Refining Nodes and Edges of State Machines

State machines are hierarchical automata that are widely used to structure complex behavioural specifications. We develop two notions of refinement of state machines, node refinement and edge refinement. We compare the two notions by means of examples and argue that, by adopting simple conventions, they can be combined into one method of refinement. In the combined method, node refinement can be used to develop architectural aspects of a model and edge refinement to develop algorithmic aspects. The two notions of refinement are grounded in previous work. Event-B is used as the foundation for our refinement theory and UML-B state machine refinement influences the style of node refinement. Hence we propose a method with direct proof of state machine refinement avoiding the detour via Event-B that is needed by UML-B

Long-term trends in tropical cyclone tracks around Korea and Japan in late summer and early fall

This study investigates long-term trends in tropical cyclones (TCs) over the extratropical western North Pacific (WNP) over a period of 35 years (1982-2016). The area analyzed extended across 30-45 degrees N and 120-150 degrees E, including the regions of Korea and Japan that were seriously affected by TCs. The northward migration of TCs over the WNP to the mid-latitudes showed a sharp increase in early fall. In addition, the duration of TCs over the WNP that migrated northwards showed an increase, specifically in early to mid-September. Therefore, more recently, TC tracks have been observed to significantly extend into the mid-latitudes. The recent northward extension of TC tracks over the WNP in early fall was observed to be associated with changes in environmental conditions that were favorable for TC activities, including an increase in sea surface temperature (SST), decrease in vertical wind shear, expansion of subtropical highs, strong easterly steering winds, and an increase in relative vorticity. In contrast, northward migrations of TCs to Korea and Japan showed a decline in late August, because of the presence of unfavorable environmental conditions for TC activities. These changes in environmental conditions, such as SST and vertical wind shear, can be partially associated with the Pacific decadal oscillation

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking

Comprehensive characterization of the Published Kinase Inhibitor Set

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome

The crystal structure of the RhoA-AKAP-Lbc DH-PH domain complex

The RhoGEF domain of AKAP-Lbc (AKAP13) catalyses nucleotide exchange on RhoA and is involved in development of cardiac hypertrophy. The RhoGEF activity of AKAP-Lbc has also been implicated in cancer. We have determined the X-ray crystal structure of the complex between RhoA:GDP and the AKAP-Lbc RhoGEF (DH-PH) domain to 2.1 {Angstrom} resolution. The structure reveals important differences compared to related RhoGEF proteins such as Leukemia-associated RhoGEF. Nucleotide exchange assays comparing the activity of the DH-PH domain to the DH domain alone showed no role for the PH domain in nucleotide exchange, which is explained by the RhoA:AKAP-Lbc structure. Comparison to a structure of the isolated AKAP-Lbc DH domain revealed a change in conformation of the N-terminal 'GEF switch' region upon binding to RhoA. Isothermal titration calorimetry showed that AKAP-Lbc has only micromolar affinity for RhoA which combined with the presence of potential binding pockets for small molecules on AKAP-Lbc raises the possibility of targeting AKAP-Lbc with guanine nucleotide exchange factor inhibitors

Nuclear medicine program progress report for quarter ending December 31, 1991

This report presents information on (1) a new improved synthesis of carrier-free rhenium-188-labeled Re(V) dimercaptosuccinic acid (DMSA) complex as a potential therapeutic agent for treatment of thyroid medullary carcinoma; and (2) the synthesis and evaluation of a series of iodine-125-labeled analogues of altanserine for imaging of serotonin receptors

Metabolites of IPPA, BMIPP, and DMIPP fatty acids in rats hearts: A quantitative HPLC-study

The significance of the use of radioiodinated fatty acid analogues such as 15-(p-iodophenyl) pentadecanoic acid (IPPA), 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP), and 15-(p-iodophenyl)-3-dimethylpentadecanoic acid (DMIPP) for the evaluation of regional myocardial fatty acid uptake is well documented. An understanding of the relative incorporation of these fatty acid analogues into various fatty acid pools is important to correlate fatty acid uptake and release with flux through the various metabolic pathways. While the free fatty acid (FFA) pool is immediately available for oxidation to meet energy demands for contraction under normoxic conditions, the FFA are also stored as triglycerides (TG) for oxidation at a later period. Although the incorporation of IPPA, BMIPP, and DMIPP into the major phospholipid classes has not been previously investigated, demonstration of the incorporation of IPPA and BMIPP into phospholipids would be important as further evidence that these modified'' fatty acids are, at least qualitatively, metabolized through the usual metabolic pathways. The goals of the present studies were thus to develop the necessary HPLC techniques and evaluate the incorporation of IPPA, BMIPP, and DMIPP into complex endogenous lipids in dual label studies. 2 refs., 6 figs