ERC FUNDED PROJECTS

Several observed anomalies in neutrino oscillation data can be explained by a hypothetical fourth neutrino separated from the three standard neutrinos by a squared mass difference of a few eV2. This hypothesis can be tested with a PBq (ten kilocurie scale) 144Ce antineutrino beta-source deployed at the center of a large low background liquid scintillator detector, such like Borexino, KamLAND, and SNO+. In particular, the compact size of such a source could yield an energy-dependent oscillating pattern in event spatial distribution that would unambiguously determine neutrino mass differences and mixing angles. The proposed program aims to perform the necessary research and developments to produce and deploy an intense antineutrino source in a large liquid scintillator detector. Our program will address the definition of the production process of the neutrino source as well as its experimental characterization, the detailed physics simulation of both signal and backgrounds, the complete design and the realization of the thick shielding, the preparation of the interfaces with the antineutrino detector, including the safety and security aspects.

1 500 000 €

Start date: 2012-10-01, End date: 2018-09-30

We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.

1 499 930 €

Start date: 2013-09-01, End date: 2018-08-31

Rapid changes in ocean circulation and climate have been observed in marine sediment and ice cores, notably over the last 60 thousand years (ky), highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. Two main obstacles prevent going beyond the current state of knowledge: - Paleoclimatic proxy data are by essence only indirect indicators of the climatic variables, and thus can not be directly compared with model outputs; - A 4-D (latitude, longitude, water depth, time) reconstruction of Atlantic water masses over the past 40 ky is lacking: previous studies have generated isolated records with disparate timescales which do not allow the causes of circulation changes to be identified. Overcoming these two major limitations will lead to major breakthroughs in climate research. Concretely, I will create the first database of Atlantic deep-sea records over the last 40 ky, and extract full climatic information from these records through an innovative model-data integration scheme using an isotopic proxy forward modeling approach. The novelty and exceptional potential of this scheme is twofold: (i) it avoids hypotheses on proxy interpretation and hence suppresses or strongly reduces the errors of interpretation of paleoclimatic records; (ii) it produces states of the climate system that best explain the observations over the last 40 ky, while being consistent with the model physics. Expected results include: • The elucidation of the mechanisms explaining rapid changes in ocean circulation and climate over the last 40 ky, • Improved climate model physics and parameterizations, • The first projections of future climate changes obtained with a model able to reproduce the highly non linear behavior of the climate system observed over the last 40 ky.

3 000 000 €

Start date: 2014-02-01, End date: 2019-01-31

Actanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action). Actions take place in the physical space while they originate in the –robot or human– sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence: - Motion segmentation: what are the sub-manifolds that define the structure of a given action? - Motion generation: among all the solution paths within a given sub-manifold, what is the underlying law that makes the selection? In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action. A unique “Anthropomorphic Action Factory” supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.

2 500 000 €

Start date: 2014-01-01, End date: 2018-12-31

"Computer vision is concerned with the automated interpretation of images and video streams. Today's research is (mostly) aimed at answering queries such as ""Is this a picture of a dog?"", (classification) or sometimes ""Find the dog in this photo"" (detection). While categorisation and detection are useful for many tasks, inferring correct class labels is not the final answer to visual recognition. The categories and locations of objects do not provide direct understanding of their function i.e., how things work, what they can be used for, or how they can act and react. Such an understanding, however, would be highly desirable to answer currently unsolvable queries such as ""Am I in danger?"" or ""What can happen in this scene?"". Solving such queries is the aim of this proposal. My goal is to uncover the functional properties of objects and the purpose of actions by addressing visual recognition from a different and yet unexplored perspective. The main novelty of this proposal is to leverage observations of people, i.e., their actions and interactions to automatically learn the use, the purpose and the function of objects and scenes from visual data. The project is timely as it builds upon the two key recent technological advances: (a) the immense progress in visual recognition of objects, scenes and human actions achieved in the last ten years, as well as (b) the emergence of a massive amount of public image and video data now available to train visual models. ACTIVIA addresses fundamental research issues in automated interpretation of dynamic visual scenes, but its results are expected to serve as a basis for ground-breaking technological advances in practical applications. The recognition of functional properties and intentions as explored in this project will directly support high-impact applications such as detection of abnormal events, which are likely to revolutionise today's approaches to crime protection, hazard prevention, elderly care, and many others."

1 497 420 €

Start date: 2013-01-01, End date: 2018-12-31

"During the twentieth century, the development of macroscopic engineering has been largely stimulated by progress in digital prototyping: cars, planes, boats, etc. are nowadays designed and tested on computers. Digital prototypes have progressively replaced actual ones, and effective computer-aided engineering tools have helped cut costs and reduce production cycles of these macroscopic systems. The twenty-first century is most likely to see a similar development at the atomic scale. Indeed, the recent years have seen tremendous progress in nanotechnology - in particular in the ability to control matter at the atomic scale. Similar to what has happened with macroscopic engineering, powerful and generic computational tools will be needed to engineer complex nanosystems, through modeling and simulation. As a result, a major challenge is to develop efficient simulation methods and algorithms. NANO-D, the INRIA research group I started in January 2008 in Grenoble, France, aims at developing efficient computational methods for modeling and simulating complex nanosystems, both natural and artificial. In particular, NANO-D develops SAMSON, a software application which gathers all algorithms designed by the group and its collaborators (SAMSON: Software for Adaptive Modeling and Simulation Of Nanosystems). In this project, I propose to develop a unified theory, and associated algorithms, for adaptive particle simulation. The proposed theory will avoid problems that plague current popular multi-scale or hybrid simulation approaches by simulating a single potential throughout the system, while allowing users to finely trade precision for computational speed. I believe the full development of the adaptive particle simulation theory will have an important impact on current modeling and simulation practices, and will enable practical design of complex nanosystems on desktop computers, which should significantly boost the emergence of generic nano-engineering."

1 476 882 €

Start date: 2012-09-01, End date: 2017-08-31

AMPA glutamate receptors (AMPAR) play key roles in information processing by the brain as they mediate nearly all fast excitatory synaptic transmission. Their spatio-temporal organization in the post synapse with respect to presynaptic glutamate release sites is a key determinant in synaptic transmission. The activity-dependent regulation of AMPAR organization is at the heart of synaptic plasticity processes underlying learning and memory. Dysfunction of synaptic transmission - hence AMPAR organization - is likely at the origin of a number of brain diseases. Building on discoveries made during my past ERC grant, our new ground-breaking objective is to uncover the mechanisms that link synaptic transmission with the dynamic organization of AMPAR and associated proteins. For this aim, we have assembled a team of neurobiologists, computer scientists and chemists with a track record of collaboration. We will combine physiology, cellular and molecular neurobiology with development of novel quantitative imaging and biomolecular tools to probe the molecular dynamics that regulate synaptic transmission. Live high content 3D SuperResolution Light Imaging (SRLI) combined with electron microscopy will allow unprecedented visualization of AMPAR organization in synapses at the scale of individual subunits up to the level of intact tissue. Simultaneous SRLI and electrophysiology will elucidate the intricate relations between dynamic AMPAR organization, trafficking and synaptic transmission. Novel peptide- and small protein-based probes used as protein-protein interaction reporters and modulators will be developed to image and directly interfere with synapse organization. We will identify new processes that are fundamental to activity dependent modifications of synaptic transmission. We will apply the above findings to understand the causes of early cognitive deficits in models of neurodegenerative disorders and open new avenues of research for innovative therapies.

2 491 157 €

Start date: 2014-02-01, End date: 2019-01-31

The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans. This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.

1 472 690 €

Start date: 2013-09-01, End date: 2018-08-31

"In our largely unchanging radio Universe, a highly dynamic component was recently discovered: flashes of bright radio emission that last only milliseconds but appear all over the sky. Some of these radio bursts can be traced to intermittently pulsating neutron stars. Other bursts however, apparently originate far outside our Galaxy. Due to great observational challenges, the evolution of the neutron stars is not understood, while more importantly, the nature of the extragalactic bursts remains an outright mystery. My overall aim is to understand the physics that drives both kinds of brief and luminous bursts. My primary goal is to identify the highly compact astrophysical explosions powering the extragalactic bursts. My previous surveys are the state of the art in fast-transient detection; I will now increase by a factor of 10 this exploration volume. In real-time I will provide arcsec positions, 10,000-fold more accurate than currently possible, to localize such extragalactic bursts for the first time and understand their origin. My secondary goal is to unravel the unexplained evolution of intermittently pulsating neutron stars (building on e.g., my recent papers in Science, 2013), by doubling their number and modeling their population. To achieve these goals, I will carry out a highly innovative survey: the Apertif-LOFAR Exploration of the Radio Transient Sky. ALERT is over an order of magnitude more sensitive than all current state-of-the art fast-transient surveys. Through its novel, extremely wide field-of-view, Westerbork/Apertif will detect many tens of extragalactic bursts. Through real-time triggers to LOFAR I will next provide the precise localisation that is essential for radio, optical and high-energy follow-up to, for the first time, shed light on the physics and objects driving these bursts – evaporating primordial black holes; explosions in host galaxies; or, the unknown?"

1 999 823 €

Start date: 2014-12-01, End date: 2019-11-30

The goal of this PoC proposal is to boost the creation of a start-up (AllYours) targeting both Internet users as well as small to medium companies (SME) offering full-fledged personalization in notification systems. The Web is now all about users; they are the greediest bandwidth consumers, the ultimate deciders of which applications are actually adopted and also the most prolific content generators. While social networks have taken off at an unexpected scale and speed, Web navigation has radically changed to the point that notification is taking over search: many users now navigate through the links they discover rather than explicit search operations. Yet, users get quickly overwhelmed with the huge amount of information in a click range. For such notification systems to be truly useful, they should be personalized depending on the user activity, operations, posts, interests. Yet, personalization poses several issues such as scalability (it is expensive to store a large amount of information per user) and privacy (users are more and more reluctant to give away their preferences to large companies). At the same time, SMEs are struggling to provide fully personalized services given the expertise and amount of resources such algorithms require. AllYours is an implicit instant item recommender providing personalization in the notification process without requiring explicit subscriptions to feeds or interests. They only let the system know whether they like the items received or not (eg like/dislike button). In addition, users personal data are stored on their own machine, leaving the space to provide a wide spectrum of privacy guarantees while enabling cross application benefits. Behind the scene, AllYours provides each user with a live social network of participants sharing similar interests, called an implicit social network. AllYours come in two different flavors: (1) Enterprise-AllYours provides a scalable notification and recommendation system targeting all SMEs operating Web content editors & ecommerce sites (2) P2P-AllYours provides a fully decentralized solution without requiring users to ever reveal their private preferences through a clever obfuscation mechanism.

149 236 €

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

Malaria parasite infection in humans has been called “the strongest known force for evolutionary selection in the recent history of the human genome”, and I hypothesize that a similar statement may apply to the mosquito vector, which is the definitive host of the malaria parasite. We previously discovered efficient malaria-resistance mechanisms in natural populations of the African malaria vector, Anopheles gambiae. Aim 1 of the proposed project will implement a novel genetic mapping design to systematically survey the mosquito population for common and rare genetic variants of strong effect against the human malaria parasite, Plasmodium falciparum. A product of the mapping design will be living mosquito families carrying the resistance loci. Aim 2 will use the segregating families to functionally dissect the underlying molecular mechanisms controlled by the loci, including determination of the pathogen specificity spectra of the host-defense traits. Aim 3 targets arbovirus transmission, where Anopheles mosquitoes transmit human malaria but not arboviruses such as Dengue and Chikungunya, even though the two mosquitoes bite the same people and are exposed to the same pathogens, often in malaria-arbovirus co-infections. We will use deep-sequencing to detect processing of the arbovirus dsRNA intermediates of replication produced by the RNAi pathway of the mosquitoes. The results will reveal important new information about differences in the efficiency and quality of the RNAi response between mosquitoes, which is likely to underlie at least part of the host specificity of arbovirus transmission. The 3 Aims will make significant contributions to understanding malaria and arbovirus transmission, major global public health problems, will aid the development of a next generation of vector surveillance and control tools, and will produce a definitive description of the major genetic factors influencing host-pathogen interactions in mosquito immunity.

2 307 800 €

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

"In plants, receptor kinases form the largest family of plasma membrane (PM) receptors and they are involved in virtually all aspects of the plant life, including development, immunity and reproduction. In animals, key molecules that orchestrate the recruitment of signaling proteins to membranes are anionic phospholipids (e.g. phosphatidylinositol phosphate or PIPs). Besides, recent reports in animal and yeast cells suggest the existence of PM nanodomains that are independent of cholesterol and lipid phase and rely on anionic phospholipids as well as electrostatic protein/lipid interactions. Strikingly, we know very little on the role of anionic phospholipids in plant signaling. However, our preliminary data suggest that BKI1, an inhibitory protein of the steroid receptor kinase BRI1, interacts with various PIPs in vitro and is likely targeted to the PM by electrostatic interactions with these anionic lipids. These results open the possibility that BRI1, but also other receptor kinases, might be regulated by anionic phospholipids in plants. Here, we propose to analyze the function of anionic phospholipids in BRI1 signaling, using the root epidermis as a model system. First, we will ask what are the lipids that control membrane surface charge in this tissue and recruit BR-signaling component to the PM. Second, we will probe the presence of PIP-enriched nanodomains at the plant PM using super-resolution microscopy techniques and investigate the roles of these domains in BRI1 signaling. Finally, we will analyze the function of the BKI1-related plant-specific family of anionic phospholipid effectors in plant development. In summary, using a transversal approach ranging from in vitro studies to in vivo validation and whole organism physiology, this work will unravel the interplay between anionic phospholipids and receptor signaling in plants."

1 797 840 €

Start date: 2014-02-01, End date: 2019-01-31

Quantum Chaos is an emerging discipline which is crossing over from Physics into Pure Mathematics. The recent crossover is driven in part by a connection with Number Theory. This project explores several aspects of this interrelationship and is composed of a number of sub-projects. The sub-projects deal with: statistics of energy levels and wave functions of pseudo-integrable systems, a hitherto unexplored subject in the mathematical community which is not well understood in the physics community; with statistics of zeros of zeta functions over function fields, a purely number theoretic topic which is linked to the subproject on Quantum Chaos through the mysterious connections to Random Matrix Theory and an analogy between energy levels and zeta zeros; and with spatial statistics in arithmetic.

1 714 000 €

Start date: 2013-02-01, End date: 2019-01-31

Knowledge of the state of the Earth mantle and its temporal evolution is fundamental to a variety of disciplines in Earth Sciences, from the internal dynamics to its many expressions in the geological record (postglacial rebound, sea level change, ore deposit, tectonics or geomagnetic reversals). Mantle convection theory is the centerpiece to unravel the present and past state of the mantle. For the past 40 years considerable efforts have been made to improve the quality of numerical models of mantle convection. However, they are still sparsely used to estimate the convective history of the solid Earth, in comparison to ocean or atmospheric models for weather and climate prediction. The main shortcoming is their inability to successfully produce Earth-like seafloor spreading and continental drift self-consistently. Recent convection models have begun to successfully predict these processes (Coltice et al., Science 336, 335-33, 2012). Such breakthrough opens the opportunity to combine high-level data assimilation methodologies and convection models together with advanced tectonic datasets to retrieve Earth's mantle history. The scope of this project is to produce a new generation of tectonic and convection reconstructions, which are key to improve our understanding and knowledge of the evolution of the solid Earth. The development of sustainable high performance numerical models will set new standards for geodynamic data assimilation. The outcome of the AUGURY project will be a new generation of models crucial to a wide variety of disciplines.

1 994 000 €

Start date: 2014-03-01, End date: 2020-02-29

Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.

2 000 000 €

Start date: 2014-03-01, End date: 2019-02-28

NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.

2 499 800 €

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

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

Start date: 2013-10-01, End date: 2018-09-30

Graphene – a one atom thin material – has the potential to act as a sensor, primarily the surface and the edges of graphene. This proposal aims at exploring new biosensing routes by exploiting the unique surface and edge chemistry of graphene.

1 499 996 €

Start date: 2014-05-01, End date: 2019-04-30

The aetiology of many musculoskeletal (MS) diseases is related to biomechanical factors. However, the tools to assess the biomechanical condition of patients used by clinicians and researchers are often crude and subjective leading to non-optimal patient analyses and care. In this project innovations related to imaging, sensor technology and biomechanical modelling are utilized to generate versatile, accurate and objective methods to quantify the (pathological) MS condition of the lower extremity of patients in a unique manner. The project will produce advanced diagnostic, pre-planning and outcome tools which allow clinicians and researchers for detailed biomechanical analysis about abnormal tissue deformations, pathological loading of the joints, abnormal stresses in the hard and soft tissues, and aberrant joint kinematics. The key objectives of this proposal are: 1) Develop and validate image-based 3-D volumetric elastographic diagnostic methods that can quantify normal and pathological conditions under dynamic loading and which can be linked to biomechanical modelling tools. 2) Create an ultrasound (US)-based system to assess internal joint kinematics which can be used as a diagnostic tool for clinicians and researchers and is a validation tool for biomechanical modelling. 3) Generate and validate an ambulant functional (force and kinematic) diagnostic system which is easy to use and which can be used to provide input data for biomechanical models. 4) Create and validate a new modelling approach that integrates muscle-models with finite element models at a highly personalized level. 5) Generate biomechanical models which have personalized mechanical properties of the hard and soft tissues. 6) Demonstrate the applicability of the personalized diagnostic and pre-planning platform by application to healthy individuals and patient subjects. Support from the ERC will open new research fields related to biomechanical patient assessment and modeling of MS pathologies.

2 456 400 €

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

"The ability to apply forces to single molecules and bio-polymers has fundamentally changed the way we can interact with and understand biological systems. Yet, for many cellular mechanisms, it is rather the torque that is the relevant physical parameter. Excitingly, novel single-molecule techniques that utilize this parameter are now poised to contribute to novel discoveries. Here, I will study the angular dynamical behavior and response to external torque of biological systems at the molecular and cellular levels using the new optical torque wrench that I recently developed. In a first research line, I will unravel the angular dynamics of the e.coli flagellar motor, a complex and powerful rotary nano-motor that rotates the flagellum in order to propel the bacterium forwards. I will quantitatively study different aspects of torque generation of the motor, aiming to connect evolutionary, dynamical, and structural principles. In a second research line, I will develop an in-vivo manipulation technique based on the transfer of optical torque and force onto novel nano-fabricated particles. This new scanning method will allow me to map physical properties such as the local viscosity inside living cells and the spatial organization and topography of internal membranes, thereby expanding the capabilities of existing techniques towards in-vivo and ultra-low force scanning imaging. This project is founded on a multidisciplinary approach in which fundamental optics, novel nanoparticle fabrication, and molecular and cellular biology are integrated. It has the potential to answer biophysical questions that have challenged the field for over two decades and to impact fields ranging from single-molecule biophysics to scanning-probe microscopy and nanorheology, provided ERC funding is granted."

1 500 000 €

Start date: 2013-01-01, End date: 2017-12-31

The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.

1 625 000 €

Start date: 2014-01-01, End date: 2018-12-31

Gravity is successfully described by Einstein’s theory of general relativity (GR), governing the structure of our entire universe. Yet it remains the least understood of all forces in nature, resisting unification with quantum physics. One of the most fundamental predictions of GR are black holes (BHs). Their defining feature is the event horizon, the surface that light cannot escape and where time and space exchange their nature. However, while there are many convincing BH candidates in the universe, there is no experimental proof for the existence of an event horizon yet. So, does GR really hold in its most extreme limit? Do BHs exist or are alternatives needed? Here we propose to build a Black Hole Camera that for the first time will take an actual picture of a BH and image the shadow of its event horizon. We will do this by providing the equipment and software needed to turn a network of existing mm-wave radio telescopes into a global interferometer. This virtual telescope, when supplemented with the new Atacama Large Millimetre Array (ALMA), has the power to finally resolve the supermassive BH in the centre of our Milky Way – the best-measured BH candidate we know of. In order to compare the image with the theoretical predictions we will need to perform numerical modelling and ray tracing in GR and alternative theories. In addition, we will need to determine accurately the two basic parameters of the BH: its mass and spin. This will become possible by precisely measuring orbits of stars with optical interferometry on ESO’s VLTI. Moreover, our equipment at ALMA will allow for the first detection of pulsars around the BH. Already a single pulsar will independently determine the BH’s mass to one part in a million and its spin to a few per cent. This unique combination will not only produce the first-ever image of a BH, but also turn our Galactic Centre into a fundamental-physics laboratory to measure the fabric of space and time with unprecedented precision.

13 975 744 €

Start date: 2014-10-01, End date: 2020-09-30

Mindfulness-based therapy has become an increasingly popular treatment to reduce stress, increase well-being and prevent relapse in depression. A key component of these therapies includes mindfulness practice that intends to train attention to detect and regulate afflictive cognitive and emotional patterns. Beyond its therapeutic application, the empirical study of mindfulness practice also represents a promising tool to understand practices that intentionally cultivate present-centeredness and openness to experience. Despite its clinical efficacy, little remains known about its means of action. Antithetic to this mode of experiential self-focus are states akin to depression, that are conducive of biased attention toward negativity, biased thoughts and rumination, and dysfunctional self schemas. The proposed research aims at implementing an innovative framework to scientifically investigate the experiential, cognitive, and neural processes underlining mindfulness practice building on the current neurocognitive understanding of the functional and anatomical architecture of cognitive control, and depression. To identify these mechanisms, this project aims to use paradigms from cognitive, and affective neuroscience (MEG, intracortical EEG, fMRI) to measure the training and plasticity of emotion regulation and cognitive control, and their effect on automatic, self-related affective processes. Using a cross-sectional design, this project aims to compare participants with trait differences in experiential self-focus mode. Using a longitudinal design, this project aims to explore mindfulness-practice training’s effect using a standard mindfulness-based intervention and an active control intervention. The PI has pioneered the neuroscientific investigation of mindfulness in the US and aspires to assemble a research team in France and a network of collaborators in Europe to pursue this research, which could lead to important outcomes for neuroscience, and mental health.

1 868 520 €

Start date: 2014-11-01, End date: 2019-10-31

My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.

1 499 900 €

Start date: 2013-09-01, End date: 2018-08-31

Microfluidic techniques developed since the year 2000 have now matured to provide a unique tool to produce large amounts of microbubbles that are not only finely tuned in size, but that can also be embedded in tiny microfabricated structures. In the present proposal, we plan to take advantage of these novel microfabrication techniques to develop two innovative acoustic applications. These applications, which were out of reach without current techniques, are based on the use of microbubbles with a huge acoustic resonance. The project is structured in two parts that only differ in the way bubbles are embedded in microfluidic environments: 1) Arrays of bubbles: Acoustic Laser This first part is the development of an acoustic laser, based on microbubbles trapped in a microfluidic circuit. To obtain the conditions for an acoustic laser, arrays of microbubbles will be designed so that they bubbles pulsate in phase, reemitting their energy coherently. The applications are novel systems for high ultrasonic emission power, or meta-materials that store vibration energy. 2) Mobile “armoured” bubbles: swimming micro-robots remotely powered by ultrasound The second part is the conception of ultrasonically activated microswimming devices, with microbubbles embedded within freely moving objects. Their application is to behave as carriers, such as drug carriers, activated at a distance, or to be active tracers that enhance mixing. Microswimmers are mechanical analogues to RFID devices (where electromagnetic vibration is converted into current), here sound is converted into motion at small scales. Both parts include the same three complementary steps: step 1 is the 3D microfabrication of the geometry where bubbles are embedded, step 2 is their ultrasonic activation, and then step 3 is the optimisation of their resonance by a study of individual resonators.

1 856 542 €

Start date: 2014-04-01, End date: 2019-03-31

Some of the primary questions in extragalactic astronomy concern the formation and evolution of galaxies in the distant Universe. In particular, little is known about the less luminous (and therefore less massive) galaxy populations, which are currently missed from large observing surveys and could contribute significantly to the overall star formation happening at early times. One way to overcome the current observing limitations prior to the arrival of the future James Webb Space Telescope or the European Extremely Large Telescopes is to use the natural magnification of strong lensing clusters to look at distant sources with an improved sensitivity and resolution. The aim of CALENDS is to build and study in great details a large sample of accurately-modelled, strongly lensed galaxies at high redshift (1<z<5) selected in the fields of massive clusters, and compare them with the more luminous or lower redshift populations. We will develop novel techniques in this process, in order to improve the accuracy of strong-lensing models and precisely determine the mass content of these clusters. By performing a systematic modelling of the cluster sample we will look into the relative distribution of baryons and dark matter as well as the amount of substructure in cluster cores. Regarding the population of lensed galaxies, we will study their global properties through a multiwavelength analysis covering the optical to millimeter domains, including spectroscopic information from MUSE and KMOS on the VLT, and ALMA. We will look for scaling relations between the stellar, gas and dust parameters, and compare them with known relations for lower redshift and more massive galaxy samples. For the most extended sources, we will be able to spatially resolve their inner properties, and compare the results of individual regions with predictions from simulations. We will look into key physical processes: star formation, gas accretion, inflows and outflows, in these distant sources.

1 450 992 €

Start date: 2013-09-01, End date: 2019-08-31

The mammalian nervous system is in some respect surprisingly robust to perturbations, as suggested by the virtually complete recovery of brain function after strokes or the pre-clinical asymptomatic phase of Parkinson’s disease. Ultimately though, cognitive and behavioral robustness relies on the ability of single neurons to cope with perturbations, and in particular to maintain a constant and reliable transfer of information. So far, the main facet of robustness that has been studied at the neuronal level is homeostatic plasticity of electrical activity, which refers to the ability of neurons to stabilize their activity level in response to external perturbations. But neurons are also able to maintain their function when one of the major ion channels underlying their activity is deleted or mutated: the number of ion channel subtypes expressed by most excitable cells by far exceeds the minimal number of components necessary to achieve function, offering great potential for compensation when one of the channel’s function is altered. How ion channels are dynamically co-regulated to maintain the appropriate pattern of activity has yet to be determined. In the current project, we will develop a systems-level approach to robustness of neuronal activity based on the combination of electrophysiology, microfluidic single-cell qPCR and computational modeling. We propose to i) characterize the electrical phenotype of dopaminergic neurons following different types of perturbations (ion channel KO, chronic pharmacological treatment), ii) measure the quantitatives changes in ion channel transcriptome (40 voltage-dependent ion channels) associated with these perturbations and iii) determine the mathematical relationships between quantitative changes in ion channel expression and electrical phenotype. Although focused on dopaminergic neurons, this project will provide a general framework that could be applied to any type of excitable cell to decipher its code of robustness.

1 972 797 €

Start date: 2014-05-01, End date: 2019-04-30

Clouds and precipitation play a crucial role in the Earth's energy balance, global atmospheric circulation and the water cycle. Despite their importance, clouds still pose the largest uncertainty in climate research. I propose a new approach for studying anthropogenic effects on cloud fields and rain, tackling the challenge from both scientific ends: reductionism and systems approach. We will develop a novel research approach using observations and models interactively that will allow us to “peel apart” detailed physical processes. In parallel we will develop a systems view of cloud fields looking for Emergent Behavior rising out of the complexity, as the end result of all of the coupled processes. Better understanding of key processes on a detailed (reductionist) manner will enable us to formulate the important basic rules that control the field and to look for emergence of the overall effects. We will merge ideas and methods from four different disciplines: remote sensing and radiative transfer, cloud physics, pattern recognition and computer vision and ideas developed in systems approach. All of this will be done against the backdrop of natural variability of meteorological systems. The outcomes of this work will include fundamental new understanding of the coupled surface-aerosol-cloud-precipitation system. More importantly this work will emphasize the consequences of human actions on the environment, and how we change our climate and hydrological cycle as we input pollutants and transform the Earth’s surface. This work will open new horizons in cloud research by developing novel methods and employing the bulk knowledge of pattern recognition, complexity, networking and self organization to cloud and climate studies. We are proposing a long-term, open-ended program of study that will have scientific and societal relevance as long as human-caused influences continue, evolve and change.

1 428 169 €

Start date: 2012-09-01, End date: 2017-08-31

"Spatially distributed multi-agent networks have been used successfully to model a wide range of natural, social and engineered complex systems, such as animal groups, online communities and electric power grids. In various contexts, it is crucial to introduce control actions into such networks to either achieve desired collective dynamics or test the understanding of the systems’ behavior. However, controlling such systems is extremely challenging due to agents’ complicated sensing, communication and control interactions that are distributed in space. Systematic methodologies to attack this challenge are in urgent need, especially when vast efforts are being made in multiple disciplines to apply the model of complex multi-agent networks. The goal of the project is twofold. First, understand whether a complex multi-agent network can be controlled effectively when the agents can only sense and communicate locally. Second, provide methodologies to implement distributed control in typical spatially distributed complex multi-agent networks. The project requires integrated skills since both rigorous theoretical analysis and novel empirical explorations are necessary. The research methods that I plan to adopt have two distinguishing features. First, I use tools from algebraic graph theory and complex network theory to investigate the impact of network topologies on the systems’ controller performances characterized by mathematical control theory. Second, I utilize a homemade robotic-fish testbed to implement various multi-agent control algorithms. The unique combination of theoretical and empirical studies is expected to lead to breakthroughs in developing an integrated set of principles and techniques to control effectively spatially distributed multi-agent networks. The expected results will make original contributions to control engineering and robotics, and inspire innovative research methods in theoretical biology and theoretical sociology."

1 495 444 €

Start date: 2013-01-01, End date: 2017-12-31

We shall develop a microfluidic and microsystems toolbox allowing the construction and study of complex cellular assemblies (“tissue or organ mimics on chip”), in a highly controlled and parallelized way. This platform will allow the selection of specific cells from one or several populations, their deterministic positioning and/or connection relative to each other, yielding functional assemblies with a degree of complexity, determinism and physiological realism unavailable to current in vitro systems We shall in particular develop “semi-3D” architectures, reproducing the local 3D arrangement of tissues, but presenting at mesoscale a planar and periodic arrangement facilitating high resolution stimulation and recording. This will provide biologists and clinicians with new experimental models able to bridge the gap between current in vitro systems, in which cells can be observed in parallel at high resolution, but lack the highly ordered architecture present in living systems, and in vivo models, in which observation and stimulation means are more limited. This development will follow a functional approach, and gather competences and concepts from micr-nano-systems, surface science, hydrodynamics, soft matter and biology. We shall validate it on three specific applications, the sorting and study of circulating tumour cells for understanding metastases, the creation of “miniguts”, artificial intestinal tissue, for applications in developmental biology and cancerogenesis, and the in vitro construction of active and connected neuron arrays, for studying the molecular mechanisms of Alzheimer, and signal processing by neuron networks. This platform will also open new routes for drug testing, replacing animal models and reducing the health and economic risk of clinical tests, developmental biology , stem cells research. and regenerative medicine.

2 260 000 €

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

The everyday lives of contemporary youths are awash with chemicals and pharmaceutical compounds to boost pleasure, moods, sexual performance, vitality, appearance and health. Nevertheless, most studies of chemical use among young people have focused on the abuse of specific recreational drugs and their role within deviant youth sub-cultures. Instead of explaining drug abuse with the purpose of controlling it, this project aims to examine the pervasive use of chemicals from the perspectives of youths themselves. It aims to understand what chemical and pharmaceutical substances, and not only illicit narcotics, ‘do’ for youths. How are chemicals a part of their everyday lives? What role do they play in calming their fears or in achieving their dreams and aspirations? How can we understand the ways in which chemicals affect their bodies and minds? The theoretical innovation promised by this project lies in its combining of disciplines – most notably medical anthropology, science and technology studies and youth studies – to formulate a new groundbreaking framework for understanding the complex sociality of chemicals in youths’ everyday lives. The framework will have both scientific and societal impact. Ethnographic research will be conducted in four medium-sized cities: Marseille in France, Amsterdam in the Netherlands, Makassar in Indonesia, and Batangas in the Philippines.

2 489 967 €

Start date: 2013-06-01, End date: 2018-05-31

With its emergence as a global power, China aspires to move from a “made in China” towards a “created in China” country. Creativity and culture have become a crucial source for innovation and financial growth, but are also mobilised to promote a new and open China to both the citizenry as well as the outside world. They are part of what is termed China’s “soft power.” What does creativity mean in the context of China, and what does it do? When both the state and profoundly globalised creative industries are so deeply implicated in the promotion of creativity, what are the possibilities of criticality, if any? Whereas creativity has been extensively researched in the fields of psychology, law and neurosciences, scholarship in the humanities has by and large side-tracked the thorny issue of creativity. Yet, the worldwide resurgence of the term under the banner of creative industries makes it all the more urgent to develop a theory of creativity. This project understands creativity as a textual, a social as well as a heritage practice. It aims to analyse claims of creativity in different cultural practices, and to analyse how emerging creativities in China are part of tactics of governmentality and disable or enable possibilities of criticality. Using a comparative, multi-disciplinary, multi-method and multi-sited research design, five subprojects analyse (1) contemporary art, (2) calligraphy, (3) independent documentary cinema, (4) television from Hunan Satellite TV and (5) “fake” (shanzhai) art. By including both popular and high arts, by including both more Westernized as well as more specifically Chinese art forms, by including both the “real” as well as the “fake,” by studying different localities, and by mobilising methods from both the social sciences and the humanities, this project is pushing the notion of comparative research to a new level.

1 947 448 €

Start date: 2014-09-01, End date: 2019-08-31

"Our cells receive tens of thousands of different DNA lesions per day. Failure to repair these lesions will lead to cell death, mutations and genome instability, which contribute to human diseases such as neurodegenerative disorders and cancer. Efficient recognition and repair of DNA damage, however, is complicated by the fact that genomic DNA is packaged, through histone and non-histone proteins, into a condensed structure called chromatin. The DNA repair machinery has to circumvent this barrier to gain access to the damaged DNA and repair the lesions. Our recent work suggests that chromatin-modifying enzymes (CME) help to overcome this barrier at sites of DNA damage. However, the identity of these CME, their mode of action and interconnections with DNA repair pathways remain largely enigmatic. The aim of this project is to systematically identify and characterize the CME that operate during DNA repair processes in both yeast and human cells. To reach this goal we will use a cross-disciplinary approach that combines novel and cutting-edge genomics approaches with bioinformatics, genetics, biochemistry and high-resolution microscopy. Epigenetics-IDentifier (Epi-ID) will be used as a tool to unveil novel CME, whereas RNAi-interference and genetic interaction mapping studies will pinpoint the CME that may potentially regulate repair of DNA damage. A series of functional assays will eventually characterize their role in distinct DNA repair pathways, focusing on those that counteract DNA strand breaks and replication stress. Together these studies will provide insight into how CME assist cells to repair DNA damage in chromatin and inform on the relevance of CME to maintain genome stability and counteract human diseases."

1 999 575 €

Start date: 2014-03-01, End date: 2019-02-28

"Electronic spins are usually detected by their interaction with electromagnetic fields at microwave frequencies. Since this interaction is very weak, only large ensembles of spins can be detected. In circuit quantum electrodynamics (cQED) on the other hand, artificial superconducting atoms are made to interact strongly with microwave fields at the single photon level, and quantum-limited detection of few-photon microwave signals has been developed. The goal of this project is to apply the concepts and techniques of cQED to the detection and manipulation of electronic and nuclear spins, in order to reach a novel regime in which a single electronic spin strongly interacts with single microwave photons. This will lead to 1) A considerable enhancement of the sensitivity of spin detection by microwave methods. We plan to detect resonantly single electronic spins in a few milliseconds. This could enable A) to perform electron spin resonance spectroscopy on few-molecule samples B) to measure the magnetization of various nano-objects at millikelvin temperatures, using the spin as a magnetic sensor with nanoscale resolution. 2) Applications in quantum information science. Strong interaction with microwave fields at the quantum level will enable the generation of entangled states of distant individual electronic and nuclear spins, using superconducting qubits, resonators and microwave photons, as “quantum data buses” mediating the entanglement. Since spins can have coherence times in the seconds range, this could pave the way towards a scalable implementation of quantum information processing protocols. These ideas will be primarily implemented with NV centers in diamond, which are electronic spins with properties suitable for the project."

1 999 995 €

Start date: 2014-03-01, End date: 2019-02-28

The overall objective is to fully understand the Chiral Induced Spin Selectivity (CISS) effect, which was discovered recently. It was found that the transmission or conduction of electrons through chiral molecules is spin dependent. The CISS effect is a change in the pradigm that assumed that any spin manipulation requiers magnetic materials or materials with high spin-orbit coupling. These unexpected new findings open new possibilities for applying chiral molecules in spintronics applications and may provide new insights on electron transfer processes in Biology. The specific goals of the proposed research are (i) To establish the parameters that affect the magnitude of the CISS effect. (ii) To demonstrate spintronics devices (memory and transistors) that are based on the CISS effect. (iii) To investigate the role of CISS in electron transfer in biology related systems. The experiments will be performed applying a combination of experimental methods including photoelectron spectroscopy, single molecule conduction, light-induced electron transfer, and spin specific conduction through magneto-electric devices. The project has a potential to have very large impact on various fields from Physics to Biology. It will result in the establishment of chiral organic molecules as a new substrate for wide range of spintronics related applications including magnetic memory, and in determining whether spins play a role in electron transfer processes in biology.

2 499 998 €

Start date: 2013-10-01, End date: 2018-09-30

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials. Most –if not all- of the efforts of organic chemists were directed to the development of creative strategies to built carbon-carbon and carbon-heteroatom bonds in a predictable and efficient manner. But is the creation of new bonds the only approach that organic chemistry should follow? Could we design the synthesis of challenging molecular skeleton no more through the construction of carbon-carbon bonds but rather through selective cleavage of carbon-carbon bonds (C-C bond activation)? The goal of this work is to develop powerful synthetic approaches for the selective C-C bond activation and demonstrate that it has the potential to be a general principle in organic synthesis for the regio-, diastereo- and even enantiomerically enriched preparation of adducts despite that C-C single bonds belong among the least reactive functional groups in chemistry. The realization of this synthetic potential requires the ability to functionalize selectively one C-C bond in compounds containing many such bonds and an array of functional groups. This site selective C-C bond activation is one of the greatest challenges that must be met to be used widely in complex-molecular synthesis. To emphasize the practicality of C-C bond activation, we will prepare in a single-pot operation challenging molecular framework possessing various stereogenic centers from very simple starting materials through selective C-C bond activation. Ideally, alkenes will be in-situ transformed into alkanes that will subsequently undergo the C-C activation even in the presence of functional group. This work will lead to ground-breaking advances when non-strained cycloalkanes (cyclopentane, cyclohexane) will undergo this smooth C-C bond activation with friendly and non toxic organometallic species.

2 367 495 €

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

Error correcting codes play a fundamental role in computer science. Good codes are codes with rate and distance that are asymptotically optimal. Some of the most successful good codes are constructed using expander graphs. In recent years a new notion of {\em robust} error correcting codes, known as locally testable codes (LTCs), has emerged. Locally testable codes are codes in which a proximity of a vector to an error correcting code can be achieved by probing the vector in {\em constant} many locations (independent of its length). LTCs are at the heart of Probabilistically Checkable Proofs (PCPs) and their construction has been sought since the discovery of the PCP theorem in the early 1990s. Despite 20 years of research, it is still widely open whether good locally testable codes exist. LTCs present completely new challenge to the field of error correcting codes. In the old paradigm a random code is a good code and the main focus was to construct explicit codes that imitate the random code. However, a random code is not an LTC. Thus, contrary to traditional codes, there are no natural candidates for LTCs. The known constructions of robust codes are ad hoc, and there is a lack of theory that explains their existence. The goal of the current research plan is to harness the emerging field of higher dimensional expanders and their topological properties for a systematic study of robust error correcting codes. Higher dimensional expanders are natural candidates for obtaining robust codes since they offer a strong form of redundancy that is essential for robustness. Such form of redundancy is lacking by their one dimensional analogue (i.e., expander graphs). Hence, the known expander codes are not robust. We expect that our study will draw new connections between error correcting codes, high dimensional expanders, topology and probability that will shed new light on these fields, and in particular, will advance the constructing of good and robust codes.

1 302 000 €

Start date: 2014-02-01, End date: 2020-01-31

All cancers arise due to alterations in their genomes. Although insight into the genetic lesions in tumours by genome sequencing does already assist in selecting some drug regimens, it rarely results in disease eradication due to the emergence of drug-resistant clones. More sophisticated combination therapies in which several oncogenic pathways are targeted simultaneously or in a particular sequence are believed to hold more promise. However, at present we are unable to extract and interpret the necessary information from tumours to predict which drug regimen will be most adequate. The genetic make-up of the individual, the heterogeneity of the tumour, epigenetic alterations, cell-of-origin of the tumour, and complex interactions between tumour cells and stromal cells appear important confounding factors influencing response. In addition, we are still ignorant of many of the intricate complexities of signalling networks in cells and how tumours exploit these to acquire drug resistance. It is the ambition of the team formed by members of the Netherlands Cancer Institute (NKI) and the Cancer Genome Project at the Wellcome Trust Sanger Institute (WTSI) to unravel the genomic and phenotypic complexity of human cancers in order to identify optimal drug combinations for personalized cancer therapy. Our integrated approach will entail (i) deep sequencing of human tumours and cognate mouse tumours; (ii) drug screens in a 1000+ fully characterized tumour cell line panel; (iii) high-throughput in vitro and in vivo shRNA and cDNA drug resistance and enhancement screens; (iv) computational analysis of the acquired data, leading to significant response predictions; (v) rigorous validation of these predictions in genetically engineered mouse models and patient-derived xenografts. This integrated effort is expected to yield a number of combination therapies and companion-diagnostics biomarkers that will be further explored in our existing clinical trial networks.

14 580 558 €

Start date: 2013-05-01, End date: 2019-04-30

When patients recover from coma, determining their level of consciousness can be difficult, even for an experienced clinician. Our goal is to provide a Consciousness Monitoring Index: a robust method to detect and quantitatively monitor the extent to which a human being is or is not conscious. Using electrodes attached to the scalp, we monitor the electro-encephalographic (EEG) signal which reflects ongoing brain activity. We have discovered and filed a patent for several mathematical indices which can be easily computed from the EEG, and which, alone or in combination, provide a continuous indicator of whether the person is or is not conscious. Our empirical studies in patients with coma, vegetative state show that our EEG-based markers can (1) accurately determine whether a patient is or not conscious at the time of testing; (2) establish how consciousness fluctuates from moment to moment; (3) predict, in a statistical manner, the capacity of the patient to recover consciousness. In this project, we propose to establish the scientific validity, technical feasibility, market potential, business model, and legal context for two distinct services that could be provided: (1) an off-line computer-based service for automated analysis of existing clinical EEG recordings, taking the form of a web server where clinicians would upload these data and receive a summary of indicators of consciousness. (2) an on-line bedside monitor of consciousness, taking the form of a tablet PC and dedicated EEG amplifier constantly displaying a scrolling view of indicators of consciousness, for real-time use by clinicians and by families, possibly with real-time feedback to patients. Our application is primarily intended for adult patients with disorders of consciousness, their doctors and their families, but its market could be much larger, and we will explore its possible extension to anaesthesia, sleep disorders, epilepsy, pediatric populations, professional and personal use.

149 820 €

Start date: 2014-03-01, End date: 2015-08-31

Fuel cell systems are high-efficiency, low-emission energy conversion modules for transportation, stationary and portable applications. Especially for automotive applications, low-temperature proton exchange membrane (PEM) fuel cells are considered a key-stone solution, as they can effectively reduce greenhouse gases emissions. A major barrier for the market penetration of these systems is the material scarcity of precious metals used for the fabrication of the electrocatalyst, a core-component of the system. Achieving increased performance in terms of catalytic activity and stability (corrosion resistance) while decreasing the cost, can be realized by a drastic redesign of the catalyst fabrication process using Atomic Layer Deposition (ALD) of nanoparticles. Using the understanding of the ALD coating processes obtained in the ERC-StG project AggloNanoCoat, the technique’s potential for producing tailored yet inexpensive core/shell nanoparticles for advanced catalysis applications has been identified. The innovative process characteristics (precise surface modification, mild operating conditions, scale-up potential and minimization of environmental footprint) clearly form a strong pre-commercialization starting-point. The next required step is the assessment of the market potential, effectively bridging nanoparticle ALD and the fuel cell catalyst manufacturing section. The CONiA project will establish the basis for commercial development by introducing an attractive communication package based on the outcomes of a validation case-study. The main objective of the activities will be to demonstrate the scale-up potential and provide an initial costing structure for the future venture. In parallel, a solid business proposition will be set, to enable the consecutive required actions for securing further funding and to provide the corner-stone for kick-starting a company that will commercialize the technology.

147 872 €

Start date: 2013-05-01, End date: 2014-10-31

The success of modern medical treatments such as cellular therapy and targeted treatments requires appropriate tools for in vivo monitoring. Imaging modalities, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are key candidates due to their noninvasive nature. However, these imaging techniques are extremely expensive and can involve radiation, both of which hinder their longitudinal and repetitive use. Ultrasound has so far been unsuitable due to the absence of a label to differentiate regions of interest from tissue background, the main problem being that current ultrasound contrast agents (CAs) have active lifetimes in the order of minutes. The CoNQUeST platform (Clinical Nanoparticles for Quantitative Ultrasound with high STability) proposed here is an entirely new type of ultrasound CA that is extremely stable (lifetime of a year) and is not affected by insonation. This mechanism of contrast generation appears completely novel: The polymeric particles are under 200nm in diameter and must contain a soluble metal (M.Srinivas et al., patent pending, filed 09/2012). Based on the current state of the art, these particles are too small and do not contain the requisite gaseous component for ultrasound contrast. CoNQUeST particles are applicable to longitudinal and repeated imaging, as is necessary for cell tracking, due to their stability. Furthermore, these particles can be chemically bound to targeting agents, dyes and drugs, and are suitable for multimodal imaging, including MRI (both 1H and 19F), fluorescence and SPECT. Finally, the CoNQUeST agents are suitable for clinical use. I propose the application of the CoNQUeST agents to a clinical trial for tracking dendritic cell therapy in melanoma patients, longitudinal theranostic imaging in preclinical models and thorough characterisation of this novel mechanism of ultrasound contrast generation.

1 199 882 €

Start date: 2014-04-01, End date: 2019-03-31

The transmission electron microscope (TEM) is an essential instrument facilitating studies of the nanoscale material structure at sub-1Å resolution for R&D in the area of materials science, nanoscience and nanotechnology. In order to access the highly relevant temperature range between 77 K and room temperature, special specimen cryoholders need to be used that allow for a double tilt of the specimen under study. However, it is impossible to make images with sub-1Å resolution with the existing commercial double-tilt cryoholders. This is due to effects of thermal gradient-induced drift and mechanical vibrations. As part of my ERC Advanced Grant I have pioneered single-tilt cryoholders with electrical feedthroughs that largely overcome these problems, resulting in sub-1Å high resolution TEM at ~100 K in at least 15% of the images that are recorded. With this proposal, I wish to take these advances towards a proof of concept for a double-tilt cryoholder that allows sub-1Å high-resolution TEM in at least 80% of the recordings at any temperature between 77 K and 300 K and represents a user-friendly standard technique with commercial potential. I plan to make these holders available to researchers at similar price levels of currently available holders. Based on my acknowledged track record in developing microscopy innovations, I have drafted a plan to prototype this invention. I will seek an industrial partner to perform a design cycle for real production, and next produce the holders.

149 953 €

Start date: 2012-11-01, End date: 2013-12-31

Societies in past and present are regularly confronted with major hazards, which sometimes have disastrous effects. Some societies are successful in preventing these effects and buffering threats, or they recover quickly, while others prove highly vulnerable. Why is this? Increasingly it is clear that disasters are not merely natural events, and also that wealth and technology alone are not adequate to prevent them. Rather, hazards and disasters are social occurrences as well, and they form a tough test for the organizational capacities of a society, both in mitigation and recovery. This project targets a main element of this capacity, namely: the way societies have organized the exchange, allocation and use of resources. It aims to explain why some societies do well in preventing or remedying disasters through these institutional arrangements and others not. In order to do so, this project analyses four key variables: the mix of coordination systems available within that society, its degree of autarky, economic equity and political equality. The recent literature on historical and present-day disasters suggests these factors as possible causes of success or failure of institutional arrangements in their confrontation with hazards, but their discussion remains largely descriptive and they have never been systematically analyzed. This research project offers such a systematic investigation, using rural societies in Western Europe in the period 1300-1800 - with their variety of socio-economic characteristics - as a testing ground. The historical perspective enables us to compare widely differing cases, also over the long run, and to test for the variables chosen, in order to isolate the determining factors in the resilience of different societies. By using the opportunities offered by history in this way, we will increase our insight into the relative performance of societies and gain a better understanding of a critical determinant of human wellbeing.

2 227 326 €

Start date: 2014-03-01, End date: 2019-02-28

"Materials with strong electronic Coulomb correlations present unique electronic properties such as exotic magnetism, charge or orbital order, or unconventional optical or transport properties, including superconductivity, thermoelectricity or metal-insulator transitions. The concerted behavior of the electrons in these ``correlated materials"" moreover leads to an extreme sensitivity to external stimuli such as changes in temperature, pressure, or external fields. This tuneability of even fundamental properties is both a harbinger for technological applications and a challenge to currently available theoretical methods: Indeed, these properties are the result of strong electron-electron interactions and subtle quantum correlations, and cannot be understood without a proper description of excited states. The aim of the present project is to elaborate, implement and test new approaches to investigate the spectral and optical properties of correlated materials ``from first principles"", that is, without adjustable parameters. I will build on the success of state-of-the-art dynamical mean field-based electronic structure techniques, but aim at developing them into truly first-principles methods, where a full treatment of the long-range Coulomb interactions replaces the current practice of purely local Hubbard interaction parameters. My target materials are among the most interesting for modern technologies, such as transition metal oxides (with potential applications ranging from oxide electronics to battery materials) and rare earth compounds used as environmentally-responsible pigments. Establishing first-principles techniques with truly predictive power for these classes of materials will bring us closer to the final goal of tailoring correlated materials with preassigned properties."

1 713 600 €

Start date: 2014-07-01, End date: 2019-06-30

Cosmic explosions, the violent deaths of stars, play a crucial role in many of the most interesting open questions in physics today. These events serve as “cosmic accelerators” for ultra-high-energy particles that are beyond reach for even to most powerful terrestrial accelerators, as well as distant sources for elusive neutrinos. Explosions leave behind compact neutron stars and black hole remnants, natural laboratories to study strong gravity. Acting as cosmic furnaces, these explosions driven the chemical evolution of the Universe Cosmic explosions trigger and inhibit star formation processes, and drive galactic evolution (“feedback”). Distances measured using supernova explosions as standard candles brought about the modern revolution in our view of the accelerating Universe, driven by enigmatic “dark energy”. Understanding the nature of cosmic explosions of all types is thus an extremely well-motivated endeavour. I have been studying cosmic explosions for over a decade, and since the earliest stages of my career, have followed an ambition to figure out the nature of cosmic explosions of all types, and to search for new types of explosions. Having already made several key discoveries, I now propose to undertake a comprehensive program to systematically tackle this problem.I review below the progress made in this field and the breakthrough results we have achieved so far, and propose to climb the next step in this scientific and technological ladder, combining new powerful surveys with comprehensive multi-wavelength and multi-disciplinary (observational and theoretical) analysis. My strategy is based on a combination of two main approaches: detailed studies of single objects which serve as keys to specific questions; and systematic studies of large samples, some that I have, for the first time, been able to assemble and analyze, and those expected from forthcoming efforts. Both approaches have already yielded tantalizing results.

1 499 302 €

Start date: 2012-09-01, End date: 2017-08-31

"This project aims to ""crack"" the emotional code of music, i.e. to provide, for the first time, a precise characterization of what type of music signal is able to activate one emotion or another. Research into this problem so far has been mainly correlating indistinct emotional reactions to uncontrolled musical stimuli, with much technical sophistication but to little avail. Project CREAM builds on the PI's unique bi-disciplinary career spanning both computer science and cognitive neuroscience, to propose a radically novel approach: instead of using audio signal processing to simply observe musical stimuli a posteriori, we will harvest a series of recent developments in the field to build powerful new tools of experimental control, able to engineer musical stimuli that can activate specific emotional pathways (e.g. music manipulated to sound like expressive speech, or to sound like survival-relevant environmental sounds). By combining this creative use of new technologies with a well-concerted mix of methods from experimental psychology and cognitive neuroscience (incl. psychoacoustics, fNIRS brain imaging, EEG/ERP paradigms, intercultural studies, infant studies), project CREAM will yield the first functional description of the neural and cognitive processes involved in the induction of emotions by music, and establish new avenues for interdisciplinary research between the life sciences and the information sciences. But most spectacularly, the fundamental breakthroughs brought by project CREAM will unlatch the therapeutic potential of musical emotions. Music will become a cognitive technology, with algorithms able to ""engineer"" it to mobilize one neuronal pathway or another, non-intrusively and non-pharmacologically. Within the proposed 5-year plan, support from the ERC will allow to implement a series of high-impact clinical studies with are direct applications of our findings, e.g. for the linguistic rehabilitation of aphasic stroke victims."

1 499 992 €

Start date: 2014-10-01, End date: 2019-09-30

Many companies have already started the migration to the Cloud and many individuals share their personal informations on social networks. Unfortunately, in the current access mode, the provider first authenticates the client, and grants him access, or not, according to his rights in the access-control list. Therefore, the provider itself not only has total access to the data, but also knows which data are accessed, by whom, and how: privacy, which includes secrecy of data (confidentiality), identities (anonymity), and requests (obliviousness), should be enforced. The industry of the Cloud introduces a new implicit trust requirement: nobody has any idea at all of where and how his data are stored and manipulated, but everybody should blindly trust the providers. Privacy-compliant procedures cannot be left to the responsibility of the provider: however strong the trustfulness of the provider may be, any system or human vulnerability can be exploited against privacy. This presents too huge a threat to tolerate. The distribution of the data and the secrecy of the actions must be given back to the users. It requires promoting privacy as a global security notion. A new generation of secure multi-party computation protocols is required to protect everybody in an appropriate way, with privacy and efficiency: interactive protocols will be the core approach to provide privacy in practical systems. Privacy for the Cloud will have a huge societal impact since it will revolutionize the trust model: users will be able to make safe use of outsourced storage, namely for personal, financial and medical data, without having to worry about failures or attacks of the server. It will also have a strong economic impact, conferring a competitive advantage on Cloud providers implementing these tools.

2 168 261 €

Start date: 2014-06-01, End date: 2019-05-31

The major causes of death in the Western world are cardiovascular diseases and cancer. More accurate detection of these diseases will improve clinical outcomes. Thus, we will develop unique X-ray contrast reagents for use in spectral computerized tomography (CT) that bind active proteases to reveal the exact location and stage of cancer and atherosclerosis. Activity-based probes (ABPs) are small molecules that covalently bind to active proteases. Based on our success in developing optical ABPs for non-invasive optical detection of cancer and atherosclerosis, we will focus on two novel types of reagents: (1) ABPs conjugated to the various contrast elements that can be visualized by x-rays. (2) “smart probes” conjugated to different contrast reagents on each side of the molecule to overcome clearance limitations. Protease found in diseased tissue will selectively bind and remove a part of the molecule, changing the physical properties of the bound probe. Thus, different signals from bound and unbound probes could be detected by photon counting spectral CT scanners. Our initial target, cysteine cathepsin proteases, are overexpressed and activated in cancer and arthrosclerosis. The level of active cathepsins correlates with progression of both diseases, thereby serving as a promising biomarker for these pathologies. The “smart probes” are an innovative type of spectral CT agent that will enable high-resolution rapid imaging in humans before probe clearance. Our probes increase imaging sensitivity since the contrast element remains at the desired site. Moreover, the levels of active cathepsins will reveal critical information regarding disease progression, yielding more accurate diagnoses and improved personalized treatment. For example, these reagents can distinguish between a vulnerable and stable atherosclerotic plaque. Thus, our novel probes will directly reduce cancer and cardiovascular disease mortality by enabling earlier and more accurate disease detection.

1 499 780 €

Start date: 2013-12-01, End date: 2018-11-30

"Frontier research in statistical mechanics and soft condensed matter focuses on systems of ever-increasing complexity. Among these are systems where microscopic dynamics are not controlled by thermal fluctuations, either because the sources of the fluctuations have not a thermal origin, or because “microscopic” sources of fluctuations are altogether absent. Practical applications comprise everyday products such as paints or foodstuff which are soft solids composed of dense suspensions of particles that are too large for thermal fluctuations to play any role. Non-Brownian “active” matter, obtained when particles internally produce motion, represents another growing field with applications in biophysics and soft matter. Because these systems all evolve far from equilibrium, there exists no general framework to tackle these problems theoretically from a fundamental perspective. I will develop a radically new approach to lay the foundations of a detailed theoretical understanding of the physics of a broad but coherent class of materials evolving far from equilibrium. To go beyond phenomenology, I will carry theoretical research to elucidate the physics of particle systems that are simultaneously Dense, Disordered, Driven and Dissipative—D4PARTICLES. By combining numerical analysis of model systems to fully microscopic statistical mechanics analysis, my overall aim is to discover the general principles governing the physics of athermal particle systems far from equilibrium and to reach a complete theoretical understanding and obtain predictive tools regarding the phase behavior, structure and dynamics of D4PARTICLES. Reaching a new level of theoretical understanding of a broad range of materials will impact fundamental research by opening up statistical physics to a whole new class of complex systems and should foster experimental activity towards design and quantitative characterization of large class of disordered solids and soft materials."

1 339 800 €

Start date: 2012-10-01, End date: 2017-09-30