ERC FUNDED PROJECTS

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

Run away, sidestep, duck-and-cover, watch: when under threat, humans immediately choreograph a large repertoire of defensive actions. Understanding action-selection under threat is important for anybody wanting to explain why anxiety disorders imply some of these behaviours in harmless situations. Current concepts of human defensive behaviour are largely derived from rodent research and focus on a small number of broad, cross-species, action tendencies. This is likely to underestimate the complexity of the underlying action-selection mechanisms. This research programme will take decisive steps to understand these psychological mechanisms and elucidate their neural implementation. To elicit threat-related action in the laboratory, I will use virtual reality computer games with full body motion, and track actions with motion-capture technology. Based on a cognitive-computational framework, I will systematically characterise the space of actions under threat, investigate the psychological mechanisms by which actions are selected in different scenarios, and describe them with computational algorithms that allow quantitative predictions. To independently verify their neural implementation, I will use wearable magnetoencephalography (MEG) in freely moving subjects. This proposal fills a lacuna between defence system concepts based on rodent research, emotion psychology, and clinical accounts of anxiety disorders. By combining a stringent experimental approach with the formalism of cognitive-computational psychology, it furnishes a unique opportunity to understand the mechanisms of action-selection under threat, and how these are distinct from more general-purpose action-selection systems. Beyond its immediate scope, the proposal has a potential to lead to a better understanding of anxiety disorders, and to pave the way towards improved diagnostics and therapies.

1 998 750 €

Start date: 2019-10-01, End date: 2024-09-30

Gas turbines are an essential ingredient in the long-term energy and aviation mix. They are flexible, offer fast start-up and the ability to burn renewable-generated fuels. However, they generate NOx emissions, which cause air pollution and damage human health, and reducing these is an air quality imperative. A major hurdle to this is that lean premixed combustion, essential for further NOx emission reductions, is highly susceptible to thermoacoustic instability. This is caused by a two-way coupling between unsteady combustion and acoustic waves, and the resulting large pressure oscillations can cause severe mechanical damage. Computational methods for predicting thermoacoustic instability, fast and accurate enough to be used as part of the industrial design process, are urgently needed. The only computational methods with the prospect of being fast enough are those based on coupled treatment of the acoustic waves and unsteady combustion. These exploit the amenity of the acoustic waves to analytical modelling, allowing costly simulations to be directed only at the more complex flame. They show real promise: my group recently demonstrated the first accurate coupled predictions for lab-scale combustors. The method does not yet extend to industrial combustors, the more complex flow-fields in these rendering current acoustic models overly-simplistic. I propose to comprehensively overhaul acoustic models across the entirety of the combustor, accounting for real and important acoustic-flow interactions. These new models will offer the breakthrough prospect of extending efficient, accurate predictive capability to industrial combustors, which has a real chance of facilitating future, instability free, very low NOx gas turbines.

1 985 288 €

Start date: 2018-06-01, End date: 2023-05-31

The Anthropocene, the current geological epoch, is characterised by human-induced ecological changes, which have prompted a global biodiversity crisis. Human-introduced alien plants could help to offset native species loss, augmenting diversity and maintaining the services and capital that humans derive from nature. However, alien species that become invasive are themselves a key threat to biodiversity. Alien species thus presents a huge challenge for biodiversity conservation in the Anthropocene: should their arrival and establishment be inhibited or disregarded as they can potentially both exacerbate and ameliorate biodiversity loss? Coupling empirical and theoretical approaches, ALIENIMPACTS will directly address this challenge by developing an approach for accurately predicting impacts of alien plant invasions on plant community diversity and identifying the circumstances under which negative impacts will occur. Using temperate grasslands as a model system, ALIENIMPACTS will use innovative field experiments and global observations to systematically quantify – for the first time – how often, for how long, to what extent, under what conditions and in what ways alien plants can impact plant community diversity. ALIENIMPACTS will develop mechanistic niche models, validated with empirical data from grasslands in North America, Europe and Australia, that will enable realistic scenarios of invasion biodiversity impacts to be forecast, now and in the future. Developing empirically accurate mechanistic models that predict invasions and their biodiversity impact is a highly ambitious goal. Its achievement will mark a step-change in ecological theory and understanding, will inform environmental policy and management, and address a critical research challenge of the Anthropocene: how to conserve the biodiversity of plants – the dominant life form on earth – under global environmental change.

1 999 997 €

Start date: 2021-04-01, End date: 2026-03-31