Towards automatic generation of UML profile graphical editors for papyrus

We present an approach for defining the abstract and concrete syntax of UML profiles and their equivalent Papyrus graphical editors using annotated Ecore metamodels, driven by automated model-to-model and model-to-text transformations. We compare our approach against manual UML profile specification and implementation using Archimate, a non-trivial enterprise modelling language, and we demonstrate the substantial productivity and maintainability benefits it delivers

Allosteric Interactions between the Myristate- and ATP-Site of the Abl Kinase

Abl kinase inhibitors targeting the ATP binding pocket are currently employed as potent anti-leukemogenic agents but drug resistance has become a significant clinical limitation. Recently, a compound that binds to the myristate pocket of Abl (GNF-5) was shown to act cooperatively with nilotinib, an ATP-competitive inhibitor to target the recalcitrant “T315I” gatekeeper mutant of Bcr-Abl. To uncover an explanation for how drug binding at a distance from the kinase active site could lead to inhibition and how inhibitors could combine their effects, hydrogen exchange mass spectrometry (HX MS) was employed to monitor conformational effects in the presence of both dasatinib, a clinically approved ATP-site inhibitor, and GNF-5. While dasatinib binding to wild type Abl clearly influenced Abl conformation, no binding was detected between dasatinib and T315I. GNF-5, however, elicited the same conformational changes in both wild type and T315I, including changes to dynamics within the ATP site located approximately 25 Å from the site of GNF-5 interaction. Simultaneous binding of dasatinib and GNF-5 to T315I caused conformational and/or dynamics changes in Abl such that effects of dasatinib on T315I were the same as when it bound to wild type Abl. These results provide strong biophysical evidence that allosteric interactions play a role in Abl kinase downregulation and that targeting sites outside the ATP binding site can provide an important pharmacological tool to overcome mutations that cause resistance to ATP-competitive inhibitors

Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases

Synchromodal Transport Planning at a Logistics Service Provider

In this chapter, we consider synchromodal planning of transport orders with the objective to minimize costs, delays, and CO2 emissions. Synchromodal planning is a form of multimodal planning in which the best possible combination of transport modes is selected for every transport order. The underlying problem is known as the multi-objective k-shortest path problem, in which we search for the k-shortest paths through a multimodal network, taking into account time-windows of orders, schedules for trains and barges, and closing times of hubs. We present a synchromodal planning algorithm that is implemented at a 4PL service provider located in the Netherlands. We illustrate our approach using simulation with order and network data from this logistics service provider. On the corridor from the Netherlands to Italy, an average cost reduction of 10.1 % and a CO2 reduction of 14.2 % can be achieved with synchromodal planning

What approaches exist to evaluate the effectiveness of UK-relevant natural flood management measures? A systematic map protocol

Natural flood management (NFM) measures seek to protect, enhance, emulate, or restore the natural function of rivers as part of approaches to flood risk management (FRM). While there is agreement in both academic and practice/policy literature that NFM, in a general sense, should be part of a holistic FRM strategy to address current and future flood risk, the specifics of how to consistently implement NFM successfully in practice are less well known. This is particularly acute for practitioners in the UK given the nature of the UK’s biophysical and socio-political context. There is a recognition that existing reviews of NFM effectiveness in the UK tend to focus on the natural science basis and it is unclear how studies account for climate change. Further, studies tend to focus only on UK studies. This systematic map aims to highlight the way in which existing NFM studies, from different disciplinary backgrounds and across Europe, evaluate effectiveness, and the extent to which they account for climate change. This knowledge can help to make recommendations for future areas of research where the multiple issues around understanding effectiveness can be synthesised, and where climate change is systematically taken into account. Methods This systematic map protocol addresses the following question: what approaches exist to evaluate the effectiveness of UK-relevant natural flood management measures? The protocol details the methodology that will be used to conduct a systematic map of the range of peer-reviewed journal papers, policy documents, guidance, and other forms of grey literature which currently exist on NFM to give an overview on the way in which the effectiveness of NFM is conceived. The methods detail the search strategy employed for gathering items across the peer-reviewed academic literature and grey literature. Additionally, the methods outline how the reviewers will approach article screening, and the eligibility criteria to include/exclude articles. The methods section also details the steps taken to ensure consistency across all reviewers, the data coding strategy, and methods for presenting the final systematic map. Together, the methods employed will help to identify current knowledge gaps, and will enable recommendations to be made for future research