ERC FUNDED PROJECTS

Chromatin packaging into the nucleus of eukaryotic cells is highly sophisticated. It not only serves to condense the genomic content into restricted space, but mainly to encode epigenetic traits ensuring temporally controlled and balanced transcription of genes and coordinated DNA replication and repair. The non-random three-dimensional chromatin architecture including looped structures between genomic control elements relies on the action of architectural proteins. However, despite increasing interest in spatio-temporal chromatin organization, mechanistic details of their contributions are not well understood. With this proposal I aim at unveiling molecular mechanisms of protein–mediated chromatin organization by in vivo single molecule tracking and quantitative super-resolution imaging of architectural proteins using reflected light sheet microscopy (RLSM). I will measure the interaction dynamics, the spatial distribution and the stoichiometry of architectural proteins throughout the nucleus and at specific chromatin loci within single cells. In complement single molecule force spectroscopy experiments using magnetic tweezers (MT), I will study mechanisms of DNA loop formation in vitro by structure-mediating proteins. Integrating these spatio-temporal and mechanical single molecule information, I will in the third sup-project measure the dynamics of relative end-to-end movements and the forces acting within a looped chromatin structure in living cells. Taken together, my experiments will greatly enhance our mechanistic understanding of three-dimensional chromatin architecture and inspire future experiments on its regulatory effects on nuclear functions and potential therapeutic utility upon controlled modification.

1 486 578 €

Start date: 2015-05-01, End date: 2021-04-30

Rapid translation between European languages is a cornerstone of good governance in the EU, and of great academic and commercial interest. Statistical approaches to machine translation constitute the state-of-the-art. The basic knowledge source is a parallel corpus, texts and their translations. For domains where large parallel corpora are available, such as the proceedings of the European Parliament, a high level of translation quality is reached. However, in countless other domains where large parallel corpora are not available, such as medical literature or legal decisions, translation quality is unacceptably poor. Domain adaptation as a problem of statistical machine translation (SMT) is a relatively new research area, and there are no standard solutions. The literature contains inconsistent results and heuristics are widely used. We will solve the problem of domain adaptation for SMT on a larger scale than has been previously attempted, and base our results on standardized corpora and open source translation systems. We will solve two basic problems. The first problem is determining how to benefit from large out-of-domain parallel corpora in domain-specific translation systems. This is an unsolved problem. The second problem is mining and appropriately weighting knowledge available from in-domain texts which are not parallel. While there is initial promising work on mining, weighting is not well studied, an omission which we will correct. We will scale mining by first using Wikipedia, and then mining from the entire web. Our work will lead to a break-through in translation quality for the vast number of domains with less parallel text available, and have a direct impact on SMEs providing translation services. The academic impact of our work will be large because solutions to the challenge of domain adaptation apply to all natural language processing systems and in numerous other areas of artificial intelligence research based on machine learning approaches.

1 228 625 €

Start date: 2015-12-01, End date: 2020-11-30

This research project aims to enlarge substantially our understanding of the dialogue between 19th-century music and natural science. It examines in particular how a scientific-materialist conception of sound was formed alongside a dominant culture of romantic idealism. Placing itself at the intersection of historical musicology and the history and philosophy of science, the project will investigate the view that musical sound, ostensibly the property of metaphysics, was also regarded by writers, composers, scientists and engineers as tangible, material and subject to physical laws; that scientific thinking was not anathema but—at key moments—intrinsic to music aesthetics and criticism; that philosophies of mind and theories of the creative process also drew on mechanical rules of causality and associative ‘laws’; and that the technological innovations brought about by scientific research—from steam trains to stethoscopes—were accompanied by new concepts and new ways of listening that radically impacted the sound world of composers, critics, and performers. It seeks, in short, to uncover for the first time a fully integrated view of the musical and scientific culture of the 19th century. The research will be broken down into four areas, each of which circumscribes a particular set of discourses: machines and mechanism; forms of nature; technologies for sound; and music medicalised. Drawing on a range of archival and printed sources in Great Britain, France and Germany, the project offers an innovative approach by examining historical soundscapes and new listening practices, by adopting a media perspective on scientific and musical instruments, and by investigating the interrelations between artistic sounds and non-artistic, industrial technologies. The cross-disciplinary research, divided between the PI and four postdoctoral scholars, will open up new interactions between music and materialism as a concealed site of knowledge and historically significant nexus.

1 496 345 €

Start date: 2015-09-01, End date: 2020-08-31

Secondary structures such as G-quadruplexes (G4s) can form within DNA or RNA. They pose a dramatic risk for genome stability, because due to their stability they can block DNA replication and this could lead to DNA breaks. In certain cancer cells mutations/deletions are observed at G4s, if a helicase that is important for G4 unwinding is mutated. Nevertheless, G4s are also discussed to be functional elements for cellular processes such as telomere protection, transcription, replication, and meiosis. The aim of this research proposal is to use various biochemical and computational tools to determine which proteins are essential for formation and regulation of G4s. Proposed experiments will gain insights into both “effects” of G4s, the risk for genome stability and its significant function for the cell. In aim 1 we will elucidate and identify novel proteins that bind, regulate, and repair G4s, especially in the absence of helicases, in vitro and in vivo. Our focus is to understand how G4s become mutated in the absence of helicases, which proteins are involved, and how genome stability is preserved. In aim 2, we will use cutting edge techniques to identify regions that form G4s in vivo. Although there is experimental proof for G4s in vivo, this is not commonly accepted, yet. We will provide solid data that will support the existence of G4s in vivo. Furthermore, we will survey genome-wide when and why G4s become a risk for genome stability. Aim 3 will focus on the in silico observation that G4 structures are connected to meiosis. In this aim we will use a combination of techniques to unravel the biological significance of G4s during meiosis in vivo. Due to the connection of G4s and cancer the data obtained from this research proposal will not only be important to understand G4 regulation and formation, but will also provide unique knowledge on the impact of G4 structures for genome stability and thereby for human health.

1 531 625 €

Start date: 2015-07-01, End date: 2021-02-28