ERC FUNDED PROJECTS

This project focuses on one of the most fascinating events of the long history of the human species: the origins and spread of agriculture. Research over the past 40 years has provided an invaluable dataset on crop domestication and the spread of agriculture into Europe. However, despite the enormous advances in research there are important areas that remain almost unexplored, some of immense interest. This is the case of the western Mediterranean region from where our knowledge is still limited (Iberian Peninsula) or almost inexistent (northern Morocco). The last few years have witnessed a considerable increase in archaeobotany and the effort of a group of Spanish researchers working together in different aspects of agriculture has started to produce the first results. My proposal will approach the study of the arrival of agriculture to the western Mediterranean by exploring different interrelated research areas. The project involves the application of different techniques (analysis of charred plant remains, pollen and non-pollen microfossils, phytoliths, micro-wear analyses, isotopes, soil micromorphology, genetics, and ethnoarchaeology) which will help to define the emergence and spread of agriculture in the area, its likely place of origin, its main technological attributes as well as the range crop husbandry practices carried out. The interaction between the different approaches and the methodologies involved will allow achieving a greater understanding of the type of agriculture that characterized the first farming communities in the most south-western part of Europe.

1 545 169 €

Start date: 2009-04-01, End date: 2013-03-31

This project focuses on two questions about host/parasite interactions: how do biotrophic plant pathogens suppress host defence? and, what is the basis for pathogen specialization on specific host species? A broadly accepted model explains resistance and susceptibility to plant pathogens. First, pathogens make conserved molecules ( PAMPS ) such as flagellin, that plants detect via cell surface receptors, leading to PAMP-Triggered Immunity (PTI). Second, pathogens make effectors that suppress PTI. Third, plants carry 100s of Resistance (R) genes that detect an effector, and activate Effector-Triggered Immunity (ETI). One effector is sufficient to trigger resistance. Albugo candida (Ac) (white rust) strongly suppresses host defence; Ac-infected Arabidopsis are susceptible to pathogen races to which they are otherwise resistant. Ac is an oomycete, not a fungus. Arabidopsis is resistant to races of Ac that infect brassicas. The proposed project involves three programs. First ( genomics, transcriptomics and bioinformatics ), we will use next-generation sequencing (NGS) methods (Solexa and GS-Flex), and novel transcriptomics methods to define the genome sequence and effector set of three Ac strains, as well as carrying out >40- deep resequencing of 7 additional Ac strains. Second, ( effectoromics ), we will carry out functional assays using Effector Detector Vectors (Sohn Plant Cell 19:4077 [2007]), with the set of Ac effectors, screening for enhanced virulence, for suppression of defence, for effectors that are recognized by R genes in disease resistant Arabidopsis and for host effector targets. Third, ( resistance diversity ), we will characterize Arabidopsis germplasm for R genes to Ac, both for recognition of Arabidopsis strains of Ac, and for recognition in Arabidopsis of effectors from Ac strains that infect brassica. This proposal focuses on Ac, but will establish methods that could discover new R genes in non-hosts against many plant diseases.

2 498 923 €

Start date: 2009-01-01, End date: 2014-06-30

Attosecond light pulses are generated when an intense laser interacts with a gas target. These pulses are not only short, enabling the study of electronic processes at their natural time scale, but also coherent. The vision of this proposal is to extend temporal coherent control concepts to a completely new regime of time and energy, combining (i) ultrashort pulses (ii) broadband excitation (iii) high photon energy, allowing scientists to reach not only valence but also inner shells in atoms and molecules, and, when needed, (iv) high spatial resolution. We want to explore how elementary electronic processes in atoms, molecules and more complex systems can be controlled by using well designed sequences of attosecond pulses. The research project proposed is organized into four parts: 1. Attosecond control of light leading to controlled sequences of attosecond pulses We will develop techniques to generate sequences of attosecond pulses with a variable number of pulses and controlled carrier-envelope-phase variation between consecutive pulses. 2. Attosecond control of electronic processes in atoms and molecules We will investigate the dynamics and coherence of phenomena induced by attosecond excitation of electron wave packets in various systems and we will explore how they can be controlled by a controlled sequence of ultrashort pulses. 3. Intense attosecond sources to reach the nonlinear regime We will optimize attosecond light sources in a systematic way, including amplification of the radiation by injecting a free electron laser. This will open up the possibility to develop nonlinear measurement and control schemes. 4. Attosecond control in more complex systems, including high spatial resolution We will develop ultrafast microscopy techniques, in order to obtain meaningful temporal information in surface and solid state physics. Two directions will be explored, digital in line microscopic holography and photoemission electron microscopy.

2 250 000 €

Start date: 2008-12-01, End date: 2013-11-30

This four-year interdisciplinary project addresses the question what has been learned through the use of better regulation ? Better regulation is a flagship policy on the Lisbon agenda for growth and jobs. Its aims are to provide new governance architectures for law-making, to increase the competitiveness of the regulatory environment, and to secure wide social legitimacy for multi-level systems of rules. Whilst most of the research has looked at how better regulation is changing, this project will produce findings on what has changed because of better regulation. Theoretically, the project will use (and significantly improve on) theories of policy learning. Empirically, it will cover Denmark, Italy, the Netherlands, Poland, the UK and the EU including multi-level analysis and analysis by sector of regulation. Methodologically, the project will draw on comparative analysis of types of learning, experiments with regulatory policy-makers in six countries and the European Commission, large-n analysis of impact assessments, backward-mapping of legislation (to appraise the role played by better regulation in the formulation or laws in the UK and the EU), meta-analysis of case-studies and co-production of knowledge with better regulation officers. Dissemination will target both stakeholders (i.e., policy officers, civil society organizations, and business federations) and academic conferences in political science, law, and risk analysis, with a major research monograph to be completed in year 4 and a final interdisciplinary conference.

948 448 €

Start date: 2009-09-01, End date: 2013-09-30

Applied mathematics is concerned with developing models with predictive capability, and with probing those models to obtain qualitative and quantitative insight into the phenomena being modelled. Statistics is data-driven and is aimed at the development of methodologies to optimize the information derived from data. The increasing complexity of phenomena that scientists and engineers wish to model, together with our increased ability to gather, store and interrogate data, mean that the subjects of applied mathematics and statistics are increasingly required to work in conjunction. This research proposal is concerned with a research program at the interface between these two disciplines, aimed at problems in differential equations where profusion of data and the sophisticated model combine to produce the mathematical problem of obtaining information from a probability measure on function space. Applications are far-reaching and include the atmospheric sciences, geophysics, chemistry, econometrics and signal processing. The objectives of the research are: (i) to create the systematic foundations for a range of problems at the applied mathematics and statistics interface which share the common mathematical structure underpinning the range of applications described above; (ii) to exploit this common mathematical structure to design effecient algorithms to sample probability measures on function space; (iii) to apply these algorithms to attack a range of significant problems arising in molecular dynamics and in the atmospheric sciences.

1 693 501 €

Start date: 2008-12-01, End date: 2014-11-30

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

Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.

2 500 000 €

Start date: 2009-11-01, End date: 2015-10-31

Magnetic fields in stars, planets, accretion discs, and galaxies are believed to be the result of a dynamo process converting kinetic energy into magnetic energy. This work focuses on the solar dynamo, but dynamos in other astrophysical systems will also be addressed. In particular, direct high-resolution three-dimensional simulations are used to understand particular aspects of the solar dynamo and ultimately to simulate the solar dynamo as a whole. Phenomenological approaches will be avoided in favor of obtaining rigorous results. A major problem is catastrophic quenching, i.e. the decline of dynamo effects in inverse proportion to the magnetic Reynolds number, which is huge. Tremendous advances have been made in the last few years since the cause of catastrophic quenching in dynamos has been understood in terms of magnetic helicity evolution. The numerical tools are now in place to allow for magnetic helicity fluxes via coronal mass ejections, thus alleviating catastrophic quenching. This work employs simulations in spherical shells, augmented by Cartesian simulations in special cases. The roles of the near-surface shear layer, the tachocline, as well as pumping in the bulk of the convection zone are to be clarified. The Pencil Code will be used for most applications. The code is third order in time and sixth order in space and is used for solving the hydromagnetic equations. It is a public domain code developed by roughly 20 scientists world wide and maintained under an a central versioning system at Nordita. Automatic nightly tests of currently 30 applications ensure the integrity of the code. It is used for a wide range of applications and may include the effects of radiation, self-gravity, dust, chemistry, variable ionization, cosmic rays, in addition to those of magnetohydrodynamics. The code with its infrastructure offers a good opportunity for individuals within a broad group of people to develop new tools that may automatically be useful to others.

2 220 000 €

Start date: 2009-02-01, End date: 2014-01-31

While heparin, a glacosaminoglycan (GAG) has served as an anticoagulant for more than 60 years, the structure-activity relationship of heparin and chondroitin sulfate for specific interactions with proteins are still poorly understood. It has become evident that defined lengths and sequences or patterns are responsible for binding to a particular protein and modulating its biological activity. Determination of the structure-activity relationships of heparins and chondroitins creates an opportunity to modulate processes underlying viral entry, angiogenesis, kidney diseases and diseases of the central nervous system. The isolation of pure GAGs is extremely tedious and chemical synthesis is often the only means to access defined oligosaccharides. Currently available synthetic methods for the preparation of heparins and chondroitins are time consuming and lack generality. Therefore, it is still impossible to create large collections of GAG oligosaccharides for systematic studies of GAG-protein interactions. The overall goal of the project is the development of all aspects of automated GAG synthesis, the procurement of a large collection of heparin and chondroitin oligosaccharides of 2-10 sugars in length with a linker for ready attachment to microarray surfaces and other tools. These molecular tools will be employed to study the interaction of GAGs with growth factors, chemokines and other proteins. The specific aims include: 1) Synthesis of uronic acid and galactosamine building blocks; 2) Development of a new linker for automated GAG solid phase synthesis; 3) Construction of a new automated oligosaccharide synthesizer; 4) Development of methods for the automated assembly of heparin and chondroitin sulfate oligosaccharides; 5) Synthesis of a collection of defined heparin and chondroitin sulfate oligosaccharides; 6) Construction of synthetic GAG microarrays and SPR; 7) Preparation of GAG dendrimers and quantum dots.

2 500 000 €

Start date: 2009-01-01, End date: 2014-12-31

BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways

2 290 046 €

Start date: 2009-04-01, End date: 2014-03-31

Autonomous programmable computing devices made of biological molecules hold the promise of interacting with the biological environment in future biological and medical applications. Our laboratory's long-term objective is to develop a 'Doctor in a cell': molecular-sized device that can roam the body, equipped with medical knowledge. It would diagnose a disease by analyzing the data available in its biochemical environment based on the encoded medical knowledge and treat it by releasing the appropriate drug molecule in situ. This kind of device might, in the future, be delivered to all cells in a specific tissue, organ or the whole organism, and cure or kill only those cells diagnosed with a disease. Our laboratory embarked on the attempt to design and build these molecular computing devices and lay the foundation for their future biomedical applications. Several important milestones have already been accomplished towards the realization of the Doctor in a cell vision. The subject of this proposal is a construction of autonomous biomolecular computers that could be delivered into a living cell, interact with endogenous biomolecules that are known to indicate diseases, logically analyze them, make a diagnostic decision and couple it to the production of an active biomolecule capable of influencing cell fate.

2 125 980 €

Start date: 2009-01-01, End date: 2013-10-31

Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.

2 489 643 €

Start date: 2009-01-01, End date: 2014-12-31

In the field of economics, individual decision making is the basic building block for studying complex environments such as markets, political systems, and social dynamics. Individual decision making is embodied in the neoclassical economically rational agent, whose only concern is the maximization of utility from his own material consumption. Two qualities of this agent are especially important for the research we will undertake: He has perfect understanding of the problems he faces - today and in the future - and unbounded computational ability to solve them. He also has no regard for the consumption of other members of the society or for their feelings about his actions. Huge empirical and experimental evidence shows that departure from these qualities is robust and significant. The failure of the existing models to incorporate bounded rationality and social concerns has proven critical in socially relevant and complex situations such as lifetime consumption and saving, taxation and expenditure policy, labour search and wage determination. The objective of this project is to bring these phenomena into the framework of neoclassical economics, to test their implications, and to tackle important applications. A novel and central feature of our approach is the attempt to retain the parsimonious methodological approach of economic modelling, which has scored groundbreaking successes in matters such as the design of auctions, markets, contracts, and voting mechanisms. Our project envisions the development of theory on individual decision making, the use of experiments to illuminate and test the theory, and the concrete application of theory - mainly to financial markets. The project will push the frontiers of the understanding of the above mentioned socially relevant situations. The explanatory power of our approach will be guaranteed by the continuous feed-back between theory and evidence- experimental and neuroexperimental, and by a departure from ad hoc modelling.

1 399 800 €

Start date: 2009-01-01, End date: 2013-12-31

We have developed a new numerical method to consistently compute atmospheric trace gas and aerosol chemistry and cloud processes. The method is computationally efficient so that it can be used in climate models. For the first time cloud droplet formation on multi-component particles can be represented based on first principles rather than parameterisations. This allows for a direct coupling in models between aerosol chemical composition and the continuum between hazes and clouds as a function of ambient relative humidity. We will apply the method in a new nested global-limited area model system to study atmospheric chemistry climate interactions and anthropogenic influences. We will focus on the Mediterranean region because it is a hot spot in climate change exposed to drying and air pollution. The limited area model will also be applied as cloud-resolving model to study aerosol influences on precipitation and storm development. By simulating realistic meteorological conditions at high spatial resolution our method can be straightforwardly tested against observations. Central questions are: - How does the simulated haze-cloud continuum compare with remote sensing measurements and what is the consequence of abandoning the traditional and artificial distinction between aerosols and clouds? - How are cloud and precipitation formation influenced by atmospheric chemical composition changes? - To what extent do haze and cloud formation in polluted air exert forcings of synoptic meteorological conditions and climate? - Can aerosol pollution in the Mediterranean region exacerbate the predicted and observed drying in a changing climate? The model system is user-friendly and will facilitate air quality and climate studies by regional scientists. The project will be part of the Energy, Environment and Water Centre of the newly founded Cyprus Institute, provide input to climate impact assessments and contribute to a regional outreach programme.

2 196 000 €

Start date: 2009-01-01, End date: 2014-12-31

"In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."

2 000 000 €

Start date: 2009-04-01, End date: 2015-03-31

We propose the development of novel nanodevices, such as nanoscale bridges and nanovectors, based on functionalized carbon nanotubes (CNT) for manipulating neurons and neuronal network activity in vitro. The main aim is to put forward innovative solutions that have the potential to circumvent the problems currently faced by spinal cord lesions or by neurodegenerative diseases. The unifying theme is to use recent advances in chemistry and nanotechnology to gain insight into the functioning of hybrid neuronal/CNT networks, relevant for the development of novel implantable devices to control neuronal signaling and improve synapse formation in a controlled fashion. The proposal s core strategy is to exploit the expertise of the PI in the chemical control of CNT properties to develop devices reaching various degrees of functional integration with the physiological electrical activity of cells and their networks, and to understand how such global dynamics are orchestrated when integrated by different substrates. An unconventional strategy will be represented by the electrical characterization of micro and nano patterned substrates by AFM and conductive tip AFM, both before and after neurons have grown on the substrates. We will also use the capability of AFM to identify critical positions in the neuronal network, while delivering time-dependent chemical stimulations. We will apply nanotechnology to contemporary neuroscience in the perspective of novel neuro-implantable devices and drug nanovectors, engineered to treat neurological and neurodegenerative lesions. The scientific strategy at the core of the proposal is the convergence between nanotechnology, chemistry and neurobiology. Such convergence, beyond helping understand the functioning and malfunctioning of the brain, can stimulate further research in this area and may ultimately lead to a new generation of nanomedicine applications in neurology and to new opportunities for the health care industry.

2 500 000 €

Start date: 2009-02-01, End date: 2014-01-31

CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.

1 969 644 €

Start date: 2009-02-01, End date: 2014-05-31

One of the major outcomes of recent studies on the formation of the Solar System is the reconnaissance of the fundamental importance of processes which took place during the first 10 thousands to 2 or 3 millions years of the lifetime of the Sun and its accretion disk. Astrophysical observations in the optical to infrared wavelengths of circumstellar disks around young stars have shown the existence in the inner disk of high-temperature processing of the dust. X-ray observations of T-Tauri stars revealed that they exhibit X-ray flare enhancements by several orders of magnitude. The work we have performed over the last years on the isotopic analysis of either solar wind trapped in lunar soils or of Ca-, Al-rich inclusions and chondrules from primitive chondrites, has allowed us to link some of these astrophysical observations around young stars with processes, such as irradiation by energetic particles and UV light, which took place around the T-Tauri Sun. The aim of this project is to make decisive progress in our understanding of the early solar system though the development of in situ high-precision isotopic measurements by ion microprobe in extra-terrestrial matter. The project will be focused on the exploration of the variations in the isotopic composition of O and Mg and in the concentration of short-lived radioactive nuclides, such as 26Al and 10Be, with half-lives shorter than 1.5 millions years. A special emphasis will be put on the search for nuclides with very short half-lives such as 32Si (650 years) and 14C (5730 years), nuclides which have never been discovered yet in meteorites. These new data will bring critical information on, for instance, the astrophysical context for the formation of the Sun and the first solids in the accretion disk, or the timing and the processes by which protoplanets were formed and destroyed close to the Sun during the first 2 million years of the lifetime of the Solar System.

1 270 419 €

Start date: 2009-01-01, End date: 2013-12-31

Neuroscience is one of the fastest-developing areas of science, but it is fair to say that we are still far from understanding how the brain produces subjective experience. For example, simple questions about the origin of thought, imagination, social interaction, or feelings lack even rudimentary answers. We have learnt much about the workings of individual cells and synapses, but psychological phenomena cannot be understood only at this level. These phenomena all emerge from interactions between large numbers of diverse cells in intermingled neural circuits. A major obstacle has been the absence of concepts and tools for investigating neural computation at the circuit level. The aim of this proposal is to combine new transgenic methods for cell type-specific intervention with large-scale multisite single-cell recording to determine how a basic cognitive function self-localization is generated in a functionally well-described mammalian neural circuit. We shall use our recent discovery of entorhinal grid cells as an access ramp. Grid cells fire only when the animal moves through certain locations. For each cell, these locations define a periodic triangular array spanning the whole environment. Grid cells co-exist with other entorhinal cell types encoding head direction, geometric borders, or conjunctions of features. This network is thought to form an essential part of the brain s coordinate system for metric navigation but the detailed wiring, the mechanism of grid formation, and the function of each morphological and functional cell type all remain to be determined. We shall address these open questions by measuring how dynamic spatial representation is affected by transgene-induced activation or inactivation of the individual components of the circuit. The endeavour will pioneer the functional analysis of neural circuits and may, perhaps for the first time, provide us with mechanistic insight into a non-sensory cognitive function in the mammalian cortex.

2 499 112 €

Start date: 2009-01-01, End date: 2013-12-31

The key objective of this project is to promote cleaner and more efficient combustion technologies through the development of theoretically grounded and more accurate chemical models. This is motivated by the fact that the current models which have been developed for the combustion of constituents of gasoline, kerosene, and diesel fuels do a reasonable job in predicting auto-ignition and flame propagation parameters, and the formation of the main regulated pollutants. However their success rate deteriorates sharply in the prediction of the formation of minor products (alkenes, dienes, aromatics, aldehydes) and soot nano-particles, which have a deleterious impact on both the environment and on human health. At the same time, despite an increasing emphasis in shifting from hydrocarbon fossil fuels to bio-fuels (particularly bioethanol and biodiesel), there is a great lack of chemical models for the combustion of oxygenated reactants. The main scientific focus will then be to enlarge and deepen the understanding of the reaction mechanisms and pathways associated with the combustion of an increased range of fuels (hydrocarbons and oxygenated compounds) and to elucidate the formation of a large number of hazardous minor pollutants. The core of the project is to describe at a fundamental level more accurately the reactive chemistry of minor pollutants within extensively validated detailed mechanisms for not only traditional fuels, but also innovative surrogates, describing the complex chemistry of new environmentally important bio-fuels. At the level of individual reactions rate constants, generalized rate constant classes and molecular data will be enhanced by using techniques based on quantum mechanics and on statistical mechanics. Experimental data for validation will be obtained in well defined laboratory reactors by using analytical methods of increased accuracy.

1 869 450 €

Start date: 2008-12-01, End date: 2013-11-30

Collective behaviour is a widespread phenomenon in nature and technology making it a very important subject to study in various contexts. The main goal we intend to achieve in our multidisciplinary research is the identification and documentation of new unifying principles describing the essential aspects of collective motion, being one of the most relevant and spectacular manifestations of collective behaviour. We shall carry out novel type of experiments, design models that are both simple and realistic enough to reproduce the observations and develop concepts for a better interpretation of the complexity of systems consisting of many organisms and such non-living objects as interacting robots. We plan to study systems ranging from cultures of migrating tissue cells through flocks of birds to collectively moving devices. The interrelation of these systems will be considered in order to deepen the understanding of the main patterns of group motion in both living and non-living systems by learning about the similar phenomena in the two domains of nature. Thus, we plan to understand the essential ingredients of flocking of birds by building collectively moving unmanned aerial vehicles while, in turn, high resolution spatiotemporal GPS data of pigeon flocks will be used to make helpful conclusions for the best designs for swarms of robots. In particular, we shall construct and build a set of vehicles that will be capable, for the first time, to exhibit flocking behaviour in the three-dimensional space. The methods we shall adopt will range from approaches used in statistical physics and network theory to various new techniques in cell biology and collective robotics. All this will be based on numerous prior results (both ours and others) published in leading interdisciplinary journals. The planned research will have the potential of leading to ground breaking results with significant implications in various fields of science and technology.

1 248 000 €

Start date: 2009-03-01, End date: 2015-02-28

Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.

2 499 465 €

Start date: 2009-01-01, End date: 2013-12-31

The goal of this project is to study conformally invariant fractal structures from the perspectives of analysis, dynamics, probability, geometry and physics, emphasizing interrelations of these fields. In the last two decades such structures emerged in several areas: continuum scaling limits of 2D critical models in statistical physics (percolation, Ising model); extremal configurations for various problems in complex analysis (multifractal harmonic measures, coefficient growth of univalent maps, Brennan's conjecture); chaotic sets for complex dynamical systems (Julia sets, Kleinian groups). Capitalizing on recent successes, I plan to continue my work in these areas, exploiting their interactions and connections to physics. I intend to achieve at least some of the following goals: * To establish that several critical lattice models have conformally invariant scaling limits, by building upon results on percolation and Ising models and finding discrete holomorphic observables. * To study geometric properties of arising fractal curves and random fields by connecting them to Schramm's SLE curves and Gaussian Free Fields. * To investigate massive scaling limits by describing them geometrically with generalizations of SLEs. * To lay mathematical framework behind relevant physical notions, such as Coulomb Gas (by relating height functions to GFFs) and Quantum Gravity (by identifying limits of random planar graphs with Liouville QGs). * To improve known bounds in several old questions in complex analysis by studying multifractal spectra of harmonic measures. * To estimate extremal behavior of such spectra by using holomorphic motions of (quasi) conformal maps and thermodynamic formalism. * To understand nature of extremal multifractals for harmonic measure by studying random and dynamical fractals. The topics involved range from century old to very young ones. Recently connections between them started to emerge, opening exciting possibilities for new developments in some long standing open problems.

1 278 000 €

Start date: 2009-01-01, End date: 2013-12-31

Cooperation poses a problem to evolutionary theory because it can be exploited by selfish individuals. Evolutionary biologists have developed a detailed theoretical overview of possible solutions to the problem of cooperation. In contrast to our theoretical understanding of potential solutions, however,, we have been relatively unsuccessful at applying theory to understand observations of cooperative behaviour nature. We present a novel and interdisciplinary programme of research to address this problem by empirically testing assumptions and predictions of several leading explanations for cooperation. We will develop theory to make explicit testable predictions for specific systems. We will exploit the advantage offered by different study systems: experiments with bacteria, comparative studies on cooperative breeding vertebrates, and experiments on humans. In addition to addressing specific hypotheses, we will show how evolutionary theory links and differentiates explanations for cooperation across various taxa and levels of biological organization.

1 200 000 €

Start date: 2009-10-01, End date: 2015-09-30

Neurons in primary visual cortex (area V1) receive feedforward inputs from thalamic afferents and lateral inputs from other cortical neurons. Little is known about how these components interact to determine the responses of a V1 neuron. One camp ascribes most responses to feedforward mechanisms. The other camp ascribes them mostly to lateral interactions. We propose that these two apparently opposed views can be simply reconciled in a single framework. We hypothesize that area V1 can operate both in a feedforward regime and in a lateral interaction regime, depending on the nature of the stimulus and on the cognitive task at hand, and that the transition from one regime to the other is governed by synaptic inhibition. We will test these hypotheses by recording from individual V1 neurons while monitoring the activity of nearby populations of cortical neurons via multiprobe electrodes. In Aim 1 we will relate the activity of V1 neurons to that of nearby populations. We will use simple measures of correlation and nonlinear models that predict individual spikes to measure how responses depend on a feedforward contribution (the receptive field ) and on a lateral contribution (the connection field ). We will test our first hypothesis, concerning the role of the stimulus in changing this dependence. In Aim 2 we will extend these results to a behaving animal. We will record from V1 of mice performing a 2-alternative forced-choice psychophysical task, and we will test our second hypothesis, concerning the role of the cognitive task in determining the operating regime of the cortex. In Aim 3 we will seek a biophysical interpretation of the functional mechanisms and effective connectivity revealed by the previous Aims. We will test our third hypothesis, concerning the role of synaptic inhibition. The tools involved will include intracellular recordings and optical stimulation in transgenic mice whose cortical neurons are sensitive to light.

2 499 921 €

Start date: 2009-04-01, End date: 2014-03-31

Quantum computers offer a fundamentally new way of information processing. Within the scope of this proposal, quantum information processing with an ion trap quantum computer will be investigated. With the new combination of cryogenic technology and ion traps for quantum computing we intend to build a quantum information processor with strings of up to 50 ions and with two-dimensional ion arrays for an investigation of deterministic many-particle entanglement. The cryogenic traps will be applied for quantum simulations, for fundamental investigations concerning large-scale entanglement and for precision measurements enhanced by quantum metrology techniques employing entangled particles.

2 200 000 €

Start date: 2008-12-01, End date: 2013-11-30

The main goal of the proposed research is to investigate the possibility of allowing below-ground support systems to respond to strong seismic shaking by going beyond a number of thresholds that would conventionally imply failure and are today forbidden by codes. Such thresholds include : (a) sliding at the soil-foundation interface ; (b) separation and uplifting of a shallow foundation from the soils ; (c) mobilization of bearing capacity failure mechanism for shallow foundations ; (d) structural yielding of pile foundations ; (e) combination of some of the above. Whereas under static loading conditions a slight exceedance of such thresholds leads to failure, the oscillatory nature of seismic shaking will allow such exceedances for a short period of time, with perhaps no detrimental or irreparable consequences. The latter take the form of permanent foundation displacements, rotations, or injuries , which the designer will aspire to confine within rational limits. The motivation and the need for this research has come from : (i) observations of actual behaviour in a variety of earthquakes ; conspicuous examples : the permanent tilting , overturning, and often survival of numerous buildings on extremely soft soil in Adapazari during the Kocaeli 1999 earthquake ; (ii) the foundation design of a number of critical structures (e.g., major bridge pier, air control tower, tall monuments, elevated water tanks,) against large seismic actions ; the disproportionately large overturning moment and/or base shear force of such slender structures can hardly be faced with today s conventional foundation methods, (iii) the need to seismically retrofit and rehabilitate older structures and historical monuments; (iv) structural yielding of pile foundations is now detectable (thanks to technological advances), thus eliminating one of the reasons for avoiding it.

2 399 992 €

Start date: 2008-12-01, End date: 2013-10-31

Knowledge of the physical and chemical state of the Earth s inner silicate mantle is central to our understanding of plate tectonics, mantle convection, magma generation and the composition of the Earth as a whole. The key to this knowledge is the ability to interpret studies of seismic wave velocities through the deep Earth using laboratory measurements of mineral sound velocities at high pressures and temperatures. Scientists have for many years measured these properties as a function of pressure but due to the experimental difficulties the majority of studies have been performed only at room temperature. Large extrapolations of these data to mantle temperatures are required to link seismic velocity observations with physical and chemical properties of mantle rocks, resulting in large uncertainties that obscure firm conclusions. An additional uncertainty arises because there is currently no primary scale for accurately measuring pressure at high temperatures. In this study mineral sound velocities and densities will be measured in the diamond anvil cell at simultaneous high pressures and high temperatures to at least 50 GPa and 1300K. This will be possible by a pioneering combination of Brillouin scattering spectroscopy, to measure sound velocities, and single crystal X-ray diffraction determinations of density. By making both types of measurements on the same sample while it is maintained at a constant pressure and temperature, the pressure can be independently measured. These absolute pressure determinations will be used to derive a new universal pressure scale for use at high temperatures. Sound velocities of the major mantle minerals will be determined at high temperatures and absolute pressures thereby drastically decreasing the uncertainties in velocity calculations for rock assemblages at deep mantle conditions. The resulting data will be employed to finally interpret a host of seismic observations made at both global and local scales.

2 079 888 €

Start date: 2009-02-01, End date: 2014-07-31

We propose a feasibility demonstration of an unprecedented concept: preparation of regular two-dimensional arrays of artificial surface-mounted dipolar molecular rotors and control of their coherent motion by the application of an outside electric field. The proposal involves a highly interdisciplinary endeavor, which requires experience in synthesis (preparation of molecular rotors), surface chemistry (assembly of rotors into arrays on surfaces), surface spectroscopy and scanning microscopy (characterization of rotor arrays on surfaces), and theory (modeling of rotor dynamics). The principal investigator is presently actively working and publishing in all of these subdisciplines.

2 457 600 €

Start date: 2009-02-01, End date: 2014-07-31

Discrete Mathematics is a fundamental mathematical discipline as well as an essential component of many mathematical areas, and its study has experienced an impressive growth in recent years. Some of the main reasons for this growth are the broad applications of tools and techniques from extremal and probabilistic combinatorics in the rapid development of theoretical Computer Science, in the spectacular recent results in Additive Number Theory and in the study of basic questions in Information Theory. While in the past many of the basic combinatorial results were obtained mainly by ingenuity and detailed reasoning, the modern theory has grown out of this early stage, and often relies on deep, well developed tools, like the probabilistic method, algebraic, topological and geometric techniques. The work of the principal investigator, partly jointly with several collaborators and students, and partly in individual efforts, has played a significant role in the introduction of powerful algebraic, probabilistic, spectral and geometric techniques that influenced the development of modern combinatorics. In the present project he aims to try and further develop such tools, trying to tackle some basic open problems in Combinatorics, as well as significant questions in Additive Combinatorics, Information Theory, and theoretical Computer Science. Progress on the problems mentioned in this proposal, and the study of related ones, is expected to provide new insights on these problems and to lead to the development of novel fruitful techniques that are likely to be useful in Discrete Mathematics as well as in related areas.

1 061 300 €

Start date: 2008-12-01, End date: 2013-11-30

Certain plants, animals and micro-organisms are able to dry out completely and yet remain viable, a phenomenon known as anhydrobiosis ( life without water ), or desiccation tolerance. This proposal addresses the molecular mechanisms responsible for desiccation tolerance and aims to confer these mechanisms on desiccation-sensitive mammalian cells, establishing a new field in biotechnology: a form of synthetic biology we have called anhydrobiotic engineering. One feature of anhydrobiotic organisms is the production of many examples of highly hydrophilic proteins (or hydrophilins ) in preparation for severe dehydration. Although data are limited, these hydrophilins are suggested to fulfil various roles in preserving homeostasis of the desiccating cell, including the maintenance of protein, nucleic acid and membrane structure. The proposed project will investigate the function of hydrophilins, engineer these and other elements as desiccation protection modules, and introduce modules into mammalian cell lines. By combining protection modules and using an iterative deployment strategy, we aim to achieve an engineered mammalian cell with high viability in the dried state. Anhydrobiotic engineering will find applications in cell banking, e.g. of hybridoma collections, and cell-based technologies including tissue engineering. Principles established should be applicable to agriculture, where drought-resistant crops, or desiccation-tolerant biopesticides are envisaged. The PI has a distinguished record of achievement in several disciplines in the life sciences and biotechnology, in both academia and industry. Publications in Nature, Science and other leading journals include contributions in human genomics, the molecular genetics of the immune system and inherited disease, the molecular cell biology and biochemistry of desiccation tolerance, and invertebrate genetics. The PI is also an inventor on licensed patents and patent applications in two different fields.

2 494 963 €

Start date: 2009-01-01, End date: 2014-09-30

Different morphologies evolve in different organisms in response to changing environments. As land plants evolved, developmental mechanisms were either generated de novo, or were recruited from existing toolkits and adapted to facilitate changes in form. Some of these changes occurred once, others on multiple occasions, and others were gained and then subsequently lost in a subset of lineages. Why have certain forms survived and others not? Why does a fern look different from a flowering plant, and why should developmental biologists care? By determining how many different ways there are to generate a particular morphology, we gain an understanding of whether a particular transition is constrained. This basic information allows an assessment of the extent to which genetic variation can modify developmental mechanisms and an indication of the degree of developmental plasticity that is possible and/or tolerated both within and between species. This proposal aims to characterize the developmental mechanisms that underpin the diverse shoot forms seen in extant plant species. The main goal is to compare developmental mechanisms that operate in vegetative shoots of bryophytes, lycophytes, ferns and angiosperms, with a view to understanding the constraints that limit morphological variation. Specifically, we will investigate the developmental basis of three major innovations that altered the morphology of vegetative shoots during land plant evolution: 1) formation of a multi-cellular embryo; 2) organization of apical growth centres and 3) patterning of leaves in distinct spatial arrangements along the shoot. To facilitate progress we also aim to develop transgenic methods, create mutant populations and generate digital transcriptomes for model species at key phylogenetic nodes. The proposed work will generate scenarios to explain how land plant form evolved and perhaps more importantly, how it could change in the future.

2 230 732 €

Start date: 2009-07-01, End date: 2015-06-30

The project is multi-disciplinary by character. It focuses upon socio-historical processes of the transformation and 'circulation' of educated and ruling elites in several uniquely composite (both multi-ethnic and multi-confessional) East European regional or national societies, having experienced a number of radical changes of social and political regime as well as state souvereignty in the first half of the 20th century. The historical scope of the study extends from post-feudalism to communism. Societies involved comprise Hungary, Slovakia, Transylvania, Voivodina in the Carpathian Basin, Latvia and Estonia in the Baltics. The study draws upon sociological survey methods applied to historically successive elite brackets in form of exhaustive or quasi-exhaustive computerized prosopographical data banks, based on standardized individual biographies of elite members (as permitted by mostly archival sources to be exploited). The main targets would include secondary school graduates, students and graduates of higher education, the main intellectual professions (like doctors and lawyers.), the political power elites as well as 'reputational elites' - those cited in biographical dictionaries. The information fed into our data banks help to clarify thanks to various procedures of multi-variate statistical schemes the contrasting socio-cultural selection and recruitment of elite members, their educational path from primary to higher education, their professional career, intellectual creativity as well as socio-political standing and orientation. This is the first time that large region- or country-wide elite clusters are submitted to systematic socio-historical analyses, covering simultaneously all or most markets of activity and self-assertion of educated clusters in a vast international and comparative perspective related to culturally composite societal formations.

771 628 €

Start date: 2009-01-01, End date: 2012-03-31

Asian monsoon is a spectacular occurrence in the climate system. What make it so powerful are the combination of thermal contrast between the World s largest landmass (Eurasian continent) and ocean basin (the Indo-Pacific Ocean) and the presence of the World s largest ridge, the Tibetan Plateau. Climatologically, monsoon regions are the most convectively active areas and account for the majority of global atmospheric heat and moisture transport. Moreover, the economy, culture and rhythms of life of 60% of humanity are critically influenced by the evolution and variability of the Asian monsoon. The need to better understand the monsoon leads inevitably to the close inspection of its activity during the geological times to provide a long-term perspective from which any future change may be more effectively assessed. Our research proposal aims to understand the seeming paradox of the exceptionally intense East Asian summer monsoon (actually the strongest over the last one million years) which occurred during the relatively cool interglacial (MIS-13), 500,000 years ago. This will be done using first a model of intermediate complexity (LOVECLIM) to achieve a number of sensitivity experiments to the astronomical forcing, the Eurasian and North American ice sheets, the Tibetan Plateau and the Ocean. Ocean-atmosphere coupled general circulation models will then be used to confirm the main processes underlined by LOVECLIM, in particular those related to the wave train topographically induced by the Eurasian ice sheet, to the Tibetan Plateau, to the sea-surface temperature and to their role in reinforcing the East Asian summer monsoon. This monsoon of MIS-13 will be compared with the monsoon which occurred during the other interglacials of the upper Pleistocene and Holocene (about the last 700,000 years). All simulation results will be compared with the available proxy records, in particular-but not exclusively-those coming from the loess-soil sequences in China.

893 880 €

Start date: 2008-11-01, End date: 2013-10-31

THE OBJECTIVE of this project is to explore the various ways in which the histories of the Balkan peoples were shared, connected and entangled, and in some cases became structurally inter-dependent in the course of the nineteenth and the twentieth centuries; also to explore transfers and crossings within the region and from Western Europe and Russia. What is offered is a provisional open-ended and long-term research program guided by a general paradigm , frame of reference and key concepts. I would rather keep the project open and flexible with regard to substantial issues, though with a clear vision of the general (transnational) perspective. A list of topics includes national and social movements, disputed territories, minorities and refugees, cultural and political transfers. The variegated topics demand expertise in different areas and a trans-disciplinary and inter-disciplinary treatment without regard to established disciplinary boundaries. Systematically applying the transnational and relational perspective to the study of a region as complex as the Balkans has huge cognitive potential and innovative power. The new perspective and cutting-edge methodologies will reveal fresh vistas and bring insights to a number of topics that cannot be restricted in advance. Older research objects will look different and acquire new meanings in the new context and entirely new historical objects will be constituted. The national paradigm of self-contained national histories will be challenged. Such a project may well have wider social and political relevance. There is a positive and integrative value in showing how entangled the histories of the present-day Balkan nations and states were and still are. I would like to imagine such research as promoting good relations rather than fostering divisiveness and separation. This project will also be an input to the European integration of the region, which will hopefully involve the rest of the Balkans in the near future.

1 560 000 €

Start date: 2009-01-01, End date: 2014-06-30

Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.

2 500 000 €

Start date: 2009-04-01, End date: 2014-09-30

The point of departure of this project is that a good part of the present deficit of legitimacy of European institutions emerges from a deeply ahistoric view of Europe s past. Consequently, there is an urgent need for a more realistic history that rejects any teleological understanding of Europe as a self-propelling project on steady march towards a predetermined goal. The fragility of European peace and progress needs to be highlighted. The theoretical foundation of Europe in teleological modernisation and globalisation theories has lead to a-historical understandings of Europe s past that disturb our ability to plan for its future. Our realistic outline of Europe s past focuses on the century 1815-1914, which was the pre-war historical ground on which the peace of 1945 and our present conception of Europe were built. It testifies at least as much to conflict and fragility as to progress. The century is traversed by a series of tensions in the political, cultural, social, economic and legal fields and struggles between the protagonists of different conceptions of European modernity. The legal and political basis for a new European order established in the Vienna Treaty, called the European concert, opened an era that lasted until 1914 in which wars in Europe decreased, whereas the number of civil wars increased and the Revolution came to no end. The tensions were articulated in different geopolitical strategies, constitutional conceptions, prescriptions for economic efficiency and claims for social protection, and alternating views of the meaning of Europe. In one way or the other, they all dealt with the interactive dynamics between politics and law, nationally as well as internationally. These interactive dynamics were also visible in the permanent movement between search for and expectations of stability and experiences of fragility. The aim is to explore the tensions in deep detail and on that basis build an alternative historical view on Europe.

2 500 000 €

Start date: 2009-09-01, End date: 2014-08-31

During the last three decades, Islam has gained visibility in European public spheres through new religious symbols, but as well as new public figures, men and women, pious and secular who carry Islam in European public life. Islamic entry in the public sphere, and the claims for religious visibility provoke a series of debates on gender equality, freedom of expression and cultural (civilisational) differences in European publics. EUROPUBLICISLAM sets itself the intellectual research agenda of bringing together different fields of knowledge and analysis of the transformative forces that appear in the contemporary meeting of Islam and Europe. It proposes to develop an innovative understanding of the sporadic and at times violent ways in which Islam intervenes in the making of the European public sphere. EUROPUBLICISLAM engages with the European scholarly agenda on migration, the construction of a European public sphere, and Islam. It aims at shifting the contemporary theorization of Islam in Europe away from the integration and security paradigms, and towards a new theory of dynamics of interaction and mutual change. A new research field is marked out in combining and transforming the contemporary theorizations of European public sphere and European Islam. EUROPUBLICISLAM proposes to study religious symbols, artistic cultural productions and public figures affecting the everyday politics of cultural discord. It aims to re-conceptualize the place of Islam in the making of a European public sphere. An innovative methodology is proposed to study the constellations , the assemblages that bring together cultural differences in proximity and in confrontation across national public spheres, following a transnational dynamics. EUROPUBLICISLAM will thus contribute to the production of innovative research on the making and imaging a European public sphere where transformative cultural and aesthetic mixes and thus political pluralism are taking place.

1 414 645 €

Start date: 2008-12-01, End date: 2013-03-31

Expander graphs are finite graphs which play a fundamental role in many areas of computer science such as: communication networks, algorithms and more. Several areas of deep mathematics have been used in order to give explicit constructions of such graphs e.g. Kazhdan property (T) from representation theory of semisimple Lie groups, Ramanujan conjecture from the theory of automorphic forms and more. In recent years, computer science has started to pay its debt to mathematics: expander graphs are playing an increasing role in several areas of pure mathematics. The goal of the current research plan is to deepen these connections in both directions with special emphasis of the more recent and surprising application of expanders to group theory, the geometry of 3-manifolds and number theory.

1 082 504 €

Start date: 2008-10-01, End date: 2014-09-30

The complex interplay between Coulomb repulsion and Fermi statistics in two dimensional systems is responsible for some of the most dramatic phenomena encountered in solid state physics (High critical temperature superfluidity, Fractional Quantum Hall Effect,..). However, despite decades of efforts, many questions regarding these systems are still unsolved. In FERLODIM, we plan to take advantage of recent progress in ultracold gases, to simulate several fundamental Hamiltonians describing these many-body systems in 1 and 2 dimensions. We will realize two ultra-cold atom machines allowing for a full characterization of the many-body wave function of an ensemble of interacting fermions in periodic potentials, called optical lattices. Our experiments will rely on a high resolution imaging system allowing both for single atom detection and the possibility of tailoring optical potentials of arbitrary shape and geometry. This unique design will allow us to address a variety of physical situations, depending on the geometry of the light induced potentials. One-dimensional problems will be addressed, from spin chains to Luttinger liquids. In pure two dimensional configurations, we will investigate the link between the repulsive Hubbard model, superfluidity and the Mott insulator transition, as well as frustration effects in periodic potentials. Finally we will explore the physics of interacting fermions under rotation in the lowest Landau level, and the connection with fractional Quantum Hall systems.

2 050 000 €

Start date: 2009-01-01, End date: 2013-12-31

Polycomb group (PcG) and trithorax group (trxG) genes were discovered in Drosophila melanogaster as repressors and activators of Hox genes, a set of transcription factors that specify the antero-posterior axis of the body plan. PcG and trxG proteins form multimeric complexes that are required to maintain their expression state after the initial transcriptional regulators disappear from the embryo. Subsequent work led to a better understanding of their mechanisms of action. Moreover, PcG and trxG genes have also been identified in vertebrates, where they regulate Hox genes, they are involved in cell proliferation, stem cell identity and cancer, genomic imprinting in plants and mammals and X inactivation. PcG and trxG components form multimeric complexes. Some trxG and PcG components possess methyltransferase activities directed toward specific lysines of histone H3, whereas other trxG and PcG proteins interpret these histone marks. Recent studies have described the genomewide distribution of PcG proteins and of their related histone modification in Drosophila and other species. However, the PcG recruitment code to their target chromatin is still not understood, and the mechanism of PcG-mediated gene silencing is unclear. The formation of subnuclear silencing compartments might contribute to the stable repression of transcription. Drosophila PcG proteins have a speckled nuclear distribution and the number of these so-called PcG bodies is progressively reduced during development. We showed that multiple PREs can associate in the nucleus to enhance the strength of PcG-mediated silencing. However, we do not know how frequent is this clustering process and how important it is functionally at a genomewide level. Our project will tackle these questions by using a combination of genetics, developmental biology, cell biology, genomics and bioinformatic approaches, with the aim to gain an integrated understanding of the role of Polycomb and trithorax in biology

2 200 000 €

Start date: 2009-09-01, End date: 2015-08-31

The discovery of the fractional quantum Hall effect created a revolution in solid state research by introducing a new state of matter resulting from strong electron interactions. The new state is characterized by excitations (quasi-particles) that carry fractional charge, which are expected to obey fractional statistics. While odd denominator fractional states are expected to have an abelian statistics, the newly discovered 5/2 even denominator fractional state is expected to have a non-abelian statistics. Moreover, a large number of emerging proposals predict that the latter state can be employed for topological quantum computing ( Station Q was founded by Microsoft Corp. in order to pursue this goal). This proposal aims at studying the abelian and non-abelian fractional charges, and in particular to observe their peculiar statistics. While charges are preferably determined by measuring quantum shot noise, their statistics must be determined via interference experiments, where one particle goes around another. The experiments are very demanding since the even denominator fractions turn to be very fragile and thus can be observed only in the purest possible two dimensional electron gas and at the lowest temperatures. While until very recently such high quality samples were available only by a single grower (in the USA), we have the capability now to grow extremely pure samples with profound even denominator states. As will be detailed in the proposal, we have all the necessary tools to study charge and statistics of these fascinating excitations, due to our experience in crystal growth, shot noise and interferometry measurements.

2 000 000 €

Start date: 2009-01-01, End date: 2013-12-31

How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.

2 492 164 €

Start date: 2009-07-01, End date: 2013-09-30

The area of catalysis is now at the forefront of the chemical sciences in light of environmental and economic issues. Synthesizing bulk, fine and pharmaceutical compounds using catalysis is now a must in the modern economy. The studies described in the present proposal make use of the full arsenal of techniques available for modern synthetic chemical investigation: fundamental physicochemical studies, experiment-based rational catalyst design and catalytic studies. The exploratory physicochemical experiments to be performed make use of classical solution reaction calorimetry involving air- and moisture sensitive complexes. This area is very poorly investigated worldwide. The PI is a world leader in the area of organometallic thermochemistry, a technique that is proposed for elaboration in Spain. This section of the proposal will permit an increase of knowledge on fundamental catalytic systems, allowing for determination of enthalpy and kinetics of key reaction steps involved in homogeneous catalysis. Much needed thermodynamic information will be generated for palladium, gold, iridium and rhenium systems. The development of a rhenium-based system is proposed for investigation in the area of olefin metathesis. Furthermore, ruthenium-systems enabling alkyne metathesis are targeted for synthesis. The development of such olefin modifying system would greatly benefit Europe as catalytic transformations have huge potential in polymer, pharmaceutical and fine chemical industries. The proposed work is both fundamental and applied high risk and high reward. It is outside the presently investigated areas of research carried out by our group at the ICIQ. The Principal Investigator (PI) has 25 years of experience in fundamental and applied chemical research and 15 years of experience as an independent researcher in homogeneous catalysis and organometallic chemistry.

2 033 000 €

Start date: 2009-01-01, End date: 2014-12-31

I aim to achieve a fundamental understanding of the atomistic kinetic pathways responsible for nanostructure formation and to explore the concept of self-organization by thermodynamic segregation in functional ceramics. Model systems are advanced ceramic thin films, which will be studied under two defining cases: 1) deposition of supersaturated solid solutions or nanocomposites by magnetron sputtering (epitaxy) and arc evaporation. 2) post-deposition annealing (ageing) of as-synthesized material. Thin film ceramics are terra incognita for compositions in the miscibility gap. The field is exciting since both surface and in-depth decomposition can take place in the alloys. The methodology is based on combined growth experiments, characterization, and ab initio calculations to identify and describe systems with a large miscibility gap. A hot topic is to elucidate the bonding nature of the cubic-SiNx interfacial phase, discovered by us in TiN/Si3N4 with impact for superhard nanocomposites. I have also pioneered studies of self-organization by spinodal decomposition in TiAlN alloy films (age hardening). Here, the details of metastable c-AlN nm domain formation are unknown and the systems HfAlN and ZrAlN are predicted to be even more promising. Other model systems are III-nitrides (band gap engineering), semiconductor/insulator oxides (interface conductivity) and carbides (tribology). The proposed research is exploratory and has the potential of explaining outstanding phenomena (Gibbs-Thomson effect, strain, and spinodal decomposition) as well as discovering new phases, for which my group has a track-record, backed-up by state-of-the-art in situ techniques. One can envision a new class of super-hard all-crystalline ceramic nanocomposites with relevance for a large number of research areas where elevated temperature is of concern, significant in impact for areas as diverse as microelectronics and cutting tools as well as mechanical and optical components.

2 292 000 €

Start date: 2008-12-01, End date: 2013-11-30

This interdisciplinary project (combining social and earth sciences) addresses a key gap in the knowledge of global assessments concerning the likely consequences of future climate change on future human wellbeing. More information about the determinants of future adaptive capacity is necessary for setting policy priorities today: Should the significant funds allocated for adaptation be invested in enhancing existing infrastructure or currently practiced agricultural strategies (some of which may not be tenable under future climates), or should they invest alternatively in enhancing human empowerment through education and health which in consequence will enable affected societies to better cope with whatever challenges the future will bring? This study is expected to bring significant progress in this difficult multidisciplinary, yet highly relevant, field through a combination of: (a) New global science-based, long-term projections of human capital (population by age, sex and level of education) as a key element of adaptive capacity; (b) Three empirical multi-national studies on key factors involved in past vulnerability and adaptations to the Sahelian drought, Hurricane Mitch and the Asian tsunami; (c) Three prospective case studies assessing future adaptive capacity for the Phuket region, Mauritius and the Nicobar islands; (d) All held together and put into perspective by the elaboration of a new demographic theory of long-term social change with predictive power. This rather complex project structure is necessary for reaching generalizable and useful results. All components have been designed to complement each other to maximize the chances of achieving path-breaking and at the same time tangible results in this highly complex, multidisciplinary field. All components of the study will build on previous work of IIASA and Wolfgang Lutz and hence minimize the need to acquire additional experience for the case study sites or for the methodology used.

2 438 402 €

Start date: 2009-03-01, End date: 2014-07-31

Globalisation has changed health conditions worldwide, affecting the lives and livelihoods of hundreds of millions. While historically many health issues have readily crossed borders (e.g. Black Plague), the intensification and extensification of contemporary globalisation processes has required new forms of governance to address changed global health needs. How do we collectively protect and promote health in an increasingly globalised world? This challenge has opened up a contested space known as global health governance (GHG) where the stakes are high but where different perspectives compete and contradict. It is also a poorly understood space. This programme aims to significantly advance our understanding of this space and the competition within it. It builds on a small body of existing literature to which the two applicants have already made important contributions, but represents a step change in two important respects. First, existing analyses have been limited to single approaches or perspectives. This programme represents the first sustained attempt at a comparative analysis incorporating a variety of perspectives and health issues. Given that the space is contested, it is only through such an analysis that we can significantly advance our understanding of GHG. Such an approach would represent a major advance on the current state of the art. Second, analysis to date has focused on disease and especially infectious disease. The applicants have been at the forefront of critiquing this approach as overly narrow (for example McInnes and Lee, 2006). This programme addresses infectious disease as one of the key issues in global health governance, but also incorporates non-communicable disease and non-disease based health issues in an explicit attempt to broaden the analysis to cover more fully the space occupied by global health governance.

2 349 246 €

Start date: 2009-01-01, End date: 2013-12-31

Mental disorders put a great burden on society and their impact on personal life can be devastating. Most mental disorders begin in childhood or adolescence and co-occur with somatic disease. In children, the most common problems are ADHD and anxious/depression and these problems often co-occur with additional behavioral and emotional problems. In adults, depression is the major mental disorder. It frequently co-occurs with anxiety disorders, substance abuse, migraine, cardiovascular disease and its associated risk factors. Indeed, depression is the largest cause of nonfatal disease burden in Western countries and increasingly in low and middle income countries worldwide as well. This application focuses on the genetics of common mental disorders, co-morbid traits and diseases across the lifespan. Its primary aim is the discovery of developmental paths into risk of depression and co-morbid disorders, using genetic epidemiological, molecular genetic and gene-environment interaction models. The introduction of multivariate and longitudinal models, in particular methods introduced by my group, into these areas will lead to substantial increases in power to unravel the contributions of genotype, environment and their interactions. The project described in this application addresses three interrelated topics: 1. Neuropsychiatric disorders and cognition 2. Depression, anxiety, substance use, abuse and dependence 3. Depression, migraine and cardiovascular risk As a connecting methodological framework it will develop models for the genetic analysis of these complex traits, especially gene-environment interaction and genome-wide association models. My ambition is to discover which genes influence the risk for mental disorder and co-morbid biomedical traits, to identify the causal variants, and to explore their interaction with environmental risk factors.

2 466 923 €

Start date: 2009-02-01, End date: 2013-10-31

The main scientific questions addressed in this proposal relate to the understanding of molecular mechanisms of growth control and cancer through the combined use of high-throughput technologies and computational biology. We aim to create a systems-level understanding of the cell cycle, and its regulation by physiological growth factors and oncogenes through the use high-throughput biology to identify all or the majority of genes that are essential for cell cycle progression, and by combining this dataset with computationally predicted and experimentally validated target genes of growth factors and oncogenic pathways. In my opinion, such systems biology approach is critical for understanding of growth control, as organ-specific growth control has proven particularly refractory to genetic dissection. Much of what we know about physiological mechanisms controlling cellular growth in mammals has been revealed by human cancer genetics. These studies have revealed that a large number of genes can contribute to aberrant cell growth; there are more than 300 genes that have been linked to cancer, and mutations found in cancer are often cell type specific ( oncogene preference , i.e. PTCH mutations in medulloblastoma, APC in colon cancer, TMPRSS2-ERG in prostate cancer), suggesting that different pathways in different cell lineages are coupled to the cell cycle machinery. We have preliminary evidence that hedgehog (Hh) and Wnt signals are directly coupled to expression of N-myc and c-Myc genes, but only in tissues and cell-types that display a proliferative response to these factors. Both classical molecular and developmental biology as well as high throughput and systems biological methods will be used for dissection of the molecular mechanism of this selectivity. If successful, these experiments would establish a principle explaining why particular mutations are extremely common in some tumor types but not found at all in others.

2 200 000 €

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