ERC FUNDED PROJECTS

State-of-the-art microscopy and diffraction imaging provides insight into the atomic and sub-atomic structure of matter. They permit determination of the positions of atoms in a crystal lattice or in a molecule as well as the distribution of electrons inside atoms. State-of-the-art time-resolved spectroscopy with femtosecond and attosecond resolution provides access to dynamic changes in the atomic and electronic structure of matter. Our proposal aims at combining these two frontier techniques of XXI century science to make a long-standing dream of scientist come true: the direct observation of atoms and electrons in their natural state: in motion. Shifts in the atoms positions by tens to hundreds of picometers can make chemical bonds break apart or newly form, changing the structure and/or chemical composition of matter. Electronic motion on similar scales may result in the emission of light, or the initiation of processes that lead to a change in physical or chemical properties, or biological function. These motions happen within femtoseconds and attoseconds, respectively. To make them observable, we need a 4-dimensional (4D) imaging technique capable of recording freeze-frame snapshots of microscopic systems with picometer spatial resolution and femtosecond to attosecond exposure time. The motion can then be visualized by slow-motion replay of the freeze-frame shots. The goal of this project is to develop a 4D imaging technique that will ultimately offer picometer resolution is space and attosecond resolution in time.

2 500 000 €

Start date: 2010-03-01, End date: 2015-02-28

Some of the most extreme tests of physical law come from its manifestations in the behaviour of black holes and neutron stars, and as such these objects should be used as fundamental physics labs. Due to advances in both theoretical work and observational techniques, I have a major opportunity now to significantly push this agenda forward and get better answers to questions like: How are black holes born? How can energy be extracted from black holes? What is the origin of magnetic fields and cosmic rays in jets and shocks? Is their primary energy stream hadronic or magnetic? I propose to do this by exploiting the advent of wide-field radio astronomy: extreme objects are very rare and usually transient, so not only must one survey large areas of sky, but also must one do this often. I propose to form and shape a group that will use the LOFAR wide-field radio telescope to hunt for these extreme transients and systematically collect enough well-documented examples of the behaviour of each type of transient. Furthermore, I propose to expand LOFAR with a true 24/7 all-sky monitor to catch and study even the rarest of events. Next, I will use my experience in gamma-ray burst followup to conduct a vigorous multi-wavelength programme of study of these objects, to constrain their physics from as many angles as possible. This will eventually include results from multi-messenger astrophysics, in which we use neutrinos, gravity waves, and other non-electromagnetic messengers as extra diagnostics of the physics of these sources. Finally, I will build on my experience in modelling accretion phenomena and relativistic explosions to develop a theoretical framework for these phenomena and constrain the resulting models with the rich data sets we obtain.

3 499 128 €

Start date: 2010-10-01, End date: 2016-09-30

The aim of this project is the realisation of efficient mid-infrared and THz optoelectronic emitters. This work is motivated by the fact that the spontaneous emission in this frequency range is characterized by an extremely long lifetime when compared to non-radiative processes, giving rise to devices with very low quantum efficiency. To this end we want to develop hybrid light-matter systems, already well known in quantum optics, within optoelectronics devices, that will be driven by electrical injection. With this project we want to extend the field of optoelectronics by introducing some of the concepts of quantum optic, particularly the light-matter strong coupling, into semiconductor devices. More precisely this project aims at the implementation of novel optoelectronic emitters operating in the strong coupling regime between an intersubband excitation of a two-dimensional electron gas and a microcavity photonic mode. The quasiparticles issued from this coupling are called intersubband polaritons. The major difficulties and challenges of this project, do not lay in the observation of these quantum effects, but in their exploitation for a specific function, in particular an efficient electrical to optical conversion. To obtain efficient quantum emitters in the THz frequency range we will follow two different approaches: - In the first case we will try to exploit the additional characteristic time of the system introduced by the light-matter interaction in the strong (or ultra-strong) coupling regime. - The second approach will exploit the fact that, under certain conditions, intersubband polaritons have a bosonic character; as a consequence they can undergo stimulated scattering, giving rise to polaritons lasers as it has been shown for excitonic polaritons.

1 761 000 €

Start date: 2010-05-01, End date: 2015-04-30

Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.

2 411 547 €

Start date: 2010-03-01, End date: 2015-02-28

Our aim is to provide a theoretical framework for studies of dynamical aspects of magnetic materials and magnetisation reversal, which has potential for applications for magnetic data storage and magnetic memory devices. The project focuses on developing and using an atomistic spin dynamics simulation method. Our goal is to identify novel materials and device geometries with improved performance. The scientific questions which will be addressed concern the understanding of the fundamental temporal limit of magnetisation switching and reversal, and the mechanisms which govern this limit. The methodological developments concern the ability to, from first principles theory, calculate the interatomic exchange parameters of materials in general, in particular for correlated electron materials, via the use of dynamical mean-field theory. The theoretical development also involves an atomistic spin dynamics simulation method, which once it has been established, will be released as a public software package. The proposed theoretical research will be intimately connected to world-leading experimental efforts, especially in Europe where a leading activity in experimental studies of magnetisation dynamics has been established. The ambition with this project is to become world-leading in the theory of simulating spin-dynamics phenomena, and to promote education and training of young researchers. To achieve our goals we will build up an open and lively environment, where the advances in the theoretical knowledge of spin-dynamics phenomena will be used to address important questions in information technology. In this environment the next generation research leaders will be fostered and trained, thus ensuring that the society of tomorrow is equipped with the scientific competence to tackle the challenges of our future.

2 130 000 €

Start date: 2010-01-01, End date: 2014-12-31

We propose to investigate a new frontier in Physics: the study of Magnetic systems using attosecond laser pulses. The main disciplines concerned are: Ultrafast laser sciences, Magnetism and Spin-Photonics, Relativistic Quantum Electrodynamics. Three issues of modern magnetism are addressed. 1. How fast can one modify and control the magnetization of a magnetic system ? 2. What is the role and essence of the coherent interaction between light and spins ? 3. How far spin-photonics can bring us to the real world of data acquisition and storage ? - We want first to provide solid ground experiments, unravelling the mechanisms involved in the demagnetization induced by laser pulses in a variety of magnetic materials (ferromagnetic nanostructures, aggregates and molecular magnets). We will explore the ultrafast magnetization dynamics of magnets using an attosecond laser source. - Second we want to explore how the photon field interacts with the spins. We will investigate the dynamical regime when the potential of the atoms is dressed by the Coulomb potential induced by the laser field. A strong support from the relativistic Quantum Electro-Dynamics is necessary towards that goal. - Third, even though our general approach is fundamental, we want to provide a benchmark of what is realistically possible in ultrafast spin-photonics, breaking the conventional thought that spin photonics is hard to implement at the application level. We will realize ultimate devices combining magneto-optical microscopy with the conventional magnetic recording. This new field will raise the interest of a number of competitive laboratories at the international level. Due to the overlapping disciplines the project also carries a large amount of educational impact both fundamental and applied.

2 492 561 €

Start date: 2010-05-01, End date: 2015-04-30

This interdisciplinary proposal has the objective to greatly enhance our understanding of fundamental biomineralization processes involved in the formation of calcium carbonates by marine organisms, such as corals, foraminifera and bivalves, in order to better understand vital effects. This is essential to the application of these carbonates as proxies for global (paleo-) environmental change. The core of the proposal is an experimental capability that I have pioneered during 2008: Dynamic stable isotopic labeling during formation of carbonate skeletons, tests, and shells, combined with NanoSIMS imaging. The NanoSIMS ion microprobe is a state-of-the-art analytical technology that allows precise elemental and isotopic imaging with a spatial resolution of ~100 nanometers. NanoSIMS imaging of the isotopic label(s) in the resulting biocarbonates and in associated cell-structures will be used to uncover cellular-level transport processes, timescales of formation of different biocarbonate components, as well as trace-elemental and isotopic fractionations. This will uncover the origin of vital effects. With this proposal, I establish a new scientific frontier and guarantee European leadership. The technical and scientific developments resulting from this work are broadly applicable and will radically change scientific ideas about marine carbonate biomineralization and compositional vital effects.

2 182 000 €

Start date: 2010-07-01, End date: 2015-06-30

Bioinorganic chemistry is a rapidly expanding area of research, but the potential for the therapeutic application of metal complexes is highly underdeveloped. The basic principles required to guide the development of metal-containing therapeutic agents are lacking, despite the unique therapeutic opportunities which they offer. It is the goal of the proposed research to establish basic principles of medicinal coordination chemistry of metals that will allow the rational screening of future metallopharmaceuticals. We propose to utilize the power of inorganic chemistry to provide new knowledge of and new approaches for intervention in biological systems. This will be based on improved understanding of reactions of metal complexes under physiological conditions, on improving the specificity of their interactions, and gaining control over the potential toxicity of synthetic metal complexes. The research programme is highly interdisciplinary involving chemistry, physics, biology and pharmacology, with potential for the discovery of truly novel medicines, especially for the treatment of diseases and conditions which are currently intractable, such as cancer. The challenging and ambitious goals of the present work involve transition metal complexes with novel chemical and biochemical mechanisms of action. They will contain novel features which allow them (i) to be selectively activated by light in cells, or (ii) to be activated by a structural transition, or (ii) exhibit catalytic activity in cells. This ground-breaking research potentially has a very high impact and is based on recent discoveries in the applicant s laboratory. A feature of the programme is the use of state-of-the-art-and-beyond methodology to advance knowledge of medicinal metal coordination chemistry.

1 565 397 €

Start date: 2010-07-01, End date: 2015-12-31

This project addresses a key issue in fundamental research - one that has challenged ecologists ever since Darwin s time that is why some species are common, and others rare, and why, despite marked turnover at the level of individual species abundances, the structure of a community is generally conserved through time. Its aim is to examine the temporal dynamics of species abundance distributions (SADs), and to assess the capacity of these distributions to withstand change (resistance) and to recover from change (resilience). These are topical and important questions given the increasing impact that humans are having on the natural world. There are three components to the research. First, we will model SADs and predict responses to a range of events including climate change and the arrival of invasive species. A range of modeling approaches (including neutral, niche and statistical) will be adopted; by incorporating temporal turnover in hitherto static models we will advance the field. Second, we will test predictions concerning the resistance and resilience of SADs by a comparative analysis of existing data sets (that encompass communities in terrestrial, freshwater and marine environments for ecosystems extending from the poles to the tropics) and through a new field experiment that quantifies temporal turnover across a community (unicellular organisms to vertebrates) in relation to factors both natural (dispersal limitation) and anthropogenic (human disturbance) thought to shape SADs. In the final part of the project we will apply these new insights into the temporal dynamics of SADs to two important conservation challenges. These are 1) the conservation of biodiversity in a heavily utilized European landscape (Fife, Scotland) and 2) the conservation of biodiversity in Mamirauá and Amaña reserves in Amazonian flooded forest. Taken together this research will not only shed new light on the structure of ecological communities but will also aid conservation.

1 812 782 €

Start date: 2010-08-01, End date: 2016-01-31

Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).

2 499 947 €

Start date: 2010-04-01, End date: 2016-03-31

We envisage a new generation of dynamic holographic laser tweezers and stretching tools with unprecedented spatial control of gradient and scattering light forces, to unravel functional mysteries of cell biology and genetics: Based on our recently developed, highly successful and widely recognized amplitude and phase shaping techniques with cascaded spatial light modulators (SLM), we will create new holographic optical manipulators consisting of a line-shaped trap with balanced net scattering forces and controllable local phase-gradients. Combining these line stretchers with spiral phase contrast imaging or nonlinear optical microscopy will allow quantitative study of functional shape changes. The novel tool is hugely more versatile than standard optical tweezers, since direction and magnitude of the scattering force can be designed to precisely follow the structure. In combination with conventional multi-spot traps the line stretcher acts as a sensitive and adaptable local force sensor. In collaboration with local experts we want to tackle hot topics in Genetics, e.g. search for force profile signatures in regions with Copy Number Variations. Possibly the approach may shed light on basic physical characteristics such as, for example, chromosomal fragility in Fra(X) syndrome, the most common monogenic cause of mental retardation. The new design intrinsically offers enhanced microscopic resolution, as SLM-synthesized apertures and waveforms can enlarge the number of spatial frequencies forming the image. Ultimately, nonlinear holography can be implemented, sending phase shaped wavefronts to target samples. This can, e.g., be used to push the sensitivity of nonlinear chemical imaging, or for controlled photo-activation of targeted regions in neurons.

1 987 428 €

Start date: 2010-05-01, End date: 2015-04-30

Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.

2 076 126 €

Start date: 2010-04-01, End date: 2015-03-31

Cellular clearance is a fundamental process required by all cells in all species. Important physiological processes, such as aging, and pathological mechanisms, such as neurodegeneration, are strictly dependent on cellular clearance. In eukaryotes, most of the cellular clearing processes occur in a specialized organelle, the lysosome. This project is based on a recent discovery, made in our laboratory, of a gene network, which we have named CLEAR, that controls lysosomal biogenesis and function and regulates cellular clearance. The specific goals of the project are: 1) the comprehensive characterization of the mechanisms underlying the CLEAR network, 2) the thorough understanding of CLEAR physiological function at the cellular and organism levels, 3) the development of strategies and tools to modulate cellular clearance, and 4) the implementation of proof-of-principle therapeutic studies based on the activation of the CLEAR network in murine models of human lysosomal storage disorders and of neurodegenerative diseases, such as Alzheimers s and Huntington s diseases. A combination of genomics, bioinformatics, systems biology, chemical genomics, cell biology, and mouse genetics approaches will be used to achieve these goals. Our goal is to develop tools to modulate cellular clearance and to use such tools to develop therapies to cure human disease. The potential medical relevance of this project is very high, particularly in the field of neurodegenerative disease. Therapies that prevent, ameliorate or delay neurodegeneration in these diseases would have a huge impact on human health.

2 100 000 €

Start date: 2010-03-01, End date: 2015-02-28

Revolutionary combination of principles of spectral domain and time domain coherence gating will be researched. The present proposal puts forward: (i) a novel class of optical interferometers, (ii) a novel class of wavefront sensors and (iii) combinations of imaging channels with the novel wavefront sensors. All these are driven by the needs to address the limitations in terms of speed of the time domain (TD) optical coherence tomography (OCT), in terms of range, resolution and focus of the spectral (SD) OCT methods and in terms of spatial resolution of wavefront sensors. A new class of OCT systems is researched, as a marriage between the TD-OCT and SD-OCT methods. The novel methods present the generality of being compatible with both TD-OCT and SD-OCT. It is envisaged that the research results will revolutionise the field of high resolution imaging and high sensitive sensing and open applications not currently possible with the present OCT, confocal microscopy or multiphoton microscopy technology. The method to be researched will allow versatile functionality in measurements, in 3D imaging of moving tissue and functional/low noise imaging by making use of angular compounding or polarisation. Novel directions are opened in the tracking of the axial position of objects (cornea or retina), automatic dispersion compensation as well as improvement in the synchronism between the coherence gate and the focus in axial scanning. Simultaneous measurements over multiple path lengths becomes feasible, with potential applications in high throughput sensing. The methods proposed open novel avenues in biosensing by amplification of tiny frequency shifts or tiny changes in the optical paths. Possible outcome are high sensitive biosensors, multiple imaging at different depths, fast and long range tracking, long axial scanning, coherence gated wavefront sensors with applications in vision sciences and microscopy, protein identification and contrast agents developments.

1 999 241 €

Start date: 2010-05-01, End date: 2015-10-31

How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.

1 992 000 €

Start date: 2010-05-01, End date: 2015-04-30

COUNTING ATOMS IN NANOMATERIALS Advanced electron microscopy for solid state materials has evolved from a qualitative imaging setup to a quantitative scientific technique. This will allow us not only to probe and better understand the fundamental behaviour of (nano) materials at an atomic level but also to guide technology towards new horizons. The installation in 2009 of a new and unique electron microscope with a real space resolution of 50 pm and an energy resolution of 100 meV will make it possible to perform unique experiments. We believe that the position of atoms at an interface or at a surface can be determined with a precision of 1 pm; this precision is essential as input for modelling the materials properties. It will be first applied to explain the fascinating behaviour of multilayer ceramic materials. The new experimental limits will also allow us to literally count the number of atoms within an atomic columns; particularly counting the number of foreign atoms. This will not only require experimental skills, but also theoretical support. A real challenge is probing the magnetic and electronic information of a single atom column. According to theory this would be possible using ultra high resolution. This new probing technique will be of extreme importance for e.g. spintronics. Modern (nano) technology more and more requires information in 3 dimensions (3D), rather than in 2D. This is possible through electron tomography; this technique will be optimised in order to obtain sub nanometer precision. A final challenge is the study of the interface between soft matter (bio- or organic materials) and hard matter. This was hitherto impossible because of the radiation damage of the electron beam. With the possibility to lower the voltage to 80 kV and possibly 50 kV, maintaining more or less the resolution, we will hopefully be able to probe the active sites for catalysis.

2 000 160 €

Start date: 2010-01-01, End date: 2014-12-31

Proposal summary: The present project will investigate the main principles of development and neuroplasticity in humans in the domain of multisensory processes (the interplay between sensory systems). It will be tested how learning plasticity of the human brain changes from childhood to adulthood and how early experience constraints neuroplasticity at later developmental stages as well as in adults. The project is based upon animal findings in sensory development and plasticity. Both a prospective (studies in children) and a retrospective (studies in people with a history of visual or auditory deprivation) approach are employed. Behavioural paradigms from experimental psychology addressing multisensory processes are combined with electroencephalographic recordings (EEG). First, we investigate the functional principles and neural correlates of multisensory development. Second, we investigate multisensory processes in people who suffered from a transient phase of sensory deprivation after birth: (a) in people who were born with bilateral dense cataracts that were removed later, and (b) in congenitally deaf individuals, who were equipped with a cochlear implant to restore hearing. This line of research will reveal the critical contribution of single sensory systems as well as the synchronized input across modalities with regard to the emergence of successful multisensory binding. Third, we will investigate whether it is possible to alleviate neural changes demarcating the end of sensitive phases or critical periods by implementing an incremental training procedure. Last, we will look at whether experimentally induced transient sensory deprivation increases neuroplasticity loss during a sensitive phase or critical period. We are convinced that basic research, such as the present, will reveal important principles of development and neuroplasticity which will be useful in applied setting to improve education, the rehabilitation of individuals with sensory defects and the treatment of developmental disorders.

2 396 640 €

Start date: 2010-12-01, End date: 2016-11-30

An intense debate is raging within evolutionary anthropology as to whether the evolution of human behaviour is driven by selection pressure on the individual or on the group. Until recently there was consensus amongst evolutionary biologists and evolutionary anthropologists that natural selection caused behaviours to evolve that benefit the individual or close kin. However the idea that cultural behaviours that favour the group can evolve, even at the expense of individual well-being, is now being supported by some evolutionary anthropologists and economists. Models of cultural group selection rely on patterns of cultural transmission that maintain differences between cultural groups, because either decisions are based on what most others in the group do, or non-conformists are punished in some way. If such biased transmission occurs, then humans may be following a unique evolutionary trajectory towards extreme sociality; such models potentially explain behaviours such as altruism towards non-relatives or limiting your reproductive rate. However, relevant empirical evidence from real world populations, concerning behaviour that potentially influences reproductive success, is almost entirely lacking. The projects proposed here are designed to help fill that gap. In micro-evolutionary studies we will seek evidence for the patterns cultural transmission or social learning that enable cultural group selection to act, and ask how these processes depend on properties of the community, and thus how robust are they to the demographic and societal changes that accompany modernisation. These include studies of the spread of modern contraception through communities; and studies of punishment of selfish players in economic games. In macro-evolutionary studies, we will use phylogenetic cross-cultural comparative methods to show how different cultural traits change over the long term, and ask whether social or ecological variables are driving that cultural change.

1 801 978 €

Start date: 2010-05-01, End date: 2016-04-30

Much light has been shed on the number, mechanisms and functions of protein-coding genes in the human genome. In comparison, we know almost nothing about the origins and mechanisms of the functional dark matter , including sequence that is transcribed outside of protein-coding gene loci. This interdisciplinary proposal will capitalize on new theoretical and experimental opportunities to establish the extent by which long non-coding RNAs contribute to mammalian and fruit fly biology. Since 2001, the Ponting group has pioneered the comparative analysis of protein-coding genes across the amniotes and Drosophilids within many international genome sequencing consortia. This Advanced Grant will break new ground by applying these approaches to long intergenic non-coding RNA (lincRNA) genes from mammals to birds and to flies. The Grant will allow Ponting to free himself of the constraints normally associated with in silico analyses by analysing lincRNAs in vitro and in vivo. The integration of computational and experimental approaches for lincRNAs from across the metazoan tree provides a powerful new toolkit for elucidating the origins and biological roles of these enigmatic molecules. Catalogues of lincRNA loci will be built for human, mouse, fruit fly, zebrafinch, chicken and Aplysia by exploiting data from next-generation sequencing technologies. This will immediately provide a new perspective on how these loci arise, evolve and function, including whether their orthologues are apparent across diverse species. Using new evidence that lincRNA loci act in cis with neighbouring protein-coding loci, we will determine lincRNA mechanisms and will establish the consequences of lincRNA knock-down, knock-out and over-expression in mouse, chick and fruitfly.

2 400 000 €

Start date: 2010-05-01, End date: 2015-04-30

We target a frontier in nanocrystal science of combining disparate materials into a single hybrid nanosystem. This offers an intriguing route to engineer nanomaterials with multiple functionalities in ways that are not accessible in bulk materials or in molecules. Such control of novel material combinations on a single nanoparticle or in a super-structure of assembled nanoparticles, presents alongside with the synthesis challenges, fundamental questions concerning the physical attributes of nanoscale systems. My goals are to create new highly controlled hybrid nanoparticle systems, focusing on combinations of semiconductors and metals, and to decipher the fundamental principles governing doping in nanoparticles and charge and energy transfer processes among components of the hybrid systems. The research addresses several key challenges: First, in synthesis, combining disparate material components into one hybrid nanoparticle system. Second, in self assembly, organizing a combination of semiconductor (SC) and metal nanoparticle building blocks into hybrid systems with controlled architecture. Third in fundamental physico-chemical questions pertaining to the unique attributes of the hybrid systems, constituting a key component of the research. A first aspect concerns doping of SC nanoparticles with metal atoms. A second aspect concerns light-induced charge transfer between the SC part and metal parts of the hybrid constructs. A third related aspect concerns energy transfer processes between the SC and metal components and the interplay between near-field enhancement and fluorescence quenching effects. Due to the new properties, significant impact on nanocrystal applications in solar energy harvesting, biological tagging, sensing, optics and electropotics is expected.

2 499 000 €

Start date: 2010-06-01, End date: 2015-05-31

The main objective of this proposal is to design and implement a novel scheme for efficient, deterministic, lossless photon-photon interactions, and to exploit it to achieve logical processing and quantum measurements on optical light beams. For that purpose, we will create, study and exploit a new transparent medium, based on the transient excitation of Rydberg polaritons, where the optical non-linearities are so large that they can act at the single photon level. These techniques will be applied to perform quantum measurements and manipulations of light beams. This will include the deterministic generation of single photons and optical Schrödinger's cat states, the implementation of quantum non-demolition (QND) measurements for the photon number and the parity operators, and the demonstration of controlled-phase and controlled-not quantum gates. These operations will be implemented in the optical domain, where they can be combined with efficient propagation in free space or in optical fibers, and with high efficiency detectors already available, in order to open an avenue towards a fully deterministic quantum engineering of light.

2 496 000 €

Start date: 2010-01-01, End date: 2014-12-31

Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.

2 261 440 €

Start date: 2010-03-01, End date: 2015-02-28

This proposal is in the area of automated web data extraction and web data management. The aim of our project is to provide the logical, methodological, and algorithmic foundations for the knowledge-based extraction of structured data from web sites belonging to specific domains, such as estate agents, restaurants, travel agencies, car dealers, and so on. One core part of this will be a comprehensive multi-dimensional logical data model that will be used to simultaneously represent both the content of a large website, its structure, inferred user-interaction patterns and all meta-information and knowledge (factual and rule-based) that is necessary to automatically perform the desired extraction tasks. I envision that, based on these new foundations, we will be able to build extremely powerful systems that autonomously explore websites of a given domain, understand their structure and extract and output richly structured data in formats such as XML or RDF. We aim at systems that take as input a URL of a website in a given domain, automatically explore this site and deliver as output a structured data set containing all the relevant information present on that site. As an example, imagine a system specialized in the real-estate domain, that receives as input the URL of any real-estate agent, explores the site automatically and outputs richly structured records of all properties that are currently advertised for sale or for rent on the many web pages of this site. We plan to develop and implement at least two such systems for two different domains, including the one mentioned. The breakthrough in automatic data extraction that we are striving for would enable a quantum leap for two interrelated technologies which are the hottest next topics in web search: vertical search, that is, web search in specialized domains, and object search, that is, the search for web data objects rather than web pages.

2 402 846 €

Start date: 2010-04-01, End date: 2015-03-31

Disorder is ubiquitous in nature and has a strong impact on the behaviour of many physical systems. The most celebrated effect of disorder is Anderson localization of single particles, but many other more complex phenomena arise in interacting, many-body systems. A full understanding of how disorder affects the behavior of quantum systems is still missing, also because of the unavoidable presence of nonlinearities, dissipation and thermal effects that make a careful exploration of real condensed-matter systems very difficult. In this project we want to fully exploit the unprecedented potentialities offered by ultracold atomic quantum gases to explore some of the present challenges for our understanding of the physics of disorder. These systems offer indeed the possibility of controlling to a great extent crucial parameters such as the type of disorder, the nonlinearities due to interactions, the temperature and density, the dimensionality, the quantum statistics. A variety of advanced diagnostic techniques allow to gain detailed information on the static and dynamic properties of the system. The potentialities of atomic quantum gases for the study of disorder have already showed up in recent breakthrough experiments. The project aims at an experimental exploration, supported by advanced theory, of the current issues in disordered quantum systems. We will investigate a few frontier themes of general interest: 1) Anderson localization and the interplay of disorder and a weak interaction; 2) strongly correlated, disordered bosonic systems; 3) disordered, interacting fermionic systems. In the research we will employ atomic Bose and Fermi gases with tunable interactions and advanced diagnostic techniques that we have recently contributed to develop. A successful completion of the project will push forward our understanding of the behaviour of quantum systems with disorder, with a potentially large impact on many fields of physics.

2 500 000 €

Start date: 2010-03-01, End date: 2015-02-28

We plan to construct a theoretical bridge between classical dynamic allocation models used in Operations Research/Management Science, and between the modern theory of mechanism design. Our theoretical results will generate insights for the construction of applied pricing schemes and testable implications about the pattern of observed prices. The Economics literature has focused on information and incentive issues in static models, whereas the Operations Research/Management Science literature has looked at dynamic models that were often lacking strategic/ informational aspects. There is an increased recent interest in combining these bodies of knowledge, spurred by studies of yield management, and of decentralized platforms for interaction/ communication among agents. A general mechanism design analysis starts with the characterization of all dynamically implementable allocation policies. Variational arguments can be used then to characterize optimal policies. The research will focus on models with multidimensional incomplete information, such as: 1) Add incomplete information to the dynamic & stochastic knapsack problem; 2) Allow for strategic purchase time in dynamic pricing models; 3)Allow for competing mechanism designers. The ensuing control problems are often not standard and require special tools. An additional attack line will be devoted to models that combine design with learning about the environment. The information revealed by an agent affects then both the value of the current allocation, and the option value of future allocations. We plan to: 1) Derive the properties of learning processes that allow efficient, dynamic implementation; 2) Characterize second-best mechanism in cases where adaptive learning and efficiency are not compatible with each other.

1 123 200 €

Start date: 2010-05-01, End date: 2016-04-30

Our genetic material is continually subjected to damage, either from endogenous sources such as reactive oxygen species produced as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionising radiation or carcinogenic chemicals. To cope with DNA damage, cells employ elaborate and effective repair processes that specifically recognise a wide variety of lesions in DNA. These repair systems are essential for the maintenance of genome integrity. Unfortunately, some individuals are genetically predisposed to crippling diseases or cancers that are the direct result of mutations in genes involved in the DNA damage response. For several years our work has been at the forefront of basic biological research in the area of DNA repair, and in particular we have made significant contributions to the understanding of inheritable diseases such as breast cancer, Fanconi anemia, and the neurodegenerative disease Ataxia with Oculomotor Apraxia-1 (AOA-1). The focus of this ERC proposal is: (i) to define the phenotypic interplay between three inheritable cancer predisposition syndromes, Fanconi anemia, Bloom s syndrome and breast cancers caused by mutation of BRCA2, (ii) to determine the biological role of the newly discovered GEN1 Holliday junction resolvase in homologous recombination and repair, and (iii) to understand the actions of Aprataxin and Senataxin in relation to the inheritable neurodegenerative diseases AOA-1 and AOA-2, respectively. Our studies will provide an improved understanding of basic mechanisms of DNA repair and thereby underpin future therapeutic developments that will help individuals afflicted with these diseases.

2 449 091 €

Start date: 2010-06-01, End date: 2015-05-31

Plants and their pathogens are in a constant process of co-evolution. Consequently, many of the known defense genes of plants against fungal pathogens are rapidly loosing effectiveness under agricultural conditions. However, there are examples for durable resistance. It is one of the main research questions in plant biology to determine the genetic basis of such naturally occurring resistance and to understand the underlying biochemical and molecular cause for durability. This durability is characterized by the apparent inability of the pathogen to adapt to the resistance mechanism. The molecular understanding of durable resistance will contribute to future attempts to develop such resistance by design. We want to use two approaches towards understanding and developing durable resistance: the first one is based on the naturally occurring durable resistance gene Lr34 against rust and mildew diseases in wheat. This gene was recently isolated in our group and it encodes a putative ABC type of transporter protein, providing a possible link between non-host and durable resistance. Its function in resistance will be studied by genetic and biochemical approaches in the crop plant wheat, as there is no Lr34-type of resistance characterized in any other plant. However, there is a close Lr34-homolog in rice and its function will be investigated in this diploid system. The second approach will be based on natural diversity found in a specific resistance gene, conferring strong, but not durable resistance. This diversity will be used for a designed improvement of durability by developing new proteins or protein combinations to which the pathogen can not adapt. We will use the 15 naturally occurring alleles of the Pm3 powdery mildew resistance genes to identify the structural basis of specific interactions. Based on this characterization, we will develop intragenic or gene combination pyramiding strategies to obtain more broad-spectrum and more durable resistance.

2 100 000 €

Start date: 2010-04-01, End date: 2015-03-31

Swarm intelligence is the discipline that deals with natural and artificial systems composed of many individuals that coordinate using decentralized control and self-organization. In this project, we focus on the design and implementation of artificial swarm intelligence systems for the solution of complex problems. Our current understanding of how to use swarms of artificial agents largely relies on rules of thumb and intuition based on the experience of individual researchers. This is not sufficient for us to design swarm intelligence systems at the level of complexity required by many real-world applications, or to accurately predict the behavior of the systems we design. The goal of the E-SWARM is to develop a rigorous engineering methodology for the design and implementation of artificial swarm intelligence systems. We believe that in the future, swarm intelligence will be an important tool for researchers and engineers interested in solving certain classes of complex problems. To build the foundations of this discipline and to develop an appropriate methodology, we will proceed in parallel both at an abstract level and by tackling a number of challenging problems in selected research domains. The research domains we have chosen are optimization, robotics, networks, and data mining.

2 016 000 €

Start date: 2010-06-01, End date: 2015-05-31

The case of Ebla in northern Syria is certainly the most favourable one for enhancing our understanding of mechanisms of functioning of the early state. The discovery in 1975 of royal archives consisting of 17.000 cuneiform tablets dating to c. 2300 BC has supplied the scientific community with an invaluable mass of documents dealing with all aspects of state organization. These tablets inform us about the political, diplomatic and military affairs of the Eblaite state, as well as on the economic and social fabric of this early state formation. Further, considerable progresses during the past decade have been made at Ebla in seriating material culture assemblages, in interpreting the rich evidence for ancient visual communication and in exposing the urban structure. We now foresee a unique opportunity to test theories and models about the rise and structure of the early state by expanding the level of analysis to the landscape around Ebla: archaeological surface surveys, remote sensing, geomorphological studies will be evaluated together with the results of archaeological and geophysic investigations on village sites. Our research group has already considerable experience in developing calculation programs that employ along with traditional statistic and quantitative methods within a web GIS environment, including all the cuneiform tablets models of modern dynamic mathematics: the massive amount of data obtained from excavations, surveys, epigraphic studies, archeometric and archeobiological analyses will be combined and analyzed by means of mathematical, economical and computer science concepts and models, in order to build a multi-tier explanatory pattern which can be applied also to other early foci of urbanization in the Near East and elsewhere. We thus hope to gain a much richer historical framework and a sophisticated predictive model of general validity: until now no studies have ever focused on explanations of these phenomena on such an integrated scale

1 105 240 €

Start date: 2010-04-01, End date: 2014-03-31

The purpose of this project is to measure for the first time gas-phase spectra of large carbon containing cations, at low temperatures, which are of astrophysical importance. Knowledge of electronic spectroscopy of such molecules is also of pertinence in a number of areas of chemistry and physics, enabling their identification in planetary atmospheres, flames and plasmas and as intermediates in chemical reaction dynamics. This project is interdisciplinary, bridging the areas of chemistry, physics, and astrophysics. It encompasses state of the art techniques of chemical physics and aims at obtaining information to solve the long standing enigma in observational astronomy, the identification of some of the molecules causing absorption of starlight in diffuse interstellar clouds. The project uses ion trapping technology, whereby mass-selected species are held in a radio-frequency field and the vibrations and rotations are relaxed by collisions with cold helium to typical interstellar temperatures of 10-30 K. The electronic spectra of a number of cations, selected on the basis of their special properties including those of bare carbon chains, rings and fullerenes, polycyclic aromatic hydrocarbon cations and their protonated forms will be measured using new detection schemes. The first approach is based on photo-induced charge transfer which is turned on upon laser excitation and the second uses the possibility of rare-gas complexation in the ground but not excited state.

1 898 624 €

Start date: 2010-05-01, End date: 2015-04-30

Never before has media entertainment been so abundantly accessible to children. In this project, I propose an entirely new theoretical model to understand entertainment processing and effects. The model enables us to simultaneously investigate: (a) how and why certain types of media entertainment may influence certain children, (b) which children are particularly susceptible to positive, which to negative, and which to both positive and negative entertainment effects, and (c) how children s social environment can maximize positive and minimize negative entertainment effects on children. The project involves a longitudinal panel study among 900 Dutch families. To measure the variables in the model, we will use some well-established survey instruments and neuropsychological tests. We will also employ two less conventional methods (coded media-use diaries and experience sampling methods) that may enhance serendipity in the development of our theory-advancing insights. We will use state-of-the art data-analytic techniques (e.g., multi-level and latent-growth curve modelling) to analyse the data. Although adventurous, this transdisciplinary project, the first in its kind, has great theoretical significance. If the assumptions of my model are supported, it may lead to a fundamental re-evaluation of earlier media-effects theories and research on children. The project will also have tremendous social relevance, not only for parents, but also for programme makers, educators, and the society as a whole. After all, only if we truly understand why, how, and which children are influenced by certain types of media entertainment, are we able to adequately target prevention and intervention strategies at these children.

2 500 000 €

Start date: 2010-12-01, End date: 2016-08-31

Twin studies traditionally have been used to assess the relative contributions of genetic and environmental factors. Nearly all common diseases and traits have now been found to be heritable and GWA studies are discovering many novel genes. However 95% of the heritability is not yet identified and discordances within identical (MZ) twin pairs cannot be explained by known environmental factors. The missing heritability could be due to epigenetic factors- which are ideally studied with twins. The proposed study uses MZ twins discordant for 10 important age-related complex disease traits to uncover epigenetic signals that are associated with disease. We will study in detail epigenetic differences using a high throughput Illumina methylation array in the 5% most discordant pairs for the following disease susceptibility traits : obesity (BMI), type II diabetes (insulin resistance) , hypertension (BP), hyperlipidemia (lipid levels), Osteoporosis (BMD), biological aging (white cell telomere levels), Allergy (IgE) , asthma (FEV1), platelet volume (MPV) and smoking. We will use the TwinsUK cohort of 3000 phenotyped MZ twins for a discovery group. For replication of the most significant associations we will use singletons from the 200 extreme highs and lows of the remaining 4000 phenotyped twins as a ‘case’-‘control ‘association study genotyped by the same array. A sub-sample will be genotyped by sequencing. To assess tissue specificity, additional tissues for methylation analysis will be sampled (buccal, fat and skin DNA). Causality will be explored using bioinformatics, cell specificity experiments and longitudinal studies using DNA stored for up to 15 years- as well as parental and offspring DNA. Epigenomics is a major future growth area. This large scale study would enable us to maintain a European lead and act also a valuable future epidemiologic resource and enable important collaborations with other European researchers and cohorts.

2 498 658 €

Start date: 2010-07-01, End date: 2015-06-30

The ribosome is a large cellular organelle that plays a central role in the process of protein synthesis in all organisms. Currently, structural information at atomic resolution exists only for bacterial ribosomes and some of their functional complexes. Eukaryotic ribosomes are larger and significantly more complex than their bacterial counterparts. They consist of two unequal subunits with a combined molecular weight of approximately 4 million Daltons and contain 70-80 different protein molecules and four different RNAs. Currently the only structural information on eukaryotic ribosomes is available from cryo electron microscopic reconstructions in the nanometer resolution range, which is insufficient to derive information about the function of the eukaryotic ribosome at the atomic level. The aim of this proposal is to use X-ray crystallography to obtain structural and functional information on the eukaryotic ribosome and its functional complexes at high resolution. The key targets of the structural work will be: i) the structure of the small ribosomal subunit, ii) the structure of the large ribosomal subunit, and iii) structures of complexes involved in the initiation of protein synthesis. Besides the obvious fundamental importance of this research for understanding protein synthesis in eukaryotes the proposed studies will also be the prerequisite for understanding the structural basis of the regulation of protein synthesis in normal cells and how it is perturbed in various diseases. Finally, comparing the structures of bacterial and eukaryotic ribosomes is important for understanding the specificity of various clinically used antibiotics for the bacterial ribosome.

2 446 725 €

Start date: 2010-07-01, End date: 2015-06-30

The aim of this project is to map and publish in a critical edition the extensive correspondence of European intellectuals with the Swiss cultural historian Jacob Burckhardt over a period of more than half a century, from 1842 to 1897. This correspondence documents a crucial period in European history and culture, one which witnessed the emergence of art history as a separate discipline; serious political conflict in France, Germany, Italy and Switzerland; the birth of the nation-states of Italy and Germany; debate on the meaning and consequences of democracy as a system of government; and the rise of Caesarism in France. The effects of modernism are also discussed in this correspondence, from the culture of museums, art exhibitions and the first universal expositions (e.g., the Expositions Universelles in Paris) to the clash between industrial culture and neo-humanist ideals of education. The large body of correspondence received by Jacob Burckhardt (about two thousand letters conserved in various libraries and private archives) provides a cultural map of this crucial phase in the development of a new European identity.

1 215 600 €

Start date: 2010-06-01, End date: 2015-05-31

The evolution of the first rooting systems approximately 470 million years ago was a critical event in the history of life on Earth because it allowed the growth of complex multicellular eukaryotic photosynthetic organisms – plants - on the surface of the land. Rooting systems are important because they facilitate the uptake of every chemical element in the plant body with the exception of carbon. The root systems of the first land plants (liverworts) comprised a mass of unicellular tip-growing filaments (rhizoids) that grew from the plant surface into the soil. All root systems that evolved since then similarly comprise a system of tipgrowing filamentous cells located at the interface between the plant and the soil, indicating that the differentiation of filamentous root cells has been critical for root function for the past 470 million years. This proposal aims to characterize the origin and evolution of this essential cellular differentiation process. The proposed research is in three parts: First we propose to define the mechanism that controlled the development of the first land plant root system by identifying genes that control liverwort rooting system (rhizoids) development and characterizing their regulatory interactions. Second we propose to determine if the mechanism that controlled the development of the first land plant root system was inherited from algal ancestors. Third we propose to characterize the mechanism that controls filamentous root hair growth in Arabidopsis in response to environmental factors, and determine if it is conserved among land plants. In combination, these experiments will define the genetic mechanisms underpinning the development and evolution of one of the fundamental developmental processes in land plants.

2 463 835 €

Start date: 2010-10-01, End date: 2015-09-30

The approach to animal behaviour adopted by behavioural ecology is based on the investigation of the adaptive function of behaviour. A common assumption is that the action of natural selection on behaviour can be predicted without reference to processes inside the organism. I believe that it is time to combine an analysis based on evolution with one based on mechanisms, where a mechanism might be psychological, physiological or a combination of both. Animals have mechanisms that need to perform well in changing and dangerous environments. In order to understand the evolution of mechanisms, we need a fundamental change in the sort of models that are analysed. Instead of building complex models of optimal behaviour in simple environments, we need to evolve simple mechanisms that perform well in complex environments. This approach can provide a novel and unified perspective on a range of issues involving decisions by animals, including humans. The main objective of the project is to provide a comprehensive view of behaviour that can account for both adaptive and non-adaptive actions. This involves developing a novel theoretical framework based on an understanding of the underlying information-processing rules, combined with an evolutionary perspective that explains how any such rule came into existence in the first place. The theme of coping with uncertain and dangerous environments is used to investigate various features of behaviour such as rationality and self-control. These topics lead to the broader issues of the organisation of thought and emotions. The project also explores the consequences of the evolved behaviour and the implications for conservation and animal welfare.

1 749 277 €

Start date: 2010-06-01, End date: 2015-05-31

The Mexican influenza A virus (H1N1) reminds us that the threat of an influenza pandemic is real. The 1918 Spanish flu virus, also started as a low pathogenic virus that mutated into a highly pathogenic virus within months, causing more than 50 million deaths. The Mexican influenza A virus (H1N1) may follow the same path. FLUPLAN will expand our knowledge of the packaging signals that govern reassortment events between influenza A viruses in general and between the Mexican influenza A virus (H1N1) and circulating human, porcine and highly pathogenic avian influenza A viruses in particular. FLUPLAN will thus lead to fundamental insights in the mechanisms that govern reassortment phenomena, providing a risk assessment concerning the pandemic potential of circulating avian and mammalian influenza A viruses. This will provide us with a panel of possible reassortant viruses of potentially pandemic nature. The MVA vaccine vector system that efficiently induced broad protective immunity against HPAI-H5N1 viruses in macaques, will be used for the preparation of a repository of MVA-H based pandemic vaccine seed viruses.The selection will be based on the reassortant viruses mentioned above, and on a repository of avian influenza viruses of the 16HA subtypes including the Mexican influenza A virus (H1N1) of avian/swine origin. The added value of including a relevant MVA-NP in the immunization schedule to obtain broader and longer protection will be determined in a macaque infection model. Collectively these studies will provide us with a highly versatile system that anticipates on future pandemic events by having seed viruses for vaccine development ready to go on the shelf, for the rapid production of broadly protective pandemic vaccines, which will save time and thus lives.

2 187 758 €

Start date: 2010-06-01, End date: 2015-05-31

An impressive variety of motile and morphogenetic processes are driven by site-directed polarized asssembly of actin filaments. In the past ten years, breathtaking advances coming from cell biology, cell biophysics, and biochemistry have brought insight into the molecular bases for production of force and movement by site-directed actin polymerization. Yet, we do not know, with the detail sufficient to understand how force is produced, by which molecular mechanisms the filaments are nucleated or created by branching. We do not know by which elementary steps insertional polymerization of barbed ends of filaments against the membrane is performed by different protein machineries, nor how these machineries work in a coordinated fashion. Here we propose a multiscale and interdisciplinary approach of the mechanisms used by the major actin nucleators to organize the motile response of actin. The elementary reactions involved in the processive walk of formin at the growing barbed ends of filaments and the role of ATP hydrolysis in force production will be analyzed by a combination of biochemical solution studies and physical methods using functionalized GUVs and optical tweezers. The multifunctionality of WH2 domains involved in actin sequestration, filament nucleation severing and processive elongation will be similarly examined in an interdisciplinary perspective from structural biology at atomic resolution to physics at the mesoscopic scale. Biochemical and structural methods and single molecule measurements (TIRFM) will shed light into the elementary steps and structural mechanism of filament branching. Biomimetic assays with functionalized GUVs associated with biophysical methods like FRAP or fluorescence correlation spectroscopy will elucidate how different filament initiating machineries segregate in the membrane as a consequence of their interactions with growing filaments and function in a coordinated fashion during actin-based motility.

2 434 195 €

Start date: 2010-05-01, End date: 2015-10-31

We outline an ambitious 5 year interdisplinary research programme that introduces a fundamentally new platform to the fabrication of nanoelectronic and liquid crystal devices, current areas of intense scientific and technological interest. The new approach involves the use of block copolymer micelles and block comicelles prepared by Crystallization-Driven Living Polymerization (CDLP) processes. This novel method allows unprecedented access to well-defined micelle architectures (with size control, narrow size distribution, and access to segmented structures that possess heterojunctions). Crosslinking will also be used to optimize micelle mechanical properties where necessary. The new platform offers very promising advantages over competitive methods for realising nanomaterials these include ambient temperature synthesis and solution processing, easy control of dimensions and aspect ratio, electronic properties, and semiconductor/semiconductor or semiconductor/dielectric junction fabrication. In addition, the use of hydrophilic coronas should, in principle, allow the self-assembly processes and subsequent manipulations to be performed in water.

1 658 544 €

Start date: 2010-04-01, End date: 2016-03-31

DNA sequence and epigenetic chromatin maps are important in understanding how genomes are regulated. However, these maps are linear and do not account for the three-dimensional context within which the genome functions in the cell. The spatial organisation of the genome in the nucleus is not random and is conserved in evolution, implying that it is under functional selection. This proposal aims to determine the functional significance of positioning specific genome regions at the edge of the nucleus in mammalian cells. The nuclear periphery has conventionally been considered as a zone of inactive chromatin and transcriptional repression. Several regulatory gene loci move away from the nuclear periphery as they are activated during differentiation. Novel approaches, developed by ourselves and others, that allow genomic regions to be relocated from the centre of the nucleus to the periphery, have directly shown that proximity to the nuclear edge can down-regulate human gene expression. We propose to dissect the pathways that mediate this spatially-defined transcriptional regulation, to determine what features make certain genes susceptible to it, to establish the functional consequences of preventing gene repositioning during differentiation, and to examine defects of the periphery found in premature ageing. A neglected hypothesis is that positioning of inactive chromatin against the nuclear periphery is a mechanism to minimize DNA damage on sequences in the nuclear centre. We will determine whether mutation rate is altered when loci are repositioned towards the nuclear periphery. By experimentally remodelling the spatial organisation of the genome, this proposal goes beyond the current descriptive phase of 3D nuclear organisation, into an understanding of its functional consequences on multiple aspects of genome function. It will also aid in understanding human diseases characterised by alterations of the nuclear periphery.

1 701 090 €

Start date: 2010-03-01, End date: 2016-02-29

Background: Poor angiogenesis and collateral vessel formation lead to coronary heart disease, claudication, infarctions and amputations while malignant glioma is one of the most aggressive proangiogenic tumors leading to death in a few months. For these diseases either stimulation or blocking, respectively, of angiogenesis may provide novel treatment options. Advancing State-of-the-Art: Our hypothesis is that in ischemia it will be possible to support natural growth of blood vessels with Therapeutic angiogenesis and lymphangiogenesis by using local gene transfer of the new members of vascular endothelial growth factor (VEGF) family and their receptors. New co-receptors, designer mutants and PCR suffling products of VEGFs will be used. New vector technology will be used to achieve long-lasting effects of VEGFs. We aim to develop novel site-specifically integrating, targeted, regulated vectors to precisely express the new VEGFs, their soluble decoy receptors and single-chain therapeutic antibodies (scFv) for pro- and anti-angiogenic purposes. As novel approaches, we have developed metabolically biotinylated lenti- and adenoviruses suitable for targeting and Epigenetherapy where siRNA/miRNAs and short nuclear RNAs regulate endogenous gene expression at the VEGF promoter level via modification of histone code. scFv library for endothelial cells and lentivirus-siRNA library directed to all human and mouse kinases will be screened to identify new mediators of angiogenesis in order to develop next generation pro- and antiangiogenic therapies. Based on our strong track record in Clinical applications, the best new pro- and antiangiogenic approaches will be taken to phase I clinical studies in myocardial ischemia and malignant glioma. Significance: This work should lead to significant advances and new therapies for severe ischemia and malignant glioma. Epigenetherapy and new site-specifically integrating, regulated vectors should be widely applicable in medicine.

2 200 000 €

Start date: 2010-06-01, End date: 2015-05-31

Over the next decade, much effort on major astronomical facilities will be dedicated to large-scale surveys of the galaxy population. Their aim is two-fold: understanding the origin and evolution of galaxies and their central supermassive black holes, and clarifying the nature of dark matter, dark energy and the process that produced all cosmic structure. Achieving these goals will require powerful and flexible modelling tools that can simulate galaxy evolution in all viable cosmologies and under a wide variety of assumptions about the governing physical processes. Such capabilities do not currently exist. I propose to develop them through a major expansion of the functionality and scope of the Millennium Simulation archive. New simulations, new theoretical approaches and new web services will allow users to study galaxy formation across the full range of galaxy masses (from dwarf spheroidals to giant cDs). Remote users will be able to change parameters and modelling prescriptions at will, creating virtual surveys of universes with any chosen cosmology and galaxy formation model. Matching to multiwavelength surveys of real galaxies will make it possible to isolate the physical processes driving galaxy evolution, and to characterize the systematic errors that uncertain galaxy formation physics induce in precision estimates of cosmological parameters. Scientific problems where these new capabilities may be decisive in enabling progress include: the role of supermassive black holes in shaping galaxy formation; the origin of diversity in the forms of galaxies and in their nuclear activity; the effects of environment on galaxy structure; the formation history of our own Milky Way; the nature of the first galaxies and their effects on later and more easily observable generations of galaxies; the distribution and nature of dark matter; the origin of all cosmic structure; and the nature of dark energy.

1 830 000 €

Start date: 2010-01-01, End date: 2014-12-31

Much of what we know about how embryos determine their axes of symmetry comes from research in invertebrates (mainly Drosophila) and cold-blooded vertebrates (mainly Xenopus). In both cases, polarity is set up by the localisation of maternal determinants in the cytoplasm of the fertilised egg. These determinants are inherited differentially by daughter cells, leading them to acquire different fates, which effectively fixes the axes of the embryo by the 8 cell stage. In contrast, in amniotes (reptiles, birds and mammals) embryonic polarity remains plastic until much later, just before gastrulation, when the embryo may contain as many as 50,000 cells. If an embryo at this stage is cut into fragments, each fragment can generate a complete embryo. This property, called "embryonic regulation", is thought to be responsible for the generation of monozygotic (identical) and conjoined ( Siamese ) twins in humans and other amniotes. We know almost nothing about how polarity is determined in higher vertebrates or about the mechanisms of embryonic regulation and twinning. This project uses a multi-disciplinary systems approach to reveal the gene interaction network controlling polarity, regulation and twinning. The project will also generate a mathematical model of early development or "virtual embryo", allowing prediction of experimental outcomes and clinical scenarios.

1 997 899 €

Start date: 2010-06-01, End date: 2016-02-29

Sometimes in the sciences there are different yet complementary descriptions for the same object. This extends to the particle-wave duality of quantum mechanics; one mathematical analog of this duality is the Fourier transform. Questions that are difficult when formulated in one language of science may become simple when interpreted in another. The Langlands conjecture posits the existence of a correspondence between problems in arithmetic and in Representation Theory. The Langlands conjecture has only been proven for a limited number of cases, but even this has solved problems such as the famous Fermat conjecture. The aim of this project is to continue study of the "classical" aspects of the Langlands conjecture and to extend the conjecture to the quantum geometric Langlands correspondence, higher-dimensional fields, Kac-Moody groups (with D.Gaitsgory: quantum Langlands correspondence; D.Gaitsgory and E. Hrushevsi: groups over higher-dimensional fields; A. Braverman: Kac-Moody groups; R. Bezrukavnikov, S.Debacker, Y.Varshavsky: classical aspects of the correspondence; A. Berenstein: geometric crystals and crystal bases). The quantum case is much more symmetric than the classical case and can lead in the limit q->0 to new insights into the classical case. The quantum case is also related to the multiple Dirichlet series. New results in the quantum case would lead to progress in understanding important Number Theoretic questions. Extending the Langlands correspondence to groups over higher-dimensional fields could substantially enlarge its applicability. Studying Kac-Moody groups would provide tools for the new important class of L-functions. This progress could lead to a proof of the existence of the analytic continuation of classical L-functions. The geometric Langlands correspondence is closely related to T-symmetry in 4-dimensional gauge theory and the understanding of this relation is important for both Mathematics and Physics.

1 277 060 €

Start date: 2010-01-01, End date: 2014-12-31

From the late '50s until the early '70s, theoretical linguistics, computational linguistics, and psycholinguistics, were united by a common model based on Chomskian transformational generative grammar formalism. This consensus fell apart in the later 70s, because of disagreements about the role of semantics. Formal syntax has abandoned semantics and any interest in formal constraint. Semantically based functional and cognitive theories of grammar are agnostic about formalism. Current psycholinguistic theories mainly ignore formal linguistic theory, while in computational linguistics, the dominant models are generally low-level finite-state or context-free systems that are known to to be incomplete with respect to the full range of of human language. While the latter methods, aided by machine-learning, have made considerable progress in practical applications such as automatic speech recognition, machine translation, and parsing, they place inherent limits on performance that are already yielding near-asymptotic performance in some applications. The aim of the proposal is to restore grammatical theory to its necessary place in the theory of human language behaviour, by providing a more restricted theory of constructions than others on offer. This formalism is both efficiently parsable, and expressive enough to support semantic interpretation. The project seeks both to establish the explanatory adequacy of the theory in linguistic terms, and to generalize existing treebank-based computational models derived by supervised learning methods. It uses unsupervised and semi-supervised methods based on unlabeled data. A crucial component will be a fully articulated Natural Semantics closely related to the surface grammar, supporting entailment directly.

1 910 998 €

Start date: 2010-06-01, End date: 2015-05-31

One of the prominent features of Medieval Aristotelianism, both Arabic and Latin, is the fact that Aristotle has been credited with writings that, albeit Neoplatonic in origin, circulated under his name. Crucial as it might be for the genesis of Arabic-Islamic philosophy, the main text of the Neoplatonic tradition into Arabic, i.e., the so-called Theology of Aristotle, is still poorly edited and no running commentary exists on it. The Theology of Aristotle, derived in reality from Plotinus' Enneads, will be critically edited, translated and commented upon. This project will also study the Graeco-Arabic translations from a linguistic viewpoint. It will develop the extant Greek and Arabic Lexicon; of the Medieval translations of philosophical works into a computational resource. For the first time, the project allows Ancient and Arabic philosophy to interact with computational linguistics.

2 106 381 €

Start date: 2010-04-01, End date: 2015-03-31

Asthma and allergies are chronic conditions affecting billions of Europeans. These complex diseases are determined by interplay of genetic and environmental factors. Treatments can control symptoms, but cannot cure or prevent the diseases. I, and my team, have shown that children are strongly protected from asthma and allergies when growing up in a farming environment rich in microbial exposures: the prevalence of asthma and hay fever is reduced over 5 fold. We have shown that environmental exposure to microbial compounds is inversely related to asthma and allergies. We have isolated microbes from animal sheds which protect mice from allergic airway inflammation. My team is now at a critical point to move this work forward to the next step, which is to systematically identify the microbes and their immuno-stimulatory compounds that protect from asthma and allergies. We have key resources in hand. In previous population based studies large numbers of environmental samples from farm and non farm children with and without asthma and allergies have been stored in biobanks. Genome wide genotyping data have also been gathered. The HERA project aims at applying the latest innovative high throughput sequencing techniques to comprehensively characterize the microbial ecology of these environmental samples. New methods for assessing microbial immuno-stimulatory substances will be used. These innovations will allow the HERA team to identify distinct asthma and allergy protective microbial exposures taking each individual s genetic susceptibility into account. Once protective microbial exposures have been identified, the responsible substances can be isolated. These substances can be developed into novel and effective prevention strategies to combat the asthma and allergy epidemic.

2 155 697 €

Start date: 2010-05-01, End date: 2015-04-30

The project aims to take new thinking and concepts in organofluorine chemistry and apply this thinking to the design of novel performance molecules to explore properties and function in a predictable manner. The focus is on two areas. The first involves organic materials/polymers and the second focuses on selected topics in biochemical and medicinal chemistry. Both areas exploit the stereoelectronic influence of the C-F bond, and its interaction with nearby functional groups. In particular the polar nature of the C-F bond is now used as a design feature to manipulate molecular conformation across a range of case studies, judged to be of contemporary interest. One aspect of the programme will prepare a series of compounds containing multiple fluoromethylene groups. Care will be taken to prepare individual stereoisomers for comparitive studies. The aim is to develop new structural motifs for liquid crystals and polar polymers. The study e will extend to the design and synthesis of small, but highly polar, monomers for polymerisation. There is a particular focus on preparing a new generation of polar organic polymers, as potential piezo- and ferro- electric materials to meet the current challenge to prepare novel self-poling materials. The research programme emerges from an increaing recognition that the C-F bond responds to the stereo-electronic influence of neighbouring functional groups. Some functional appear frequently in biochemistry. The programme will utilise the stereogenic placement of the C-F bond in the design of neurotransmitter analogues, to influence and explore their binding conformation to receptors. The central methodology will involve advanced methods in organic synthesis, and in particular the construction of molecules with C-F at stereogenic centres. The programme will also involve advanced tecniques for conformational analysis (NMR, X-ray, computational), polymer analysis and biochemical assays.

1 418 575 €

Start date: 2010-01-01, End date: 2014-12-31

In recent years, as first established in some 6 papers in Science and Nature from the PI s group, a new paradigm has emerged. This reveals the remarkable and unsuspected - role of hydration layers in modulating frictional forces between sliding surfaces or molecular layers in aqueous media, termed hydration lubrication, in which the lubricating mode is completely different from the classic one of oils or surfactants. In this project we address the substantial challenges that have now arisen: what are the underlying mechanisms controlling this effect? what are the potential breakthroughs that it may lead to? We will answer these questions through several interrelated objectives designed to address both fundamental aspects, as well as limits of applicability. We will use surface force balance (SFB) experiments, for which we will develop new methodologies, to characterize normal and frictional forces between atomically smooth surfaces where the nature of the surfaces (hydrophilic, hydrophobic, metallic, polymeric), as well as their electric potential, may be independently varied. We will examine mono- and multivalent ions to establish the role of relaxation rates and hydration energies in controlling the hydration lubrication, will probe hydration interactions at both hydrophobic/hydrophilic surfaces and will monitor slip of hydrated ions past surfaces. We will also characterize the hydration lubrication properties of a wide range of novel surface systems, including surfactants, liposomes, polymer brushes and, importantly, liposomes, using also synchrotron X-ray reflectometry for structural information. Attainment of these objectives should lead to conceptual breakthroughs both in our understanding of this new paradigm, and for its practical implications.

2 304 180 €

Start date: 2010-05-01, End date: 2015-04-30