ERC FUNDED PROJECTS

Fundamental interactions in nature are well described by quantum gauge fields in 4 space-time dimensions (4d). When the strength of gauge interaction is weak the Feynman perturbation techniques are very efficient for the description of most of the experimentally observable consequences of the Standard model and for the study of high energy processes in QCD. But in the intermediate and strong coupling regime, such as the relatively small energies in QCD, the perturbation theory fails leaving us with no reliable analytic methods (except the Monte-Carlo simulation). The project aims at working out new analytic and computational methods for strongly coupled gauge theories in 4d. We will employ for that two important discoveries: 1) the gauge-string duality (AdS/CFT correspondence) relating certain strongly coupled gauge Conformal Field Theories to the weakly coupled string theories on Anty-deSitter space; 2) the solvability, or integrability of maximally supersymmetric (N=4) 4d super Yang-Mills (SYM) theory in multicolor limit. Integrability made possible pioneering exact numerical and analytic results in the N=4 multicolor SYM at any coupling, effectively summing up all 4d Feynman diagrams. Recently, we conjectured a system of functional equations - the AdS/CFT Y-system – for the exact spectrum of anomalous dimensions of all local operators in N=4 SYM. The conjecture has passed all available checks. My project is aimed at the understanding of origins of this, still mysterious integrability. Deriving the AdS/CFT Y-system from the first principles on both sides of gauge-string duality should provide a long-awaited proof of the AdS/CFT correspondence itself. I plan to use the Y-system to study the systematic weak and strong coupling expansions and the so called BFKL limit, as well as for calculation of multi-point correlation functions of N=4 SYM. We hope on new insights into the strong coupling dynamics of less supersymmetric gauge theories and of QCD.

1 456 140 €

Start date: 2013-11-01, End date: 2018-10-31

A massive and ever growing amount of digital image and video content is available today, on sites such as Flickr and YouTube, in audiovisual archives such as those of BBC and INA, and in personal collections. In most cases, it comes with additional information, such as text, audio or other metadata, that forms a rather sparse and noisy, yet rich and diverse source of annotation, ideally suited to emerging weakly supervised and active machine learning technology. The ALLEGRO project will take visual recognition to the next level by using this largely untapped source of data to automatically learn visual models. The main research objective of our project is the development of new algorithms and computer software capable of autonomously exploring evolving data collections, selecting the relevant information, and determining the visual models most appropriate for different object, scene, and activity categories. An emphasis will be put on learning visual models from video, a particularly rich source of information, and on the representation of human activities, one of today's most challenging problems in computer vision. Although this project addresses fundamental research issues, it is expected to result in significant advances in high-impact applications that range from visual mining of the Web and automated annotation and organization of family photo and video albums to large-scale information retrieval in television archives.

2 493 322 €

Start date: 2013-04-01, End date: 2019-03-31

Most of the technological materials have been developed by very expensive and cumbersome trial and error methods. On the other hand, computer based theoretical design of advanced materials is an area where rapid and extensive developments are taking place. Within my group new theoretical tools have now been established which are extremely well suited to the study of complex materials. In this approach basic quantum mechanical theories are used to describe fundamental properties of alloys and compounds. The utilization of such calculations to investigate possible optimizations of certain key properties represents a major departure from the traditional design philosophy. The purpose of my project is to build up a new competence in the field of computer-aided simulations of advanced materials. The main goal will be to achieve a deep understanding of the behaviour of complex metallic systems under equilibrium and non-equilibrium conditions at the atomic level by studying their electronic, magnetic and atomic structure using the most modern and advanced computational methods. This will enable us to establish a set of materials parameters and composition-structure-property relations that are needed for materials optimization. The research will be focused on fundamental technological properties related to defects in advanced metallic alloys (high-performance steels, superalloys, and refractory, energy related and geochemical materials) and alloy phases (solid solutions, intermetallic compounds), which will be studied by means of parameter free atomistic simulations combined with continuum modelling. As a first example, we will study the Fe-Cr system, which is of great interest to industry as well as in connection to nuclear waste. The Fe-Cr-Ni system will form another large group of materials under the aegis of this project. Special emphasis will also be placed on those Fe-alloys which exist under extreme conditions and are possible candidates for the Earth core.

2 000 000 €

Start date: 2009-03-01, End date: 2014-02-28

The frequency of Alzheimer's disease (AD) will dramatically increase in the ageing western society during the next decades. Currently, about 18 million people suffer worldwide from AD. Since no cure is available, this devastating disorder represents one of the most challenging socio-economical problems of our future. As onset and progression of AD is triggered by the amyloid cascade, I will put particular attention on amyloid ß-peptide (Aß). The reason for this approach is, that even though 20 years ago the Aß generating processing pathway was identified (Haass et al., Nature 1992a & b), the identity of the Aß species, which initiate the deadly cascade is still unknown. I will first tackle this challenge by investigating if a novel and so far completely overlooked proteolytic processing pathway is involved in the generation of Aß species capable to initiate spreading of pathology and neurotoxicity. I will then search for modulating proteins, which could affect generation of pathological Aß species. This includes a genome-wide screen for modifiers of gamma-secretase, one of the proteases involved in Aß generation as well as a targeted search for RNA binding proteins capable to posttranscriptionally regulate beta- and alpha-secretase. In a disease-crossing approach, RNA binding proteins, which were recently found not only to be deposited in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis but also in many AD cases, will be investigated for their potential to modulate Aß aggregation and AD pathology. Modifiers and novel antibodies specifically recognizing neurotoxic Aß assemblies will be validated for their potential not only to prevent amyloid plaque formation, but also spreading of pathology as well as neurotoxicity. In vivo validations include studies in innovative zebrafish models, which allow life imaging of neuronal cell death, as well as the establishment of microPET amyloid imaging for longitudinal studies in individual animals.

2 497 020 €

Start date: 2013-03-01, End date: 2018-02-28

Despite improved therapy, cardiovascular diseases remain the most prevalent diseases in the European Union and the incidence is rising due to increased obesity and ageing. The fine-tuned regulation of vascular functions is essential not only for preventing atherosclerotic diseases, but also after tissue injury, where the coordinated growth and maturation of new blood vessels provides oxygen and nutrient supply. On the other hand, excessive vessel growth or the generation of immature, leaky vessels contributes to pathological angiogenesis. Thus, the regulation of the complex processes governing vessel growth and maturation has broad impacts for several diseases ranging from tumor angiogenesis, diabetic retinopathy, to ischemic cardiovascular diseases. MicroRNAs (miRs) are small noncoding RNAs, which play a crucial role in embryonic development and tissue homeostasis. However, only limited information is available regarding the role of miRs in the vasculature. MiRs regulate gene expression by binding to the target mRNA leading either to degradation or to translational repression. Because miRs control patterns of target genes, miRs represent an attractive and promising therapeutic target to interfere with complex processes such as neovascularization and repair of ischemic tissues. Therefore, the present application aims to identify miRs in the vasculature, which regulate vessel growth and vessel remodelling and may, thus, serve as therapeutic targets in ischemic diseases. Since ageing critically impairs endothelial function, neovascularization and vascular repair, we will specifically identify miRs, which are dysregulated during ageing in endothelial cells and pro-angiogenic progenitor cells, in order to develop novel strategies to rescue age-induced impairment of neovascularization. Beyond the specific scope of the present application, the principle findings may have impact for other diseases, where deregulated vessel growth causes or accelerates disease states.

2 375 394 €

Start date: 2009-03-01, End date: 2014-02-28

"Humans are equipped with a variety of intrinsic immunity or host restriction factors. These evolved under positive selection pressure for diversification and represent a first line of defence against invading viruses. Unfortunately, however, many pathogens have evolved effective antagonists against our defences. For example, the capability of HIV-1 to counteract human restriction factors that interfere with reverse transcription, uncoating and virion release has been a prerequisite for the global spread of AIDS. We are just beginning to understand the diversity and induction of antiretroviral factors and how pandemic HIV-1 group M (major) strains evolved to counteract all of them. Here, I propose to use a genetics, proteomics and evolutionary approach to discover and define as-yet-unknown antiviral effectors and their inducers. To identify novel antiviral factors, we will examine the capability of all primate genes that are under strong positive selection pressure to inhibit HIV and its simian (SIV) precursors. This examination from the evolutionary perspective of the invading pathogen will also reveal which adaptations allowed HIV-1 to cause the AIDS pandemic. Furthermore, complex peptide-protein libraries representing essentially the entire human peptidome, will be utilized to identify novel specific inducers of antiviral restriction factors. My ultimate aim is to unravel the network of inducers and effectors of antiviral immunity - the ""Anti-Virome"" - and to use this knowledge to develop novel effective preventive and therapeutic approaches based on the induction of combinations of antiviral factors targeting different steps of the viral life cycle. The results of this innovative and interdisciplinary program will provide fundamental new insights into intrinsic immunity and may offer alternatives to conventional vaccine and therapeutic approaches because most restriction factors have broad antiviral activity and are thus effective against various pathogens."

1 915 200 €

Start date: 2013-04-01, End date: 2018-03-31

"The objective of this proposal is to tackle two of the greatest challenges in quantum chemistry: (i) extending the applicability of highly accurate wave function methods to large molecular systems, and (ii) developing accurate and robust multi-reference methods that can be used for studying important but very difficult problems in transition metal chemistry, catalysis, and photochemistry. Solutions to these problems have now come within reach due to three advances we recently reported: first, the steep scaling of the computational cost with molecular size can be reduced to linear by exploiting the short-range character of electron correlation (local correlation methods). Second, the accuracy, efficiency, and robustness of these local correlation methods can be strongly improved by new tensor decomposition approaches and the inclusion of terms depending explicitly on the inter-electronic distances (F12 methods). Third, the development of highly complex electronic structure theories can be greatly facilitated and accelerated by new automated tensor network evaluation techniques. We are certain that by combining and generalizing these advances the long-standing problems (i) and (ii) can be solved. We will focus especially on highly scalable algorithms in order to use massively parallel computer systems efficiently. For linear-scaling methods this means that the size of the molecules that can be treated in a fixed time will grow linearly with the number of available processors. We will furthermore explore new multi-reference ansätze and implement analytical energy gradients and response properties for local methods. Hybrid and embedding methods to account for solvent and environment effects will also be investigated. It is our priority to make our new methods as easy to use, robust, and widely applicable as possible. We believe that they will open entirely new horizons for innumerable applications in chemistry, physics, biology, and materials science."

2 454 000 €

Start date: 2013-02-01, End date: 2018-01-31

DNA double-strand breaks are perhaps the most harmful DNA damages and result in carcinogenic chromosome aberrations. Cells protect their genome by activating a complex signaling and repair network, collectively denoted DNA damage response (DDR). A key initial step of the DDR is the activation of the 360 kDa checkpoint kinase ATM (ataxia telangiectasia mutated) by the multifunctional DSB repair factor Mre11-Rad50-Nbs1 (MRN). MRN senses and tethers DSBs, processes DSBs for further resection, and recruits and activates ATM to trigger the DDR. A mechanistic basis for the activities of the core DDR sensor MRN has not been established, despite intense research over the past decade. Our recent breakthroughs on structures of core Mre11-Rad50 and Mre11-Nbs1 complexes enable us now address three central questions to finally clarify the mechanism of MRN in the DDR: - How does MRN interact with DNA or DNA ends in an ATP dependent manner? - How do MRN and associated factors such as CtIP process blocked DNA ends? - How do MRN and DNA activate ATM? We will employ an innovative structural biology hybrid methods approach by combining X-ray crystallography, electron microscopy and small angle scattering with crosslink mass spectrometry and combine the structure-oriented techniques with validating in vitro and in vivo functional studies. The anticipated outcome will clarify the structural mechanism of one of the most important but enigmatic molecular machineries in maintaining genome stability and also help understand the molecular defects associated with several prominent cancer predisposition and neurodegenerative disorders.

2 498 019 €

Start date: 2013-05-01, End date: 2018-04-30

BabMed represents the first ever comprehensive study of ancient Babylonian medical science since the decipherment of cuneiform, comprising the largest ancient collection of medical data before Hippocrates. The latest phase of Babylonian medicine, as preserved in Aramaic in the Babylonian Talmud, has never been systematically studied in the light of older cuneiform materials. The absence of accessible cuneiform medical literature has forced recent medical histories to bypass Babylonian medicine, while Aramaic medicine in the Babylonian Talmud has simply been ignored. BabMed tests a number of 'high risk' propositions, including two key hypotheses: 1) cuneiform survived much longer than previously suspected, and 2) Aramaic medicine in the Babylonian Talmud mostly derives from Akkadian medicine. BabMed's methodology relies upon native taxonomies rather than modern biomedical disease classifications, countering flawed retrospective diagnoses that obviate the entire history of medicine. Comparisons with neighbouring medical systems challenge the prevalent Eurocentricity of current histories, in which Greek medicine has become the standard for all ancient medicine. BabMed will introduce a new paradigm for knowledge transfer which will recognise the barriers between ancient arts of medicine and how they were overcome in antiquity. One such barrier was script and language, and BabMed proposes that Babylonian medicine survived the death of cuneiform script and was preserved in part in the local Aramaic of the Babylonian Talmud, a unique text which straddles the borders of Greco-Roman Palestine and Persian Babylonia and mirrors the scientific thinking of both worlds.

2 233 747 €

Start date: 2013-07-01, End date: 2018-06-30