Finding leverage points for sustainability transformation of industrial and infrastructure systems is challenging, given that transformation is emergent from the complex interactions among socio... Show moreFinding leverage points for sustainability transformation of industrial and infrastructure systems is challenging, given that transformation is emergent from the complex interactions among socio-technical system elements over time within a specific social, technical and geographical context. Participatory multi-modelling, in which modellers and stakeholders collaborate to develop multiple interacting models to support a shared understanding of systems, is a promising approach to support sustainability transformations. The participatory process of modeling can serve as a leverage point by facilitating social learning amongst stakeholders, in which models can function as boundary objects that facilitate dialogue between stakeholders from different social worlds. We propose that participatory multi-modeling allows for the creation of a boundary object ecology, which involves a set of interacting and co-evolving boundary objects emerging throughout the modeling process. To explore this, we analyse the participatory multi-modelling process in the Windmaster project in the Rotterdam Port industrial cluster to understand which design choices were key to the creation of boundary objects. Our analysis shows that two types of design choices were key: design choices that enabled translations between participants, and those between participants and their organisation. We conclude that conceptualising participatory multi-modelling as a process of an evolving boundary object ecology, creating and adapting multiple interacting boundary objects provides a novel perspective that is useful for analysis and design of future participatory multi-modeling processes. Show less
Rationale: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9,... Show moreRationale: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH.Objectives: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH.Methods: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH.Measurements and Main Results: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone.Conclusions: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH. Show less
