Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways

Climate Adaptation Engineering and Risk-based Design and Management of Infrastructure

International audienceA changing climate may also result in more intense tropical cyclones and storms, more intense rain events and flooding, and other natural hazards. Moreover, increases in CO2 atmospheric concentrations, temperature and humidity will increase corrosion of concrete and steel structures. The chapter will describe how risk-based approaches are well suited to optimising climate adaptation strategies related to the design and maintenance of existing infrastructure. Climate adaptation strategies may include retrofitting or strengthening of existing structures, more frequent inspections, or enhanced designs. An important aspect is assessing at what point in time climate adaptation becomes economically viable. Stochastic methods are used to model infrastructure performance, effectiveness of adaptation strategies, exposure, and costs. These concepts will be illustrated with state-of-the-art research of risk-based assessment of climate adaptation strategies