Developmental approach of safety in ergonomics/human factors: insights of constructed safety in six work environments.

This article brings together works on the concept of constructed safety in ergonomics, carried out over the last twenty-five years. Firstly, we situate this approach to safety in relation to previously developed existing models previously developed (e.g. regulated and managed safety) with regard to the development of activity-centred ergonomics. We then present six research actions in activity-centred ergonomics from a selection of different fields, from small companies to the industry of the future in an international group: public works, hospitals, aeronautical industry, railway transport, agriculture, and chemical industry, in order to describe constructed safety applications. The results highlight that constructed safety is respectively raised by mutual knowledge between workers and management, collective decision making, collective reflexive work on safety rules, spatiotemporal articulation of the different safety sources, knowledge integration on pesticide exposure situations by designers and regulation, social regulation sustaining risk understanding and safety aspect involving a diversity of actors (workers, preventionists, managers, local residents and public authorities). By focusing on the analysis of actual safety practices in real work and real exposure situations, constructed safety aims to account for the way in which safety is deployed on a daily basis to meet production and health objectives. This understanding contributes to the design of safe work systems in a developmental way and to propose an operating model of constructed safety.

Safety issues are paramount in work environments where high-risk work activities take place. This article proposes an operating model of 'constructed safety' to help address these health and safety issues. This developmental approach to safety is based on the models and methods of activity-centred ergonomics.

Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences.

Preeclampsia (PE) is a high-prevalence pregnancy disease characterized by placental insufficiency, gestational hypertension, and proteinuria. Overexpression of the A isoform of the STOX1 transcription factor (STOX1A) recapitulates PE in mice, and STOX1A overexpressing trophoblasts recapitulate PE patients hallmarks in terms of gene expression and pathophysiology. STOX1 overexpression induces nitroso-redox imbalance and mitochondrial hyper-activation. Here, by a thorough analysis on cell models, we show that STOX1 overexpression in trophoblasts alters inducible nitric oxide synthase (iNOS), nitric oxide (NO) content, the nitroso-redox balance, the antioxidant defense, and mitochondrial function. This is accompanied by specific alterations of the Krebs cycle leading to reduced l-malate content. By increasing NOS coupling using the metabolite tetrahydrobiopterin (BH4) we restore this multi-step pathway in vitro. Moving in vivo on two different rodent models (STOX1 mice and RUPP rats, alike early onset and late onset preeclampsia, respectively), we show by transcriptomics that BH4 directly reverts STOX1-deregulated gene expression including glutathione metabolism, oxidative phosphorylation, cholesterol metabolism, inflammation, lipoprotein metabolism and platelet activation, successfully treating placental hypotrophy, gestational hypertension, proteinuria and heart hypertrophy. In the RUPP rats we show that the major fetal issue of preeclampsia, Intra Uterine Growth Restriction (IUGR), is efficiently corrected. Our work posits on solid bases BH4 as a novel potential therapy for preeclampsia.

Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms.

STOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.