Suppression of reactive oxygen species generation in heart mitochondria from anoxic turtles: the role of complex I S-nitrosation.

Freshwater turtles (Trachemys scripta) are among the very few vertebrates capable of tolerating severe hypoxia and re-oxygenation without suffering from damage to the heart. As myocardial ischemia and reperfusion causes a burst of mitochondrial reactive oxygen species (ROS) in mammals, the question arises as to whether, and if so how, this ROS burst is prevented in the turtle heart. We find that heart mitochondria isolated from turtles acclimated to anoxia produce less ROS than mitochondria from normoxic turtles when consuming succinate. As succinate accumulates in the hypoxic heart and is oxidized when oxygen returns, this suggests an adaptation to lessen ROS production. Specific S-nitrosation of complex I can lower ROS in mammals and here we show that turtle complex I activity and ROS production can also be strongly depressed in vitro by S-nitrosation. We detect in vivo endogenous S-nitrosated complex I in turtle heart mitochondria, but these levels are unaffected upon anoxia acclimation. Thus, while heart mitochondria from anoxia-acclimated turtles generate less ROS and have a lower aerobic capacity than those from normoxic turtles, this is not due to decreases in complex I activity or expression levels. Interestingly, in-gel activity staining reveals that most complex I of heart mitochondria from normoxic and anoxic turtles forms stable super-complexes with other respiratory enzymes and, in contrast to mammals, these are not disrupted by dodecyl maltoside. Taken together, these results show that although S-nitrosation of complex I is a potent mechanism to prevent ROS formation upon re-oxygenation after anoxia in vitro, this is not a major cause of the suppression of ROS production by anoxic turtle heart mitochondria

Hierarchical models for service-oriented systems

We present our approach to the denotation and representation of hierarchical graphs: a suitable algebra of hierarchical graphs and two domains of interpretations. Each domain of interpretation focuses on a particular perspective of the graph hierarchy: the top view (nested boxes) is based on a notion of embedded graphs while the side view (tree hierarchy) is based on gs-graphs. Our algebra can be understood as a high-level language for describing such graphical models, which are well suited for defining graphical representations of service-oriented systems where nesting (e.g. sessions, transactions, locations) and linking (e.g. shared channels, resources, names) are key aspects

An Algebra of Hierarchical Graphs

We define an algebraic theory of hierarchical graphs, whose axioms characterise graph isomorphism: two terms are equated exactly when they represent the same graph. Our algebra can be understood as a high-level language for describing graphs with a node-sharing, embedding structure, and it is then well suited for defining graphical representations of software models where nesting and linking are key aspects

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Connected cities: Driving digital transformation in complex ecosystems

Digital technologies are fuelling the evolution of connected cities of the future. Our research in Copenhagen with organisations that are leading the digital transformation agenda, reveals that there are four critical and self-propelling factors that are essential to meeting the future demands of cities and its citizens

Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study.

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time.Design Nationwide register based cohort study.Setting Denmark.Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses).Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression.Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later.Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy