, two MAPK subfamilies, whose activation is more usually associated with cellular stresses, are activated by the Gq/11-protein-coupled receptor (Gq/11PCR) agonist, PE, in whole hearts. These data indicate that Gq/11PCR agonists activate multiple MAPK signalling pathways in the heart, all of which may contribute to the overall response (e.g. the development of the hypertrophic phenotype).