Neue Urbane Produktion : ein Wegweiser für das Bergische Städtedreieck

Regionale Produkte sind im Trend. Kreative Manufakturen, offene Werkstätten und moderne Fertigungsmethoden verhelfen dem Handwerk in der Stadt zu einer Renaissance. Was ist daran eigentlich das Neue? Und warum schlummert darin so ein großes Potenzial für einen nachhaltigen Wohlstand und für lebenswerte Quartiere? Knapp drei Jahre beforschte, förderte und vernetzte ein Projektteam aus Utopiastadt, dem Wuppertal Institut und dem transzent die Pioniere einer neuen Produktivität in der Region. Nun ist es an der Zeit, Bilanz zu ziehen - und nach vorne zu schauen, wo am Horizont die Visionen einer lebenswerten und produktiven Stadt von Morgen greifbar werden. Der vorliegende Wegweiser ist die Essenz aus drei Jahren Forschung, Praxis und Dialog. Er weist eine neue Richtung für die Region und ihre gestaltenden Akteure. Ob Wirtschaftsförderung, Stadtverwaltung, Zivilgesellschaft, Gründerszene, Unternehmen oder Wissenschaft: Wir laden dazu ein, den Weg gemeinsam zu beschreiten

X-Ray Co-Crystal Structure Guides the Way to Subnanomolar Competitive Ecto-5 '-Nucleotidase (CD73) Inhibitors for Cancer Immunotherapy

Ecto-5'-nucleotidase (CD73, EC 3.1.3.5) catalyzes the extracellular hydrolysis of AMP yielding adenosine, which induces immunosuppression, angiogenesis, metastasis, and proliferation of cancer cells. CD73 inhibition is therefore proposed as a novel strategy for cancer (immuno)therapy, and CD73 antibodies are currently undergoing clinical trials. Despite considerable efforts, the development of small molecule CD73 inhibitors has met with limited success. To develop a suitable drug candidate, a high resolution (2.05 degrees A) co-crystal structure of the CD73 inhibitor PSB-12379, a nucleotide analogue, in complex with human CD73 is determined. This allows the rational design and development of a novel inhibitor (PSB-12489) with subnanomolar inhibitory potency toward human and rat CD73, high selectivity, as well as high metabolic stability. A co-crystal structure of PSB-12489 with CD73 (1.85 degrees A) reveals the interactions responsible for increased potency. PSB-12489 is the most potent CD73 inhibitor to date representing a powerful tool compound and novel lead structure

CD73 controls ocular adenosine levels and protects retina from light-induced phototoxicity

ATP and adenosine have emerged as important signaling molecules involved in vascular remodeling, retinal functioning and neurovascular coupling in the mammalian eye. However, little is known about the regulatory mechanisms of purinergic signaling in the eye. Here, we used three-dimensional multiplexed imaging, in situ enzyme histochemistry, flow cytometric analysis, and single cell transcriptomics to characterize the whole pattern of purine metabolism in mouse and human eyes. This study identified ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), NTPDase2, and ecto-5'-nucleotidase/CD73 as major ocular ecto-nucleotidases, which are selectively expressed in the photoreceptor layer (CD73), optic nerve head, retinal vasculature and microglia (CD39), as well as in neuronal processes and cornea (CD39, NTPDase2). Specifically, microglial cells can create a spatially arranged network in the retinal parenchyma by extending and retracting their branched CD39(high)/CD73(low) processes and forming local "purinergic junctions" with CD39(low)/CD73(-) neuronal cell bodies and CD39(high)/CD73(-) retinal blood vessels. The relevance of the CD73-adenosine pathway was confirmed by flash electroretinography showing that pharmacological inhibition of adenosine production by injection of highly selective CD73 inhibitor PSB-12489 in the vitreous cavity of dark-adapted mouse eyes rendered the animals hypersensitive to prolonged bright light, manifested as decreased a-wave and b-wave amplitudes. The impaired electrical responses of retinal cells in PSB-12489-treated mice were not accompanied by decrease in total thickness of the retina or death of photoreceptors and retinal ganglion cells. Our study thus defines ocular adenosine metabolism as a complex and spatially integrated network and further characterizes the critical role of CD73 in maintaining the functional activity of retinal cells.</p