Research for sustainability and the European Union: from wish to will - a manifesto

Sustainability is a word full of promises, evoking peace, welfare, and harmony with nature. No wonder Europe has a strong wish for sustainability. Does it also have the will

Assessing components of the natural environment of the Upper Danube and Upper Brahmaputra river basins

A comprehensive understanding of the interplay between the natural environment and the human dimension is one of the prerequisites to successful and sustaining IWRM practises in large river basins such as the Upper Brahmaputra river basin or the Upper Danube river basin. These interactions, their dynamics and changes, and the likely future scenarios were investigated in the BRAHMATWINN project with a series of tools from remote sensing and geoinformatics. An integrated assessment of main components of the natural environment in the two river basins as well as in five reference catchments within those basins, has led to the delineation of hydrological response units (HRUs). HRUs are spatial units bearing a uniform behaviour in terms of the hydrological response regime, as a function of physical parameters land use, soil type, water, vegetation cover and climate. Besides the delineated HRUs which are available in a spatially exhaustive manner for all reference catchments, the following information were provided as spatial layers: (1) uniform digital surface models of both the twinned basins and the reference catchments; (2) glacier areas and the magnitude of glacier loss; (3) mountain permafrost distribution and identification of areas particularly affected by permafrost thaw; (4) a consistent land use/land cover information in all reference catchments; and (5) the vulnerabilities of wetlands and groundwater in terms of anthropogenic impact and climate change

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents

Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel

TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism. We now report: 1) The identification of an EET-binding pocket that specifically mediates TRPV4 activation by 5′,6′-EET, AA and hypotonic cell swelling, thereby suggesting that all these stimuli shared a common structural target within the TRPV4 channel; and 2) A structural insight into the gating of TRPV4 by a natural agonist (5′,6′-EET) in which K535 plays a crucial role, as mutant TRPV4-K535A losses binding of and gating by EET, without affecting GSK1016790A, 4α-phorbol 12,13-didecanoate and heat mediated channel activation. Together, our data demonstrates that the mechano- and osmotransducing messenger EET gates TRPV4 by a direct action on a site formed by residues from the S2-S3 linker, S4 and S4-S5 linker.The research is supported by awards from the Spanish Ministry of Economy and Competitiveness (Grants SAF2015-69762-R to M.A.V. and J.M.F.-F., and MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”), and FEDER Funds (Fondo Europeo de Desarrollo Regional). M.I.-S. holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness. FGN acknowledge the support of FONDECYT Grant 1170733 and The Centro Interdisciplinario de Neurociencia de Valparaíso (CINV) is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo. R.V.S. is funded by CONICYT PCHA/Doctorado Nacional 2013-21130631 fellowshi