Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.     

NADPH oxidases as therapeutic targets in ischemic stroke

Reactive oxygen species (ROS) act physiologically as signaling molecules. In pathological conditions, such as ischemic stroke, ROS are released in excessive amounts and upon reperfusion exceed the body's antioxidant detoxifying capacity. This process leads to brain tissue damage during reoxygenation. Consequently, antioxidant strategies have long been suggested as a therapy for experimental stroke, but clinical trials have not yet been able to promote the translation of this concept into patient treatment regimens. As an evolution of this concept, recent studies have targeted the sources of ROS generation-rather than ROS themselves. In this context, NADPH oxidases have been identified as important generators of ROS in the cerebral vasculature under both physiological conditions in general and during ischemia/reoxygenation in particular. Inhibition of NADPH oxidases or genetic deletion of certain NADPH oxidase isoforms has been found to considerably reduce ischemic injury in experimental stroke. This review focuses on recent advances in the understanding of NADPH oxidase-mediated tissue injury in the cerebral vasculature, particularly at the level of the blood-brain barrier, and highlights promising inhibitory strategies that target the NADPH oxidases.     

Structural Similarity: Spectral Methods for Relaxed Blockmodeling

In this paper we propose the concept of structural similarity as a relaxation of blockmodeling in social network analysis. Most previous approaches attempt to relax the constraints on partitions, for instance, that of being a structural or regular equivalence to being approximately structural or regular, respectively. In contrast, our approach is to relax the partitions themselves: structural similarities yield similarity values instead of equivalence or non-equivalence of actors, while strictly obeying the requirement made for exact regular equivalences. Structural similarities are based on a vector space interpretation and yield efficient spectral methods that, in a more restrictive manner, have been successfully applied to difficult combinatorial problems such as graph coloring. While traditional blockmodeling approaches have to rely on local search heuristics, our framework yields algorithms that are provably optimal for specific data-generation models. Furthermore, the stability of structural similarities can be well characterized making them suitable for the analysis of noisy or dynamically changing network data.     

Deterioration of the seventeenth-century warship Vasa by internal formation of sulphuric acid

The seventeenth-century Swedish warship, Vasa, was recovered in good condition after 333 years in the cold brackish water of Stockholm harbour. After extensive treatment to stabilize and dry the ship's timbers, the ship has been on display in the Vasa Museum since 1990. However, high acidity and a rapid spread of sulphate salts were recently observed on many wooden surfaces, which threaten the continued preservation of the Vasa. Here we show that, in addition to concentrations of sulphate mostly on the surface of oak beams, elemental sulphur has accumulated within the beams (0.2-4 per cent by mass), and also sulphur compounds of intermediate oxidation states exist. The overall quantity of elemental sulphur could produce up to 5,000 kg of sulphuric acid when fully oxidized. We suggest that the oxidation of the reduced sulphur--which probably originated from the penetration of hydrogen sulphide into the timbers as they were exposed to the anoxic water--is being catalysed by iron species released from the completely corroded original iron bolts, as well as from those inserted after salvage. Treatments to arrest acid wood hydrolysis of the Vasa and other wooden marine-archaeological artefacts should therefore focus on the removal of sulphur and iron compounds.