Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation

International audienceIon channels are desirable therapeutic targets, yet ion channel-directed drugs with high selectivity and few side effects are still needed. Unlike small-molecule inhibitors, antibodies are highly selective for target antigens but mostly fail to antagonize ion channel functions. Nanobodies-small, single-domain antibody fragments-may overcome these problems. P2X7 is a ligand-gated ion channel that, upon sensing adenosine 5′-triphosphate released by damaged cells, initiates a proinflammatory signaling cascade, including release of cytokines, such as interleukin-1b (IL-1b). To further explore its function, we generated and characterized nanobodies against mouse P2X7 that effectively blocked (13A7) or potentiated (14D5) gating of the channel. Systemic injection of nanobody 13A7 in mice blocked P2X7 on T cells and macrophages in vivo and ameliorated experimental glomerulonephritis and allergic contact dermatitis. We also generated nanobody Dano1, which specifically inhibited human P2X7. In endotoxin-treated human blood, Dano1 was 1000 times more potent in preventing IL-1b release than small-molecule P2X7 antagonists currently in clinical development. Our results show that nanobody technology can generate potent, specific therapeu-tics against ion channels, confirm P2X7 as a therapeutic target for inflammatory disorders, and characterize a potent new drug candidate that targets P2X7

Youth Participation in Context: the Impact of Youth Transition Regimes on Political Action Strategies in Europe

This article examines the impact of youth transition regimes (YTR) on the political participation strategies of young people from 26 locations in 12 European countries. The central hypothesis is that the way that youth transitions take place in different European contexts determines the position of youth as a group in the system of social relations that Bourdieu calls the ‘social space’. Depending upon this position, young people may be more inclined to participation through institutional channels or political protest, or, in contrast, remain inactive. Thus, the specific context of youth in each society (measured through the exposure to risk and vulnerability, the length of the pathway to adulthood and the role of the welfare state) plays a crucial role in defining young people's political action strategies. Multilevel logistic regression analysis using the MYPLACE survey, the specific operationalization of the YTR and other aggregate control variables reveal that YTR centrality is a very important contextual predictor for explaining different forms of political participation among young people in Europe

Youth unemployment and employment trajectories in Spain during the Great Recession: what are the determinants?

Since the beginning of the recession period in Europe, unemployment has greatly affected the young adult population. In this context, Spain is regarded as an extreme case, due to its exceptionally high youth unemployment rates. This article seeks to identify the determinants that have led certain groups of Spanish young people to suffer labour market trajectories with higher levels of unemployment and instability during the Great Recession than others. To do this, retrospective data from the 2012 Catalan Youth Survey are used. With these data and using cluster analysis, a typology of labour market trajectories is constructed. Next, multinomial logistic regressions are used to identify what individual socio-demographic characteristics and pre-crisis employment experiences are connected to these different typological career paths. Results show that the highly differentiated career paths are associated with different social profiles and differences in the presence of unemployment. Moreover, interesting differences among the most unstable career paths appear. For the most vulnerable social profiles the employment trajectory prior to the crisis seems to point towards the existence of an entrapment in low-skilled jobs that alternate with situations of unemployment. For those with a slightly better position their employment situation after the initiation of the crisis seems to have been impacted by their brief labour market trajectory before the crisis and their resulting work experience gap.We would like to thank the Catalan Youth Observatory for letting us use the data from the Catalan Youth Survey 2012. We would particularly like to thank Pau Serracant for his help and for encouraging us to send our study to the Journal of Labour Market Research in response to their call for research on Youth unemployment in Europe. We are also grateful to two anonymous referees for their comments, which enabled us to greatly improve the quality of our paper. It goes without saying that any errors in this article are the sole responsibility of the authors