ERC FUNDED PROJECTS

The focus of this project is the development of algorithms that allow one to capture and analyse dynamic events taking place in the real world. For this, we intend to develop smart camera networks that can perform a multitude of observation tasks, ranging from surveillance and tracking to high-fidelity, immersive reconstructions of important dynamic events (i.e. 4D videos). There are many fundamental questions in computer vision associated with these problems. Can the geometric, topologic and photometric properties of the camera network be obtained from live images? What is changing about the environment in which the network is embedded? How much information can be obtained from dynamic events that are observed by the network? What if the camera network consists of a random collection of sensors that happened to observe a particular event (think hand-held cell phone cameras)? Do we need synchronization? Those questions become even more challenging if one considers active camera networks that can adapt to the vision task at hand. How should resources be prioritized for different tasks? Can we derive optimal strategies to control camera parameters such as pan, tilt and zoom, trade-off resolution, frame-rate and bandwidth? More fundamentally, seeing cameras as points that sample incoming light rays and camera networks as a distributed sensor, how does one decide which rays should be sampled? Many of those issues are particularly interesting when we consider time-varying events. Both spatial and temporal resolution are important and heterogeneous frame-rates and resolution can offer advantages. Prior knowledge or information obtained from earlier samples can be used to restrict the possible range of solutions (e.g. smoothness assumption and motion prediction). My goal is to obtain fundamental answers to many of those question based on thorough theoretical analysis combined with practical algorithms that are proven on real applications.

1 757 422 €

Start date: 2008-08-01, End date: 2013-11-30

Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.

1 607 105 €

Start date: 2008-07-01, End date: 2013-06-30

In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

750 000 €

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

Normal placental angiogenesis is critical for embryonic survival and development. Epigenetic modifications, such as methylation of CpG islands, regulate the expression and imprinting of genes. Epigenetic abnormalities have been observed in embryos from assisted reproductive technologies (ART), which could explain the poor placental vascularisation, embryonic/fetal death, and altered fetal growth in these pregnancies. Both cloned (somatic cell nuclear transfer, or SNCT) and monoparental (parthogenotes, only maternal genes; androgenotes, only paternal genes) embryos provide important models for studying defects in expression and methylation status/imprinting of genes regulating placental function. Our hypothesis is that placental vascular development is compromised during early pregnancy in embryos from ART, in part due to altered expression or imprinting/methylation status of specific genes regulating placental angiogenesis. We will evaluate fetal growth, placental vascular growth, and expression and epigenetic status of genes regulating placental angiogenesis during early pregnancy in 3 Specific Aims: (1) after natural mating; (2) after transfer of biparental embryos from in vitro fertilization, and SCNT; and (3) after transfer of parthenogenetic or androgenetic embryos. These studies will therefore contribute substantially to our understanding of the regulation of placental development and vascularisation during early pregnancy, and could pinpoint the mechanism contributing to embryonic loss and developmental abnormalities in foetuses from ART. Any or all of these observations will contribute to our understanding of and also our ability to successfully employ ART, which are becoming very wide spread and important in human medicine as well as in animal production.

363 600 €

Start date: 2008-10-01, End date: 2012-06-30

Quantum information science and atom optics are among the most active fields in modern physics. In recent years, many theoretical efforts have been made to combine these two fields. Recent experimental progresses have shown the in-principle possibility to perform scalable quantum information processing (QIP) with linear optics and atomic ensembles. The main purpose of the present project is to use atomic qubits as quantum memory and exploit photonic qubits for information transfer and processing to achieve efficient linear optics QIP. On the one hand, utilizing the interaction between laser pulses and atomic ensembles we will experimentally investigate the potentials of atomic ensembles in the gas phase to build quantum repeaters for long-distance quantum communication, that is, to develop a new technological solution for quantum repeaters making use of the effective qubit-type entanglement of two cold atomic ensembles by a projective measurement of individual photons by spontaneous Raman processes. On this basis, we will further investigate the advantages of cold atoms in an optical trap to enhance the coherence time of atomic qubits beyond the threshold for scalable realization of quantum repeaters. Moreover, building on our long experience in research on multi-photon entanglement, we also plan to perform a number of significant experiments in the field of QIP with particular emphasis on fault-tolerant quantum computation, photon-loss-tolerant quantum computation and cluster-state based quantum simulation. Finally, by combining the techniques developed in the above quantum memory and multi-photon interference experiments, we will further experimentally investigate the possibility to achieve quantum teleportation between photonic and atomic qubits, quantum teleportation between remote atomic qubits and efficient entanglement generation via classical feed-forward. The techniques that will be developed in the present project will lay the basis for future large scale

1 435 000 €

Start date: 2008-07-01, End date: 2013-12-31

When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.

1 630 000 €

Start date: 2008-10-01, End date: 2013-09-30

Biomimetic Organocatalysis – Development of Novel Synthetic Catalytic Methodology and Technology The objective of the proposed research is the design and development of unprecedented preassembled, modular, molecular factories. Inspiration comes from nature’s non-ribosomal peptide synthetases (NRPSs) and polyketide synthetases (PKSs). These large multifunctional enzymes possess catalytic modules with the capacity for recognition, activation and modification required for sequential biosynthesis of complex peptides and polyketides. Using nature as a role model we intend to design and prepare such catalyst “factories” synthetically and apply them in novel cascade reaction sequences. The single catalytic modules employed will be based on organocatalytic procedures, including enamine-, iminium-, as well as hydrogen bonding activation processes, but the potential scope is limitless. Organocatalysts have so far never been applied in a combined fashion utilizing their different activation mechanisms in multiple reaction cascades. Therefore, it is our intention to firstly demonstrate that such a production line approach is feasible and that these new catalyst systems can be applied in the synthesis of valuable enantiopure, biologically active, building blocks and natural products. Additionally, the extensive possibilities to vary organocatalyst modules in sequence will lead to science mimicking nature in its diversity.

999 960 €

Start date: 2008-09-01, End date: 2012-08-31

The overall objective of the proposal is to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in vivo and, secondly, study the role of multivalency and spatial organization in carbohydrate recognition. Both of these projects exploit the programmable pre-organization of peptide nucleic acid (PNA) to induce a chemical reaction in the first case or modulate a ligand-receptor interaction in the second case. For nucleic acid detection, a DNA or RNA fragment will be utilized to bring two PNA fragments bearing reactive functionalities in close proximity thereby promoting a reaction. Two types of reactions are proposed, the first one to release a fluorophore for imaging purposes and the second one to release a drug as an “intelligent” therapeutic. If affinities are programmed such that hybridization is reversible, the template can work catalytically leading to large amplifications. As a proof of concept, this method will be used to measure the transcription level of genes implicated in stem cell differentiation and detect mutations in oncogenes. For the purpose of studying multivalent carbohydrate ligand architectures, the challenge of chemical synthesis has been a limiting factor. A supramolecular approach is proposed herein where different arrangements of carbohydrates can be displayed in a well organized fashion by hybridizing PNA-tagged carbohydrates to DNA templates. This will be used not only to control the distance between multiple ligands or to create combinatorial arrangements of hetero ligands but also to access more complex architectures such as Hollyday junctions. The oligosaccharide units will be prepared using de novo organoctalytic reactions. This technology will be first applied to probe the recognition events between HIV and dendritic cells which promote HIV infection.

1 249 980 €

Start date: 2008-07-01, End date: 2013-06-30

This project will focus on the use of nanoporous metal organic frameworks (Fe, Zn, Ti) for bioapplications. These systems are exciting porous solids, built up from inorganic clusters and polycarboxylates. This results in open-framework solids with different pore shapes and dimensions, and applications such as catalysis, separation and storage of gases. I have recently initiated the synthesis of new trivalent transition metal carboxylates. Among them, the metal carboxylates MIL-100 and MIL-101 (MIL: Materials of Institut Lavoisier) are spectacular solids with giant pores (25-34 Å), accessible metal sites and huge surface areas (3100-5900 m2.g-1). Recently, it was shown that these solids could be used for drug delivery with a loading of 1.4 g of Ibuprofen per gram of MIL-101 solid and a total release in six days. This project will concentrate on the implication of MOFs for drug release and other bioapplications. Whereas research on drug delivery is currently focused either on the use of bio-compatible polymers or mesoporous materials, our method will combine advantages of both routes including a high loading and a slow release of therapeutic molecules. A second application will use solids with accessible metal sites to coordinate NO for its controlled delivery. This would provide exogenous NO for prophylactic and therapeutic processes, anti-thrombogenic medical devices, improved dressings for wounds and ulcers, and the treatment of fungal and bacterial infections. Finally, other applications will be envisaged such as the purification of physiological fluids. The project, which will consist of a systematic study of the relation between these properties and both the composition and structure of the hybrid solids, will be assisted by a strong modelling effort including top of the art computational methods (QSAR and QSPKR). This highly impact project will be realised by assembling experienced researchers in multidisplinary areas including materials science, biology and modelling. It will involve P. Horcajada (Institut Lavoisier), whose background in pharmaceutical science will fit with my experience in inorganic chemistry and G. Maurin (Institut Gerhardt, Montpellier) expert in computational chemistry.

1 250 000 €

Start date: 2008-06-01, End date: 2013-05-31

Shape Memory Alloys (SMAs) are nowadays widely exploited for the realization of innovative devices and have a great impact on the development of a variety of biomedical applications ranging from orthodontic archwires to vascular stents. The design, realization, and optimization of such devices are quite demanding tasks. Mathematics is involved in this process as a major tool in order to let the modeling more accurate, the numerical simulations more reliable, and the design more effective. Many material properties of SMAs such as martensitic reorientation, training, and ferromagnetic behavior, are still to be properly and efficiently addressed. Therefore, new modeling ideas, along with original analytical and numerical techniques, are required. This project is aimed at addressing novel mathematical issues in order to move from experimental materials results toward the solution of real-scale biomechanical Engineering problems. The research focus will be multidisciplinary and include modeling, analytic, numerical, and computational issues. A progress in the macroscopic description of SMAs, the computational simulation of real-scale SMA devices, and the optimization of the production processes will contribute to advance in the direction of innovative applications.

700 000 €

Start date: 2008-09-01, End date: 2013-08-31

Multiferroics (i.e. materials where ferroelectricity and magnetism coexist) are presently drawing enormous interests, due to their technologically-relevant multifunctional character and to the astoundingly rich playground for fundamental condensed-matter physics they constitute. Here, we put forward several concepts on how to break inversion symmetry and achieve sizable ferroelectricity in collinear magnets; our approach is corroborated via first-principles calculations as tools to quantitatively estimate relevant ferroelectric and magnetic properties as well as to reveal ab-initio the main mechanisms behind the dipolar and magnetic orders. In closer detail, we focus on the interplay between ferroelectricity and electronic degrees of freedom in magnets, i.e. on those cases where spin- or orbital- or charge-ordering can be the driving force for a spontaneous polarization to develop. Antiferromagnetism will be considered as a primary mechanism for lifting inversion symmetry; however, the effects of charge disproportionation and orbital ordering will also be studied by examining a wide class of materials, including ortho-manganites with E-type spin-arrangement, non-E-type antiferromagnets, nickelates, etc. Finally, as an example of materials-design accessible to our ab-initio approach, we use “chemistry” to break inversion symmetry by artificially constructing an oxide superlattice and propose a way to switch, via an electric field, from antiferromagnetism to ferrimagnetism. To our knowledge, the link between electronic degrees of freedom and ferroelectricity in collinear magnets is an almost totally unexplored field by ab-initio methods; indeed, its clear understanding and optimization would lead to a scientific breakthrough in the multiferroics area. Technologically, it would pave the way to materials design of magnetic ferroelectrics with properties persisting above room temperature and, therefore, to a novel generation of electrically-controlled spintronic devices

684 000 €

Start date: 2008-05-01, End date: 2012-04-30

"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

1 750 000 €

Start date: 2008-08-01, End date: 2013-07-31

Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.

1 529 369 €

Start date: 2008-08-01, End date: 2013-07-31

Histidine (His) is an ubiquitous ligand in the active site of metalloenzymes that is assumed by default to bind the metal center through one of its nitrogen atoms. However, protonation of His, which is likely to occur in locally slightly acidic environment, gives imidazolium sites that can bind a metal in a carbene-type structure as found in N-heterocyclic carbene complexes. Such carbene bonding has a dramatic effect on the properties of the metal center and may provide a rational for the mode of action of metalloenzymes that are still lacking a solid understanding. Up to now, the possibility of carbene bonding has been completely overlooked. Hence, any evidence for such His coordination via carbon will induce a shift of paradigm in classical peptide chemistry and will be directly included in basic textbooks. Moreover, this unprecedented bonding mode will provide access to unique and hitherto unknown reactivity patterns for artificial enzyme mimics. Undoubtedly, such a break-through will set a new stage in modern metalloenzyme research. A multicentered approach is proposed to identify for the first time carbene bonding in enzymes. This approach unconventionally combines the current frontiers of organometallic and biochemical knowledge and hence crosses traditional boarders. Specifically, we aim at probing carbene bonding of His by identifying reactivity patterns that are selective for metal-carbenes but not for metal-imine complexes. This will allow for efficient screening of large classes of metalloenzymes. In parallel, active site models will be constructed in which the His ligand is substituted by a heterocyclic carbene as a rigidly C-bonding His analog. For this purpose chemical synthesis will be considered as well as enzyme mutagenesis and subsequent carbene coordination. While such new bioorganometallic entities will be highly attractive to probe the influence of C-bound His on the metal site, they also provide conceputally new types of versatile catalysts.

1 249 808 €

Start date: 2008-07-01, End date: 2013-06-30

The search of singularities in incompressible flows has become a major challenge in the area of non-linear partial differential equations and is relevant in applied mathematics, physics and engineering. The existence of such singularities would have important consequences for the understanding of turbulence. One way to make progress in this direction, is to study plausible scenarios for the singularities supported by experiments or numerical analysis. With the more sophisticated numerical tools now available, the subject has recently gained considerable momentum. The main goal of this project is to study analytically several incompressible fluid models. In particular solutions that involve the possible formation of singularities or quasi-singular structures.

650 000 €

Start date: 2008-09-01, End date: 2013-08-31

Cell polarity is fundamental to many aspects of cell and developmental biology and it is implicated in differentiation, proliferation and morphogenesis in both unicellular and multi-cellular organisms. We study the mechanisms that regulate cell polarity during both asymmetric cell division and epithelial cell polarization in Drosophila. To understand these fundamental processes, we are currently using two complementary approaches. Firstly, we are coupling genetic tools to state of the art time-lapse microscopy to genetically dissect the mechanisms of cortical cell polarization and mitotic spindle orientation. Secondly, we are introducing two innovative inter-disciplinary methodologies into the fields of cell and developmental biology: 1) single molecule imaging during asymmetric cell division, to unravel the mechanism of polarized protein distribution within the cell; 2) multi-scale tensor analysis of epithelial tissues to describe and understand how epithelial tissues grow, acquire and maintain their shape and organization during development. Using both conventional and innovative methodologies, our goals over the next four years are to better understand how molecules and protein complexes move and are activated at different locations within the cell and how cell polarization impacts on cell identities and on epithelial tissue growth and morphogenesis. Since the mechanisms underlying cell polarization are conserved throughout evolution, the proposed experiments will improve our understanding of these processes not only in Drosophila, but in all animals.

1 159 000 €

Start date: 2008-09-01, End date: 2013-08-31

The aim of the project is to develop chemical processing systems based on the principle of swarm robotics. The inspiration for swarm robotics comes from the behaviour of collective organisms – such as bees or ants – that can perform complex tasks by the combined actions of a large number of relatively simple, identical agents. The main scientific challenge of the project will be the design and synthesis of chemical swarm robots (“chobots”), which we envisage as internally structured particulate entities in the 10-100 µm size range that can move in their environment, selectively exchange molecules with their surrounding in response to a local change in temperature or concentration, chemically process those molecules and either accumulate or release the product. Such chemically active autonomous entities can be viewed as very simple pre-biotic life forms, although without the ability to self-replicate or evolve. In the course of the project, the following topics will be explored in detail: (i) the synthesis of suitable shells for chemically active swarm robots, both soft (with a flexible membrane) and hard (porous solid shells); (ii) the mechanisms of molecular transport into and out of such shells and means of its active control; (iii) chemical reaction kinetics in spatially complex compartmental structures within the shells; (iv) collective behaviour of chemical swarm robots and their response to external stimuli. The project will be carried out by a multi-disciplinary team of enthusiastic young researchers and the concepts and technologies developed in course of the project, as well as the advancements in the fundamental understanding of the behaviour of “chemical robots” and their functional sub-systems, will open up new opportunities in diverse areas including next-generation distributed chemical processing, synthesis and delivery of personalised medicines, recovery of valuable chemicals from dilute resources, environmental clean-up, and others.

1 644 000 €

Start date: 2008-06-01, End date: 2013-05-31

DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.

893 396 €

Start date: 2008-09-01, End date: 2013-08-31

This project is about the design of cryptographic schemes that are secure even if implemented on not-secure devices. The motivation for this problem comes from an observation that most of the real-life attacks on cryptographic devices do not break their mathematical foundations, but exploit vulnerabilities of their implementations. This concerns both the cryptographic software executed on PCs (that can be attacked by viruses), and the implementations on hardware (that can be subject to the side-channel attacks). Traditionally fixing this problem was left to the practitioners, since it was a common belief that theory cannot be of any help here. However, new exciting results in cryptography suggest that this view was too pessimistic: there exist methods to design cryptographic protocols in such a way that they are secure even if the hardware on which they are executed cannot be fully trusted. The goal of this project is to investigate these methods further, unify them in a solid mathematical theory (many of them were developed independently), and propose new ideas in this area. The project will be mostly theoretical (although some practical experiments may be performed). Our main interest lies within the theory of private circuits, bounded-retrieval model, physically-observable cryptography, and human-assisted cryptography. We view these theories just as the departing points, since the area is very fresh and we expect to soon witness completely new ideas in this field.

872 550 €

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

The goal of COMMOTION is to establish a strategy whereby functional molecular devices (e.g. photo-/electroactive) can communicate with one another in solution and in organized, self-assembled media (biotic and abiotic). Despite intense research, no single strategy has been shown to satisfactorily connect artificial molecular components in networks. This is perhaps the greatest hurdle to overcome if implementation of artificial molecular devices and sophisticated molecule-based arrays are to become a reality. In this project, communication between distant sites / molecules will be based on the use of photoejected ions in solution and organized media (membranes, thin films, nanostructured hosts, micellar nanodomains). Ultimately this will lead to coded information transfer through ion movement, signalled by fluorescent reporter groups and induced by photomodulated receptor groups in small photoactive molecules. Integrated photonic and ionic processes operate efficiently in the biological world for the transfer of information and multiplexing distinct functional systems. Application in small artificial systems, combining “light-in, ion-out” (photoejection of an ion) and “ion-in, light-out” processes (ion-induced fluorescence), has great potential in a bottom-up approach to nanoscopic components and sensors and understanding and implementing logic operations in biological systems. Fast processes of photoejection and migration of ions will be studied in real-time (using time-resolved photophysical techniques) with high spatial resolution (using fluorescence confocal microscopy techniques) allowing evaluation of the versatility of this strategy in the treatment and transfer of information and incorporation into devices. Additionally, an understanding of the fundamental events implicated during the process of photoejection / decomplexion of coordinated ions and ion-exchange processes at membrane surfaces will be obtained.

1 250 000 €

Start date: 2008-09-01, End date: 2013-08-31

The project is aimed at funding a multi-disciplinary laboratory on nonlinear optics and photonics in soft-colloidal materials and on “complex lightwave systems”. A team of talented young researchers, divided among experiments, theory, parallel computation and nano-fabrication is involved. The proposed research will foster several breakthrough discoveries from soft-matter to biophysics, from nonlinear and integrated optics to the science of complexity and cryptography. The underlying vision is driven by the physics of complex systems, those displaying a large number of thermodynamically equivalent states and emergent properties. There are 4 original and high-impact activities, which explore applicative potentialities: 1) sub-wavelength light filaments in soft- and bio-matter; 2) lasers in soft-matter and bio-tissues; 3) control of soft-matter lasers by light filaments; 4) complex lightwave systems, encryption by nano-structured disordered lasers. Activity 1 will lead to ultra-thin re-addressable light beams (sub-wavelength spatial solitons) propagating in soft- and bio-matter that can be used in laser-surgery, matter manipulation and able to guide high power laser pulses; activity 2 attains novel structural diagnostic techniques in bone tissue surpassing limits of nuclear magnetic resonance imaging, and assesses the field of lasers in soft-materials; activity 3 will demonstrate the control of self-organization processes in soft-matter by light filaments probed by laser emission; activity 4 is based on specific features mutuated from spin-glass theory, and will realize a novel cryptographic technique superior to chaotic systems in terms of security. Activity 1 and 2 are propaedeutic to the others. The team is composed by the Principal Investigator (P.I.), 4 post-doctoral researchers and 3 Ph.D. students. The budget will be used for paying the P.I., two post-doctoral positions, laser sources, high performance computing facilities, and instrumentation.

1 085 000 €

Start date: 2008-05-01, End date: 2013-04-30

In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function.

996 000 €

Start date: 2008-10-01, End date: 2014-03-31

The Large Hadron Collider (LHC), a 7 + 7 TeV proton-proton collider under completion at CERN, the European Laboratory for Particle Physics in Geneva, will take experiments into a new energy domain beyond the Standard Model of strong and electroweak interactions. As the LHC will unveil the mysteries of the electroweak symmetry breaking, this will also have far-reaching implications for cosmology. The aim of this project is to work out what we may learn about the Early Universe from discoveries at the LHC. This concerns in particular the two fundamental questions of the nature of the Dark Matter and the origin of the matter-antimatter asymmetry of the Universe. The LHC-Cosmology interplay has been a topic of active research in the last years. However, studies have essentially focussed on a single class of models: supersymmetry. The original and innovative directions of this project are: 1) To investigate dark matter particle physics models that have not been explored yet and confront theoretical predictions with existing and upcoming observational constraints. Measuring the properties of the dark matter will require a complementarity between the LHC searches and the other numerous ongoing dark matter experiments such as gamma ray telescopes, neutrino telescopes, cosmic positron detectors ... etc. 2) To work out the details of the electroweak phase transition in extensions of the Standard Model. One of the best-motivated mechanism for generating the baryon asymmetry of the universe relies on a first-order electroweak phase transition. Interestingly, this has strong implications for Gravity Wave physics. We will explore thoroughly how the planned gravity wave detector and space interferometer LISA, which turns out to be a completely independent window on the electroweak scale, could complement the information provided by the LHC. This project will also serve as a solid basis for future research at the Internatinal electron-positron Linear Collider.

800 000 €

Start date: 2008-07-01, End date: 2013-06-30

Most colorectal cancers (CRCs) are initiated by activating mutations in components of the Wnt signalling pathway. Physiological Wnt signals are required for the specification and maintenance of the stem and progenitor cell compartments of the intestinal crypts. We demonstrated that early colorectal lesions exhibit a constitutive Wnt target gene programme, which is very similar to that of normal intestinal stem and progenitor cells. We originally proposed that colorectal adenomas behave as clusters of intestinal cells locked into a constitutive crypt progenitor phenotype. Given the prevalence of Wnt signalling mutations in CRC, an outstanding endeavour is the characterization of the similarities and differences in the instructions dictated by beta-catenin and Tcf to normal intestinal cells vs. CRC cells. Here, we propose to systematically compare and catalogue the beta-catenin/Tcf genetic programmes in intestinal progenitor/stem cells, intestinal adenomas and late CRCs. Transcriptomic analysis of isolated normal progenitor cells and tumor cell populations combined with bioinformatic analysis of gene regulatory networks will allow us to workout the hierarchical interactions downstream of beta-catenin and Tcf. Moreover, functional analysis of key beta-catenin/Tcf target genes using genetically modified mice models will help us to pinpoint which Wnt-controlled functions are essential for tumor maintenance and progression in vivo. Moreover, we seek to understand the tumor suppressor role of EphB2 and EphB3 receptors, two beta-catenin/Tcf target genes in normal crypts and benign colorectal adenomas, that block cancer progression by compartmentalizing tumor cells at the onset of CRC. Overall, our results will shed light on the relationship between stem/progenitor cells and cancer and hold potential for the future development of both therapeutic and diagnostic tools.

1 602 817 €

Start date: 2008-09-01, End date: 2013-08-31

Dendritic cell (DC) activation and homing from the periphery to lymph nodes is a critical first event in the immune response. It involves upregulation of the chemokine receptor CCR7 and chemoinvasion towards lymphatic vessels. Despite its critical importance in adaptive immunity, the mechanisms of DC migration towards and entry into lymphatics are still poorly understood; this severely limits new therapeutic strategies for immunomodulation and even strategies for treating lymphedema, which is exacerbated by poor immune functioning. We propose a battery of physiological, cell-biological, molecular, and computational studies to determine both the mechanisms of DC homing to lymphatic vessels and how DCs modulate lymphatic function. We approach this from the perspectives of both the DC and the lymphatic vessel. Regarding the DC, we will examine computationally and experimentally how draining flows toward the lymphatic alter their migration tactics and test our hypothesis that DCs possess a biomolecular flow-detector network (which we refer to as autologous chemotaxis) and are thus able to sense the direction of the subtle flow of fluid toward the lymphatics. Regarding the lymphatic vessel, we will elucidate how biochemical and biophysical inflammatory signals regulate their drainage function, alter cell-cell adhesions and overall permeability, and alter adhesion receptors to facilitate DC homing and entry. Finally, we will examine DC migration in mice with dysfunctional lymphatics and explore strategies to improve immune response. These will be carried out in 4 main projects, and will complement our recent work in lymphatic functional biology as well as our more therapeutic investigations in DC targeting and activation (Reddy et al., Nature Biotechnol., 2007). This deeper knowledge of mechanisms of DC-lymphatic cross-talk in a relevant biophysical context will enable our long-term goal of rational design for therapeutic immunomodulation and lymphedema.

1 730 966 €

Start date: 2008-05-01, End date: 2013-04-30

Core formation represents the major chemical differentiation event on the terrestrial planets, involving the separation of a metallic liquid from the silicate matrix that subsequently evolves into the current silicate crust and mantle. The generation of the Earth’s magnetic field is ultimately tied to the segregation and crystallization of the core, and is an important factor in establishing planetary habitability. The processes that control core segregation and the depths and temperatures at which this process took place are poorly understood, however. We propose to study those processes. Specifically, the density of the core is lower than would be expected for pure iron, indicating that a light component (O, Si, S, C, H) must be present. Similarly, the Earth’s mantle is richer in iron-loving (“siderophile”) elements, e.g, V, W, Mo, Ru, Pd, etc., than would be expected based upon low pressure metal-silicate partitioning data. Solutions to these problems are hampered by the pressure range of existing experimental data, < 25 GPa, equivalent to ~700 km in the Earth. We propose to extend the accessible range of pressures and temperatures by developing protocols that link the laser-heated diamond anvil cell with analytical techniques such as (i) the NanoSIMS, (ii) the focused ion beam device (FIB), (iii) and transmission and secondary electron microscopy, allowing us to obtain quantitative data on element partitioning and chemical composition at extreme conditions relevant to the Earth’s lower mantle. The technical motivation follows from the fact that the real limitation on trace element partitioning studies at ultra high-pressure has been the grain size of the phases produced at high P-T, relative to the spatial resolution of the analytical methods available to probe the experiments; we can bridge the gap by combining state-of-the-art laser heating experiments with new nano-scale analytical techniques.

1 509 200 €

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

Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.

1 148 522 €

Start date: 2008-09-01, End date: 2013-08-31

The bacterial microflora has always been regarded as beneficial for the host but recent studies have shown that this symbiosis has risks as well as benefits. Although active mechanisms allow tolerating the commensal flora, the physiological stress that is associated with the symbionts’ metabolism can exhaust the intestinal barrier resulting in serious effects on the health of the host. Protracted immune deregulations can lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). Several mechanisms and players are involved in the maintenance of intestinal immune homeostasis, including T regulatory cells and Immunoglobulin (Ig)-A. In this proposal we focus our attention on dendritic cells (DCs) for their ability to induce both tolerance and immunity by regulating B and T cell responses. We have recently shown that DC function is controlled by intestinal epithelial cell (EC) derived factors and in particular by Thymic stromal lymphopoietin (TSLP). EC-conditioned DCs acquire a ‘mucosal’ phenotype as they are prone to activate T regulatory cells and IgA responses. Three major issues related to the maintenance and disruption of intestinal immune homeostasis will be explored in this project: 1) What are the mediators and mechanisms that regulate the interaction between intestinal epithelial cells and dendritic cells? What is the function of TSLP? 2) Which are the sites and players for the activation of an IgA response to pathogenic and commensal bacteria? Can we visualize them in vivo? 3) Can prolonged infections or bacterial products promote intestinal tumour development? Are there different bacterial constituents acting as inducers or protectors of carcinogenesis? What is the role of Toll-like receptors?

1 195 680 €

Start date: 2008-07-01, End date: 2013-06-30

This program is dedicated to the simulation and characterization of Extrasolar Terrestrial Planet (ETP) atmospheres. Thanks to new generation codes, the team E3ARTHS aims to provide a top expertise in a key domain of astrobiology: the origin, evolution and identification of habitable worlds, and the quest for biomarkers on Earth-like planets. The team will also revisit early Earth models for a better understanding of the context of the origins of life, in the light of recent works on Earth formation, impact history and Solar evolution. The observable signatures of an ETP and its ability to sustain life are determined by atmospheric properties: chemistry, radiative transfer, climate. Although these processes are usually treated separately, they evolve in a tightly coupled scheme under the influence of astrophysical, geophysical and, if present, biological mechanisms. Eventually, realistic planetary environments will thus have to be modeled with self-consistent 3D tools, involving a multidisciplinary and international approach. Although ambitious by today's standards, such enterprise is a necessary counterpart of the planned ETP searches, and is required to study the discovered planets. Observatories like Darwin/TPF and ELTs will provide direct information on ETPs within 10-15 years. Ongoing transit searches (CoRoT, and Kepler), and radial-velocity surveys, are on the verge of detecting ETPs. In this context, E3ARTHS can become one of the cores in European theoretical research on ETPs, in close interaction with observation programs. Since his PhD, F. Selsis has developed his own research on ETPs, which already had important implications for the design of instruments for TEP search and characterization. His plan is now to take this research at the next level by creating a dedicated team that will integrate new tools such as 3D climate, photochemical and radiative transfer codes, produce virtual observations of ETPs, and study their potential for life.

719 759 €

Start date: 2008-10-01, End date: 2013-09-30

The core, comprising the innermost parts of the Earth, is one of the most dynamic regions of our planet. The inner core is solid, surrounded by a liquid iron alloy. Inner core solidification combined with motions in the fluid outer core drive the geodynamo which generates Earth's magnetic field. Solidification of the inner core also supplies some of the heat that drives mantle convection and subsequently plate tectonics at the surface of the Earth. The thermal and compositional structure of the inner core is thus key to understanding the inner workings of our planet. No direct samples can be taken of the core and our knowledge of the thermal and compositional state of the Earth's outer and inner core relies on seismology. Ray theoretical studies using short period body waves are the most commonly used seismological data; these have led to observations of a large range of anomalous structures in the Earth's inner core, including anistropy, layers and hemispherical variations. However, due to uneven station and earthquake distribution, the robustness and global distribution of these features is still controversial. Long period seismic free oscillations, on the other hand, are able to provide global constraints, but lack of appropriate theory has prevented more complicated structures from being studied using normal modes. Thus, many fundamental questions regarding the thermal history of the core and geodynamo remain unanswered. Here, I propose to develop a comprehensive seismic inner core model, employing fully-coupled normal mode theory for the first time and using data from large earthquakes such as the Sumatra-Andaman event of 26 December 2006. This will dramatically change our current ideas of structure in the inner core. Using a novel combination of fluid dynamics and mineral physics I will interpret the thermal and compositional structure found at the centre of our planet, which in turn are fundamental to understand its geodynamo and magnetic field.

1 202 744 €

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

The largest reservoir for nitrogen on earth is the atmosphere that contains 78 percent nitrogen gas. Until now the only known biological process interacting with elemental nitrogen is the bacterial reduction of nitrogen to ammonia for the build up of biomass (nitrogen fixation). This reaction requires energy and is only carried out in the absence of other nitrogen sources, such as ammonia or nitrate. Thermodynamically, the oxidation of nitrogen to nitrate with oxygen releases reasonable amounts of energy, but no bacterium using this redox couple has been known until today. We have isolated a marine bacterium, which is capable of growing in the dark with nitrogen gas as electron donor and oxygen as electron acceptor while forming nitrate. As this microorganism can also use carbondioxide as a carbon source it basically lives of air. While oxidizing atmospheric nitrogen gas the bacterium releases large amounts of nitrate and thereby enhances the amount of fixed nitrogen available for other organisms. At the moment the apparent flux of elemental nitrogen to the ocean by bacterial nitrogen fixation is much smaller than the loss of nitrogen through bacterial denitrification, suggesting that we are missing a major input of nitrogen. This newly discovered physiology of nitrogen oxidation could close this large gap in our understanding of the nitrogen cycle. The amount of biological available nitrogen determines the amount of biomass that can be build up by living organisms. Therefore, it is crucial to know the nitrogen flux into the biosphere, to understand the balances in the carbon cycle. In this project I propose to study this new bacterial physiology in order to understand, which factors control the activity of nitrogen oxidizing bacteria. We need to know how widespread these bacteria are, to estimate their influence on the global nitrogen cycle, and I propose to investigate the interactions between nitrogen oxidizers and other relevant bacteria of the nitrogen cycle.

1 450 673 €

Start date: 2008-07-01, End date: 2013-06-30

Social neuroscientists study the neural mechanisms underlying our capacity to understand our own and other people’s feelings. Despite neuroscientists’ advances in plasticity research and empathy research, little is known about cortical and behavioural plasticity in emotion understanding and empathy. Clearly, in today’s world, acquiring the capacity to effectively enhance empathy and prosocial behaviour is of the utmost importance. In the present project, we will investigate the malleability of empathy via training. We will adopt a multimethod and interdisciplinary approach, combining techniques and paradigms from the fields of neuroscience, (bio-)psychology, and economics. Studies 1-3 will provide a cross-sectional look at structural and functional differences in the brains of individuals scoring high vs. low on empathy, of those with pathological deficits in empathy (psychopaths, alexithymics), and of individuals starting vs. finishing a three-year training program in Carl Rogers’ person-centred therapy, which aims to increase emotional capacity and empathy. Study 4 will examine brain plasticity using real-time fMRI: Participants will learn to self-regulate brain activity through the use of immediate feedback from emotion-related brain areas while practicing certain mental techniques. In Study 5, a small-scale longitudinal study, healthy individuals will receive extensive training by professional instructors in either empathy- or memory-enhancing techniques previously developed in the East and the West. We will measure training-related changes in brain structure and functioning, in hormone levels, and in behaviour. Evidence for emotional brain plasticity in adults and children would not only have important implications for the implementation of scientifically validated, effective training programs for schools and for economic and political organizations, but also for the treatment of the marked social deficits in autistic and psychopathic populations.

1 499 821 €

Start date: 2008-09-01, End date: 2014-08-31

The advantage provided by the increasingly interconnected nature of our world has generated a dangerous by-product: the possibility for rapid worldwide spread of epidemics. The ability to forecast epidemic evolution – as much accurately as we can now do for weather conditions – would be of invaluable help in fighting the emergence or re-emergence of viruses such as SARS, avian influenza, HIV-AIDS, Lyme disease, West Nile virus, or more recently the threat of an influenza pandemic. With the advent of interdisciplinary tools and methods, the latest modeling approaches for the study of the spread and control of infectious diseases witness the emergence of a new area of research – computational epidemiology – that integrates mathematical and statistical epidemiology with computational sciences and informatics tools to conduct scenario analysis in public health domain. While few research groups have begun to use large scale simulations for epidemic modeling, many fundamental theoretical questions are left unanswered. How does the complex nature of real world affect our predictive capabilities in the realm of computational epidemiology? What are the fundamental limits in epidemic evolution predictability with computational modeling? How do they depend on the level of accuracy of our description and knowledge of the state of the system? The present project aims at developing a vigorous research effort along two main directions corresponding to i) the formulation of models for the basic theoretical understanding of multi-scale and agent based approaches and their predictive power; ii) the development of computational approaches and data integration tools that will provide a realistic modeling framework for the analysis of observed epidemic outbreaks and the forecast of patterns of emerging diseases. The ERC Starting Independent Researcher Grant offers an ideal opportunity to start a structured program in this direction, aimed at providing fundamental advances in the field.

684 000 €

Start date: 2008-07-01, End date: 2013-12-31

"Our aim is to built on recent combinatorial and algorithmic progress to attack a series of deeply connected problems that have independantly surfaced in enumerative topology, statistical physics, and data compression. The relation between these problems lies in the notion of ""combinatorial map"", the natural discrete mathematical abstraction of objects with a 2-dimensional structures (like geographical maps, computer graphics' meshes, or 2d manifolds). A whole new set of properties of these maps has been uncovered in the last few years under the impulsion of the principal investigator. Rougly speaking, we have shown that classical graph exploration algorithms, when correctly applied to maps, lead to remarkable decompositions of the underlying surfaces. Our methods resort to algorithmic and enumerative combinatorics. In statistical physics, these decompositions offer an approach to the intrinsec geometry of discrete 2d quantum gravity: our method is here the first to outperform the celebrated ""topological expansion of matrix integrals"" of Brezin-Itzykson-Parisi-Zuber. Exploring its implications for the continuum limit of these random geometries is our great challenge now. From a computational geometry perspective, our approach yields the first encoding schemes with asymptotically optimal garanteed compression rates for the connectivity of triangular or polygonal meshes. These schemes improve on a long series of heuristically efficient but non optimal algorithms, and open the way to optimally compact data structures. Finally we have deep indications that the properties we have uncovered extend to the realm of ramified coverings of the sphere. Intriguing computations on the fundamental Hurwitz's numbers have been obtained using the ELSV formula, famous for its use by Okounkov et al. to rederive Kontsevich's model. We believe that further combinatorial progress here could allow to bypass the formula and obtaine an elementary explanation of these results."

750 000 €

Start date: 2008-07-01, End date: 2013-06-30

Studies about brain maturation aim at providing a better understanding of brain development and links between brain changes and cognitive development. Such studies are of great interest for diagnosis help and clinical course of development and treatment of illnesses. Several teams have begun to make 3D maps of developing brain structures from children to young adults. However, working out the development of fetal and neonatal brain remains an open issue. This project aims at jumping over several theoretical and practical barriers and at going beyond the formal description of the brain maturation thanks to the development of a realistic numerical model of brain aging. In this context, Magnetic Resonance (MR) imaging is a fundamental tool to study structural brain development across age group. We will rely on new image processing tools combining morphological information provided by T2-weighted MR images and diffusion information (degree of myelination and fiber orientation) given by diffusion tensor imaging (DTI). The joint analysis of these anatomical features will stress the generic maturation of normal fetal brain. We will first rely on mathematical models to allow reconstruction of high resolution 3D MR images in order to extract relevant features of brain maturation. The results issued from this first step will be used to build statistical atlases and to characterize the neuroanatomical differences between a reference group and the population under investigation. From a methodological point of view, our approach relies on an interdisciplinary research framework aiming at combining medical research to neuroimaging, image processing, statistical modelling and computer science. The robust characterization of the anatomical features of fetal brain and the development of a realistic model of brain maturation from biological concepts will come out from the strong interactions between these different research fields.

753 393 €

Start date: 2008-09-01, End date: 2013-08-31

We propose the construction and development of a femtosecond broadband stimulated Raman setup to tackle ultra fast chemical, physical and biological processes taking advantage of the top-notch structural sensitivity inherent to the Raman process. The use of a pump-probe stimulated scheme will allow to overcome time-energy restrictions dictated by the uncertainty principle, enabling to reach the femtosecond timescale with energy resolutions which would pertain to the picosecond time domain in the Heisenberg sense. Protein dynamics span several orders of magnitude extending up to macroscopic timescales, the recipes to tailor properties of rubbers and polymers relevant for human timescales are covered by more than 500000 patents, rust reaction occurs over several days, and lethal brain strokes often lead to death within 24 hours on average. The lowest hierarchical level of such processes, however, is hidden in the very act of atomic motion and chemical binding such as the single bond dynamics in a peptide backbone, the monomer cross-linking elemental reactions, the energy flow and re-distribution in a hydrogen bond network, or the oxygen binding to heme proteins, all performing on the femtosecond stage. Mastering these processes is the essence of femtochemistry, born around the backbone of the femtosecond laser technology and boosted by scientific activity which led to the Nobel prize of Prof. A. Zewail in 1999. The new capabilities offered by femtosecond sources have often left behind in the race traditional spectroscopies, which hardly follow the growing emergence of new challenging problems in which the traditional distinction between biology, chemistry and physics is smeared out by the common ultra short timescale. The set up of a non conventional femtosecond Raman technique will be the initiating event for the establishment of a research group of interdisciplinary nature toiling over unsolved problems in which the ultrafast facet plays a key role.

1 544 400 €

Start date: 2008-09-01, End date: 2013-08-31

A fundamental but unexplored problem in biology is whether and how enzymes use mechanical strain during their functioning. It is now evident that the knowledge of atomic structures and chemical interactions is not sufficient to understand the intricate mechanisms underlying enzyme specificity and efficiency. Several lines of evidence suggest that mechanical effects play crucial roles in enzyme activity. Therefore we aim to create detailed force maps that reveal how the intramolecular distribution of mechanical strains changes during the enzyme cycle and how these rearrangements drive the enzyme processes. The applicability of current nanotechniques for the investigation of this problem is limited because they do not allow simultaneous measurement of mechanical and enzymatic parameters. Thus we seek to open new avenues of research by developing site-specific sensors and passive or photoinducible molecular springs to measure force-dependent chemical/structural changes with high spatiotemporal resolution in myosin. Since force perturbations occur very rapidly, we are able to combine experimental studies with quasi-realistic in silico simulations to describe the physical background of enzyme function. We expect that our research will yield fundamental insights into the role of intramolecular strains in enzymes and thus greatly aid the design and control of enzyme processes (specificity, activity, regulation). Our studies may also lead to new paradigms in the understanding of motor systems.

750 000 €

Start date: 2008-09-01, End date: 2014-08-31

Fiber-top sensors (D. Iannuzzi et al., patent application number PCT/NL2005/000816) are a new generation of miniaturized devices obtained by carving tiny movable structures directly on the cleaved edge of an optical fiber. The light coupled into the fiber allows measurements of the position of the micromechanical parts with sub-nanometer accuracy. The monolithic structure of the device, the absence of electronic contacts on the sensing head, and the simplicity of the working principle offer unprecedented opportunities for the development of scientific instruments for applications in and outside research laboratories. For example, a fiber-top scanning probe microscope (also in the form of a PenFM, where a fiber-top atomic force microscope would be incorporated in a pen-like stylus) could be routinely used in harsh environments and could be easily handled by untrained personnel or through remote control systems – a fascinating perspective for utilization, among others, in surgery rooms and space missions. Similarly, the development of fiber-top biochemical sensors could be exploited for the implementation of portable equipment for in vivo and Point of Care medical testing. Fiber-top sensors could be used for the measurement of parameters of medical relevance in interstitial fluid or in blood – an interesting opportunity for intensive care monitoring and early detection of life-threatening diseases. This scenario calls for a coordinated research program dedicated to this novel generation of devices. It is my intention to forge a laboratory gravitating around fiber-top technology. My group will have the opportunity to pioneer this research area and to become the reference point in the field, on the forefront of an emerging subject that might represent a major breakthrough in the future development of micromachined sensors.

1 799 915 €

Start date: 2008-06-01, End date: 2013-05-31

Gadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in &gt;50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.

1 755 805 €

Start date: 2008-09-01, End date: 2014-08-31

The proposed research contains two main directions in group theory and geometry: Independence of Group Elements and Geometric Rigidity. The first consists of problems related to the existence of free subgroups, uniform and effective ways of producing such, and analogous questions for finite groups where the analog of independent elements are elements for which the Cayley graph has a large girth, or non-small expanding constant. This line of research began almost a century ago and contains many important works including works of Hausdorff, Banach and Tarski on paradoxical decompositions, works of Margulis, Sullivan and Drinfeld on the Banach-Ruziewicz problem, the classical Tits Alternative, Margulis-Soifer result on maximal subgroups, the recent works of Eskin-Mozes-Oh and Bourgain-Gamburd, etc. Among the famous questions is Milnor's problem on the exponential verses polynomial growth for f.p. groups, originally stated for f.g. groups but reformulated after Grigorchuk's counterexample. Related works of the PI includes a joint work with Breuillard on the topological Tits alternative, where several well known conjectures were solved, e.g. the foliated version of Milnor's problem conjectured by Carriere, and on the uniform Tits alternative which significantly improved Tits' and EMO theorems. A joint work with Glasner on primitive groups where in particular a conjecture of Higman and Neumann was solved. A paper on the deformation varieties where a conjecture of Margulis and Soifer and a conjecture of Goldman were proved. The second involves extensions of Margulis' and Mostow's rigidity theorems to actions of lattices in general topological groups on metric spaces, and extensions of Kazhdan's property (T) for group actions on Banach and metric spaces. This area is very active today. Related work of the PI includes his joint work with Karlsson and Margulis on generalized harmonic maps, and his joint work with Bader, Furman and Monod on actions on Banach spaces.

750 000 €

Start date: 2008-07-01, End date: 2013-12-31

How ecology shapes genomes is a key question to be addressed in the postgenomic era. A leading theory states that species evolve as groups of genomes adapting to particular ecological niches. Thus, shifts to a new ecological niche should be connected to genome divergence, and ultimately to the making of new species. So far we know little on how ecological adaptation affects genomes, because of the difficulty of simultaneously studying evolution at both ecological and whole genome levels. Insect viruses are ideally suited to study this question because their ecological niches are defined by their hosts and because of the nature of their genomes. The transmission of baculoviruses as groups of genomes sets them apart for studying the effect of niches on populations. Their molecular biology is also well understood, which makes them ideal to investigating the genetic and functional details of adaptation. They are thus unique for linking genome changes to ecological changes. Polydnaviruses have extraordinary genomes, domesticated by wasps to deliver molecular weapons to fight the immunity of their Lepidoptera hosts. Sequencing polydnavirus genomes therefore opens windows to understanding mutualism and how parasitic wasps have adapted to different hosts. Lastly, the diversity of insect viruses provides an exceptional opportunity to examine if different evolutionary lineages have converged toward similar genomic solutions to respond to similar immunity and why some lineages have diversified more than others. Studying virus adaptation to the immunity of different insect species will reveal how viral genomes have been shaped by the ecological niches of their host immunity. At the frontier of ecology and genomics GENOVIR, takes on the challenge of studying ecological adaptation at the level of whole genomes. The innovative application of cutting-edge molecular and genomic techniques to the interface with ecology will transform our understanding of evolution.

1 000 000 €

Start date: 2008-10-01, End date: 2014-06-30

Memory (i.e. the ability to store and retrieve information) plays a crucial role in the development of an animal’s behavior within its lifespan and is often important for its survival and reproductive success. Memory is itself a product of evolution and the degree to which information is maintained in the brain varies among species and among different types of behavior. Findings from vertebrate behavioral pharmacology have challenged the traditional view of memory formation as a direct flow from short-term to long-term storage. Evidence points instead to an intricate, multiphase pathway of memory consolidation. Different components of memory emerge at different times after the event to be memorized takes place. In addition, their duration and times of onset can vary with different tasks and species If variations in memory capacities have been observed among closely-related species, the relationship between environmental conditions and evolution of these capacities have only been rarely studied despite the importance of this topic in the understanding of the evolution of behavior. I propose an experimental approach using Drosophila as a model system. This project concentrates on: Part 1: Genetic variation of the memory phases Part 2: Effect of the environmental conditions on the development of memory Part 3: fitness cost of memory Part 4: Consolidation, Reconsolidation and Extinction: similar or separate processes?

534 000 €

Start date: 2008-09-01, End date: 2011-08-31

Computer vision concerns itself with understanding the real world through the analysis of images. Typical problems are object recognition, medical image segmentation, geometric reconstruction problems and navigation of autonomous vehicles. Such problems often lead to complicated optimization problems with a mixture of discrete and continuous variables, or even infinite dimensional variables in terms of curves and surfaces. Today, state-of-the-art in solving these problems generally relies on heuristic methods that generate only local optima of various qualities. During the last few years, work by the applicant, co-workers, and others has opened new possibilities. This research project builds on this. We will in this project focus on developing new global optimization methods for computing high-quality solutions for a broad class of problems. A guiding principle will be to relax the original, complicated problem to an approximate, simpler one to which globally optimal solutions can more easily be computed. Technically, this relaxed problem often is convex. A crucial point in this approach is to estimate the quality of the exact solution of the approximate problem compared to the (unknown) global optimum of the original problem. Preliminary results have been well received by the research community and we now wish to extend this work to more difficult and more general problem settings, resulting in thorough re-examination of algorithms used widely in different and trans-disciplinary fields. This project is to be considered as a basic research project with relevance to industry. The expected outcome is new knowledge spread to a wide community through scientific papers published at international journals and conferences as well as publicly available software.

1 440 000 €

Start date: 2008-07-01, End date: 2013-06-30

"3D geometric objects play a central role in many industrial processes (modeling, scientific visualisation, numerical simulation). However, since the raw output of acquisition mechanisms cannot be used directly in these processes, converting a real object into its numerical counterpart still involves a great deal of user intervention. Geometry Processing is a recently emerged, highly competitive scientific domain that studies this type of problems. The author of this proposal contributed to this domain at its origin, and developped several parameterization algorithms, that construct a ""geometric coordinate system"" attached to the object. This facilitates converting from one representation to another. For instance, it is possible to convert a mesh model into a piecewise bi-cubic surface (much easier to manipulate in Computer Aided Design packages). In a certain sense, this retreives an ""equation"" of the geometry. One can also say that this constructs an *abstraction* of the geometry. Once the geometry is abstracted, re-instancing it into alternative representations is made easier. In this project, we propose to attack the problem from a new angle, and climb one more level of abstraction. In more general terms, a geometric coordinates system corresponds to a *function basis*. Thus, we consider the more general problem of constructing a *dynamic function basis* attached to the object. This abstract forms makes the meaningful parameters appear, and provides the user with new ""knobs"" to interact with the geometry. The formalism that we use combines aspects from finite element modeling, differential geometry, spectral geometry, topology and numerical optimization. We plan to develop applications for processing and optimimizing the representation of both static 3D objets, animated 3D objets, images and videos."

1 100 000 €

Start date: 2008-08-01, End date: 2013-07-31

Two key variables, temperature and atmospheric carbon dioxide (pCO2), define the sensitivity of the Earth’s climate system. The geological record provides our only evidence of the past climate sensitivity of the Earth system, but there is no direct quantitative measure of pCO2 or temperature beyond the 650 kyr extent of the Antarctic ice cores. The reconstruction of past climate, on timescales of millions of years, relies on the analysis of chemical or isotopic proxies in preserved shells or organic matter. Such indirect approaches depend upon empirical calibration in modern species, without understanding the biological mechanisms that underpin the incorporation of the climate signal. The intention of this ERC grant proposal is to establish a research team to investigate the “living geological record” to address this major gap in climate research. I hypothesise that direct climate signals of the past are harboured within, and can ultimately be deciphered from, the genetic make up of extant organisms. Specifically, I propose an innovative approach to the constraint of the evolution of atmospheric pCO2 during the Cenozoic. The approach is based on the statistical signal of positive selection of adaptation within the genetic sequences of marine algal Rubisco, the notoriously inefficient enzyme responsible for photosynthetic carbon fixation, but supplemented by analysis of allied carbon concentrating mechanisms. As a calibration, I will characterise the biochemical properties of Rubisco in terms of specificity for pCO2, isotopic fractionation and kinetics, from a range of marine phytoplankton. The prime motivation is a history of pCO2, but the project will yield additional insight into the feedback between phytoplankton and climate, the carbon isotopic signatures of the geological record and the mechanistic link between genetic encoding and specific

1 652 907 €

Start date: 2008-09-01, End date: 2015-08-31

Acute Respiratory Distress Syndrome and Acute Lung Injury [ALI/ARDS] are devastating diseases, causing over 20,000 deaths annually in the US. Mechanical ventilation may worsen ALI/ARDS, a process termed Ventilator Induced Lung Injury [VILI]. Hypercapnic acidosis (HA) is a central component of lung ventilatory strategies to minimize VILI, and is a potent biologic agent, exerting a myriad of effects on diverse biologic pathways. Deliberately induced HA is protective in multiple lung injury models. However, HA may inhibit the host response to bacterial sepsis. Furthermore, HA may retard the repair process and slow recovery following ALI/ARDS. Hence, the diverse biologic actions of HA may result in net beneficial – or deleterious – effects depending on the specific context. An alternative approach is to manipulate a single key effector pathway, central to the protective effects of HA, which would also be effective in patients in whom hypercapnia is contra-indicated. Hypercapnia attenuates NF-kB activation, and may exert its effects – both beneficial and deleterious – via this mechanism. NF-kB is a pivotal regulator of the pro-inflammatory response, but is also a key epithelial cytoprotectant. Selective modulation of the NF-kB pathway, at the pulmonary epithelial surface, may accentuate the beneficial effects of HA on injury but minimize the potential for delayed tissue repair. We will investigate the contribution of NF-kB to the effects of HA, and characterize the direct effects modulation of NF-kB, in both in vitro and preclinical models of lung injury and repair. We will utilize pulmonary gene therapy, which facilitates delivery of high quantities of the therapeutic agent directly to the injury site, to maximize the potential for therapeutic benefit. These studies will provide novel insights into: key pathways contributing to lung injury and to repair; the role of HA and NF-kB in these processes; and the potential of pulmonary gene therapy in ALI/ARDS.

1 052 556 €

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

Growth and development of plants are regulated by signalling substances such as hormones. In plants, interactions between hormonal pathways represent crucial factors that govern their action. As the molecular basis for such hormonal cross-talk remains largely unknown, we will investigate the underlying mechanisms with a special focus on regulation of postembryonic organogenesis. We consider lateral root formation in Arabidopsis as an ideally suited model system, because it encompasses fundamental aspects of plant growth and development, such as dedifferentiation, re-entry into the cell cycle, coordinated cell divisions and differentiation. Furthermore, in lateral root formation, these processes are controlled by multiple hormonal pathways. In our proposal, we will focus on four main research directions. 1. Convergence of hormonal pathways on transport-dependent auxin distribution upstream of lateral root formation. Here, we want to identify key points in which auxin and other signalling pathways converge during lateral root formation and the molecular components involved in the process. 2. Role of auxin-cytokinin interaction in lateral root formation. Molecular events involved in auxin-cytokinin regulated lateral root formation will be studied by transcriptome analysis. 3. Identification of components of hormonal cross-talk by genetic approaches. Using lateral root formation as a model, we will perform mutant screens that will specifically target interactions between selected hormonal pathways. The spectrum of identified molecular components will be further expanded by a chemical genomics approach. 4. Formulation of general models for hormonal regulation of organogenesis. The acquired knowledge on molecular networks and their mutual interactions will be used to mathematically model lateral root development and to extrapolate them also on other developmental situations.

1 300 000 €

Start date: 2008-07-01, End date: 2014-03-31

Even today, quantum chemical calculations with experimental accuracy are only feasible for small molecules. This statement is especially true if the considered molecule is far from the equilibrium structure, where the overwhelming majority of quantum chemical models break down. The main purpose of this proposal is to develop new quantum chemical methods that are applicable to at least medium-sized molecules and simultaneously provide results sufficiently close to the experimental data and are capable of describing entire potential energy surfaces. The accuracy goal will be achieved through the reduction of the computational cost of high-precision quantum chemical calculations, which are currently practical for molecules of up to 15 atoms. The cost reduction will be accomplished principally by decreasing the number of numerical parameters to be optimized without sacrificing accuracy. To this end, the negligible parameters will be identified and dropped by adopting the corresponding techniques of computer science. The correct behavior of the models for distorted structures will be ensured by developing new approaches that use a linear combination of functions rather than a single function as a starting point for the description of electronic states. Since the programming work associated with the implementation of the proposed schemes is very complex, the project will rely on the automated programming tools previously developed by the proposer. In addition to the outlined challenging tasks, the proposal aims to implement several more straightforward objectives. In particular, the high-accuracy calculations will be extended to molecular properties that are presently not available. Furthermore, the developed methods will be applied to real-life problems, especially in the field of spectroscopy and atmospheric chemistry.

500 000 €

Start date: 2008-07-01, End date: 2013-06-30

In a truly cross-disciplinary research project encompassing surface science, astrophysics and chemistry we aim to address two of the major outstanding questions in the field of astrochemistry, namely i) how molecular hydrogen, the most abundant molecule in the interstellar medium, form, and ii) whether it is possible to identify specific Polycyclic Aromatic Hydrocarbon (PAH) species in interstellar spectra. The insights gained from the experimental investigations may revolutionize our current understanding of astrochemistry and will have impact even beyond the field. Special emphasis will be placed on the impact our findings will have on ascertaining the suitability of PAHs as a hydrogen storage medium. By combining scanning tunneling microscopy, thermal desorption spectroscopy, laser-induced thermal desorption time-of-flight mass spectrometry, fluorescence spectroscopy experiments and density functional theory calculations we will map out the interaction of atomic hydrogen with PAHs. The goal of the investigation is to obtain atomic level understanding of the atomic hydrogen – PAH interaction in order to i) ascertain whether interstellar molecular hydrogen formation, contrary to present belief but in accordance with our recent calculations, could occur predominantly via interaction with PAHs, ii) measure the adsorption/emission spectrum of Hydrogen-PAH complexes and thereby facilitate observational detection of these complexes in the interstellar medium, iii) determine whether PAHs are a promising medium for hydrogen storage and iv) ascertain whether the hydrogen storage properties of PAHs are tunable by electro-magnetic radiation. This ambitious and cross-disciplinary research project will predominantly take place at the newly established Surface Dynamics Laboratory at the University of Aarhus, headed by the applicant, but will also benefit from fruitful collaborations already initiated with local, national and international colleagues.

1 499 810 €

Start date: 2008-07-01, End date: 2013-06-30