Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog.

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome

A Connectionless Approach to Intra- and Inter-Domain Traffic Engineering, 2nd New York Metro Area Networking Workshop

Traffic Engineering (TE) deals with the task of mapping traffic flows to the routes in an existing physical topology to improve the performance of operational IP networks. A desirable traffic engineering solution must provide network operators a precise control over the traffic flows within their routing domains. This enables the network operators to provide new services by appropriately managing the traffic. Multi Protocol Label Switching (MPLS) allows explicit setup of one or more label switched paths (LSPs) between any source and destination and the traffic can be arbitrarily mapped to the available LSPs. However, MPLS uses a connectionoriented or signaled approach. This requires that all routers along the LSP be upgraded to support MPLS. In MPLS, the problem of setting-up LSPs is de-coupled from the problem of optimally splitting traffic among the available LSPs. In contrast, current work in the area connectionless intra-domain TE is to use a parametric approach. Essentially, the link weight parameter of the routing algorithm is changed to find “good ” routes under quasi-stationary traffic assumption. The idea of optimizing OSPF link weights for the prevailing traffic conditions was proposed in [2], [4]. In this case, the paths on which the traffic is routed depend on traffic demands itself. This approach will hence lead to a route change for any desired change in traffic mapping or change in the demand matrix. A source-controlled traffic mapping on finer time-scales is not possible with the current connectionless TE approach, and leads to control traffic overhead (LSA re-advertisement) for every change in link weight. The routing algorithm (OSPF or IS-IS) only provides a single shortest path or multipl