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

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

On the expressiveness of forwarding in higher-order communication

Abstract. In higher-order process calculi the values exchanged in communications may contain processes. There are only two capabilities for received processes: execution and forwarding. Here we propose a limited form of forwarding: output actions can only communicate the parallel composition of statically known closed processes and processes received through previously executed input actions. We study the expressiveness of a higher-order process calculus featuring this style of communication. Our main result shows that in this calculus termination is decidable while convergence is undecidable.

Life cycle modelling of environmental impacts of application of processed organic municipal solid waste on agricultural land (EASEWASTE)

A model capable of quantifying the potential environmental impacts of agricultural application of composted or anaerobically digested source-separated organic municipal solid waste (MSW) is presented. In addition to the direct impacts, the model accounts for savings by avoiding the production and use of commercial fertilizers. The model is part of a larger model, Environmental Assessment of Solid Waste Systems and Technology (EASEWASTE), developed as a decisionsupport model, focusing on assessment of alternative waste management options. The environmental impacts of the land application of processed organic waste are quantified by emission coefficients referring to the composition of the processed waste and related to specific crop rotation as well as soil type. The model contains several default parameters based on literature data, field experiments and modelling by the agro-ecosystem model, Daisy. All data can be modified by the user allowing application of the model to other situations. A case study including four scenarios was performed to illustrate the use of the model. One tonne of nitrogen in composted and anaerobically digested MSW was applied as fertilizer to loamy and sandy soil at a plant farm in western Denmark. Application of the processed organic waste mainly affected the environmental impact categories global warming (0.4–0.7 PE), acidification (–0.06 (saving)–1.6 PE), nutrient enrichment (–1.0 (saving)–3.1 PE), and toxicity. The main contributors to these categories were nitrous oxide formation (global warming), ammonia volatilization (acidification and nutrient enrichment), nitrate losses (nutrient enrichment and groundwater contamination), and heavy metal input to soil (toxicity potentials). The local agricultural conditions as well as the composition of the processed MSW showed large influence on the environmental impacts. A range of benefits, mainly related to improved soil quality from long-term application of the processed organic waste, could not be generally quantified with respect to the chosen life cycle assessment impact categories and were therefore not included in the model. These effects should be considered in conjunction with the results of the life cycle assessment