ERC FUNDED PROJECTS

The paradigm of the structure-function relationship in proteins is outdated. Biological macromolecules and supramolecular assemblies are highly dynamic objects. Evidence that their motions are of utmost importance to their functions is regularly identified. The understanding of the physical chemistry of biological processes at an atomic level has to rely not only on the description of structure but also on the characterization of molecular motions. The investigation of protein motions will be undertaken with a very innovative methodological approach in nuclear magnetic resonance relaxation. In order to widen the ranges of frequencies at which local motions in proteins are probed, we will first use and develop new techniques for a prototype shuttle system for the measurement of relaxation at low fields on a high-field NMR spectrometer. Second, we will develop a novel system: a set of low-field NMR spectrometers designed as accessories for high-field spectrometers. Used in conjunction with the shuttle, this system will offer (i) the sensitivity and resolution (i.e. atomic level information) of a high-field spectrometer (ii) the access to low fields of a relaxometer and (iii) the ability to measure a wide variety of relaxation rates with high accuracy. This system will benefit from the latest technology in homogeneous permanent magnet development to allow a control of spin systems identical to that of a high-resolution probe. This new apparatus will open the way to the use of NMR relaxation at low fields for the refinement of protein motions at an atomic scale. Applications of this novel approach will focus on the bright side of protein dynamics: (i) the largely unexplored dynamics of intrinsically disordered proteins, and (ii) domain motions in large proteins. In both cases, we will investigate a series of diverse protein systems with implications in development, cancer and immunity.

1 462 080 €

Start date: 2012-01-01, End date: 2017-12-31

The fundamental 3D-BioMat project aims at providing a biomineralization model to explain the formation of microscopic calcareous single-crystals produced by living organisms. Although these crystals present a wide variety of shapes, associated to various organic materials, the observation of a nanoscale granular structure common to almost all calcareous crystallizing organisms, associated to an extended crystalline coherence, underlies a generic biomineralization and assembly process. A key to building realistic scenarios of biomineralization is to reveal the crystalline architecture, at the mesoscale, (i. e., over a few granules), which none of the existing nano-characterization tools is able to provide. 3D-BioMat is based on the recognized PI’s expertise in the field of synchrotron coherent x-ray diffraction microscopy. It will extend the PI’s disruptive pioneering microscopy formalism, towards an innovative high-throughput approach able at giving access to the 3D mesoscale image of the crystalline properties (crystal-line coherence, crystal plane tilts and strains) with the required flexibility, nanoscale resolution, and non-invasiveness. This achievement will be used to timely reveal the generics of the mesoscale crystalline structure through the pioneering explorations of a vast variety of crystalline biominerals produced by the famous Pinctada mar-garitifera oyster shell, and thereby build a realistic biomineralization scenario. The inferred biomineralization pathways, including both physico-chemical pathways and biological controls, will ultimately be validated by comparing the mesoscale structures produced by biomimetic samples with the biogenic ones. Beyond deciphering one of the most intriguing questions of material nanosciences, 3D-BioMat may contribute to new climate models, pave the way for new routes in material synthesis and supply answers to the pearl-culture calcification problems.

1 966 429 €

Start date: 2017-03-01, End date: 2022-02-28

Epigenetic inheritance entails transmission of phenotypic traits not encoded in the DNA sequence and, in the most extreme case, Transgenerational Epigenetic Inheritance (TEI) involves transmission of memory through multiple generations. Very little is known on the mechanisms governing TEI and this is the subject of the present proposal. By transiently enhancing long-range chromatin interactions, we recently established isogenic Drosophila epilines that carry stable alternative epialleles, defined by differential levels of the Polycomb-dependent H3K27me3 mark. Furthermore, we extended our paradigm to natural phenotypes. These are ideal systems to study the role of Polycomb group (PcG) proteins and other components in regulating nuclear organization and epigenetic inheritance of chromatin states. The present project conjugates genetics, epigenomics, imaging and molecular biology to reach three critical aims. Aim 1: Analysis of the molecular mechanisms regulating Polycomb-mediated TEI. We will identify the DNA, protein and RNA components that trigger and maintain transgenerational chromatin inheritance as well as their mechanisms of action. Aim 2: Role of 3D genome organization in the regulation of TEI. We will analyze the developmental dynamics of TEI-inducing long-range chromatin interactions, identify chromatin components mediating 3D chromatin contacts and characterize their function in the TEI process. Aim 3: Identification of a broader role of TEI during development. TEI might reflect a normal role of PcG components in the transmission of parental chromatin onto the next embryonic generation. We will explore this possibility by establishing other TEI paradigms and by relating TEI to the normal PcG function in these systems and in normal development. This research program will unravel the biological significance and the molecular underpinnings of TEI and lead the way towards establishing this area of research into a consolidated scientific discipline.

2 500 000 €

Start date: 2018-11-01, End date: 2023-10-31

Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.

2 349 898 €

Start date: 2017-09-01, End date: 2022-08-31

The emergence of life is one of the most fascinating and yet largely unsolved questions in the natural sciences, and thus a significant challenge for scientists from many disciplines. There is growing evidence that ribonucleic acid (RNA) polymers, which are capable of genetic information storage and self-catalysis, were involved in the early forms of life. But despite recent progress, RNA synthesis without biological machineries is very challenging. The current project aims at understanding how to synthesize RNA in abiotic conditions. I will solve problems associated with three critical aspects of RNA formation that I will rationalize at a molecular level: (i) accumulation of precursors, (ii) formation of a chemical bond between RNA monomers, and (iii) tolerance for alternative backbone sugars or linkages. Because I will study problems ranging from the formation of chemical bonds up to the stability of large biopolymers, I propose an original computational multi-scale approach combining techniques that range from quantum calculations to large-scale all-atom simulations, employed together with efficient enhanced-sampling algorithms, forcefield improvement, cutting-edge analysis methods and model development. My objectives are the following: 1 • To explain why the poorly-understood thermally-driven process of thermophoresis can contribute to the accumulation of dilute precursors. 2 • To understand why linking RNA monomers with phosphoester bonds is so difficult, to understand the molecular mechanism of possible catalysts and to suggest key improvements. 3 • To rationalize the molecular basis for RNA tolerance for alternative backbone sugars or linkages that have probably been incorporated in abiotic conditions. This unique in-silico laboratory setup should significantly impact our comprehension of life’s origin by overcoming major obstacles to RNA abiotic formation, and in addition will reveal significant orthogonal outcomes for (bio)technological applications.

1 497 031 €

Start date: 2018-02-01, End date: 2023-01-31

Listening in realistic situations is an active process that engages perceptual and cognitive faculties, endowing speech with meaning, music with joy, and environmental sounds with emotion. Through hearing, humans and other animals navigate complex acoustic scenes, separate sound mixtures, and assess their behavioral relevance. These remarkable feats are currently beyond our understanding and exceed the capabilities of the most sophisticated audio engineering systems. The goal of the proposed research is to investigate experimentally a novel view of hearing, where active hearing emerges from a deep interplay between adaptive sensory processes and goal-directed cognition. Specifically, we shall explore the postulate that versatile perception is mediated by rapid-plasticity at the neuronal level. At the conjunction of sensory and cognitive processing, rapid-plasticity pervades all levels of auditory system, from the cochlea up to the auditory and prefrontal cortices. Exploiting fundamental statistical regularities of acoustics, it is what allows humans and other animal to deal so successfully with natural acoustic scenes where artificial systems fail. The project builds on the internationally recognized leadership of the PI in the fields of physiology and computational modeling, combined with the expertise of the Co-Investigator in psychophysics. Building on these highly complementary fields and several technical innovations, we hope to promote a novel view of auditory perception and cognition. We aim also to contribute significantly to translational research in the domain of signal processing for clinical hearing aids, given that many current limitations are not technological but rather conceptual. The project will finally result in the creation of laboratory facilities and an intellectual network unique in France and rare in all of Europe, combining cognitive, neural, and computational approaches to auditory neuroscience.

3 199 078 €

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

Which brain mechanisms are responsible for the faith of the memories we make with age, whether they wither or stay, and in what form? Episodic memory function does decline with age. While this decline can have multiple causes, research has focused almost entirely on encoding and retrieval processes, largely ignoring a third critical process– consolidation. The objective of AgeConsolidate is to provide this missing link, by combining novel experimental cognitive paradigms with neuroimaging in a longitudinal large-scale attempt to directly test how age-related changes in consolidation processes in the brain impact episodic memory decline. The ambitious aims of the present proposal are two-fold: (1) Use recent advances in memory consolidation theory to achieve an elaborate model of episodic memory deficits in aging (2) Use aging as a model to uncover how structural and functional brain changes affect episodic memory consolidation in general The novelty of the project lies in the synthesis of recent methodological advances and theoretical models for episodic memory consolidation to explain age-related decline, by employing a unique combination of a range of different techniques and approaches. This is ground-breaking, in that it aims at taking our understanding of the brain processes underlying episodic memory decline in aging to a new level, while at the same time advancing our theoretical understanding of how episodic memories are consolidated in the human brain. To obtain this outcome, I will test the main hypothesis of the project: Brain processes of episodic memory consolidation are less effective in older adults, and this can account for a significant portion of the episodic memory decline in aging. This will be answered by six secondary hypotheses, with 1-3 experiments or tasks designated to address each hypothesis, focusing on functional and structural MRI, positron emission tomography data and sleep experiments to target consolidation from different angles.

1 999 482 €

Start date: 2017-05-01, End date: 2022-04-30

Alfonsine astronomy is arguably among the first European scientific achievements. It shaped a scene for actors like Regiomontanus or Copernicus. There is however little detailed historical analysis encompassing its development in its full breadth. ALFA addresses this issue by studying tables, instruments, mathematical and theoretical texts in a methodologically innovative way relying on approaches from the history of manuscript cultures, history of mathematics, and history of astronomy. ALFA integrates these approaches not only to benefit from different perspectives but also to build new questions from their interactions. For instance the analysis of mathematical practices in astral sciences manuscripts induces new ways to analyse the documents and to think about astronomical questions. Relying on these approaches the main objectives of ALFA are thus to: - Retrace the development of the corpus of Alfonsine texts from its origin in the second half of the 13th century to the end of the 15th century by following, on the manuscript level, the milieus fostering it; - Analyse the Alfonsine astronomers’ practices, their relations to mathematics, to the natural world, to proofs and justification, their intellectual context and audiences; - Build a meaningful narrative showing how astronomers in different milieus with diverse practices shaped, also from Arabic materials, an original scientific scene in Europe. ALFA will shed new light on the intellectual history of the late medieval period as a whole and produce a better understanding of its relations to related scientific periods in Europe and beyond. It will also produce methodological breakthroughs impacting the ways history of knowledge is practiced outside the field of ancient and medieval sciences. Efforts will be devoted to bring these results not only to the relevant scholarly communities but also to a wider audience as a resource in the public debates around science, knowledge and culture.

1 871 250 €

Start date: 2017-09-01, End date: 2022-08-31

Acute Myeloid Leukemia (AML), the most common leukemia diagnosed in adults, represents the paradigm of resistance to front-line therapies in hematology. Indeed, AML is so genetically complex that only few targeted therapies are currently tested in this disease and chemotherapy remains the only standard treatment for AML since the past four decades. Despite an initial sustained remission achieved by chemotherapeutic agents, almost all patients relapse with a chemoresistant minimal residual disease (MRD). The goal of my proposal is to characterize the still poorly understood biological mechanisms underlying persistence and emergence of MRD. MRD is the consequence of the re-expansion of leukemia-initiating cells that are intrinsically more resistant to chemotherapy. This cell fraction may be stochastically more prone to survive front-line therapy regardless of their mutational status (the stochastic model), or genetically predetermined to resist by virtue of a collection of chemoprotective mutations (the mutational model). I have already generated in mice, by consecutive rounds of chemotherapy, a stochastic MLL-AF9-driven chemoresistance model that I examined by RNA-sequencing. I will pursue the comprehensive cell autonomous and cell non-autonomous characterization of this chemoresistant AML disease using whole-exome and ChIP-sequencing. To establish a mutationally-induced chemoresistant mouse model, I will conduct an innovative in vivo screen using pooled mutant open reading frame and shRNA libraries in order to predict which combinations of mutations, among those already known in AML, actively promote chemoresistance. Finally, by combining genomic profiling and in vivo shRNA screening experiments, I will decipher the molecular mechanisms and identify the functional effectors of these two modes of resistance. Ultimately, I will then be able to firmly establish the fundamental relevance of the stochastic and/or the mutational model of chemoresistance for MRD genesis.

1 500 000 €

Start date: 2018-03-01, End date: 2023-02-28

Applied electrochemistry plays a key role in many technologies, such as batteries, fuel cells, supercapacitors or solar cells. It is therefore at the core of many research programs all over the world. Yet, fundamental electrochemical investigations remain scarce. In particular, electrochemistry is among the fields for which the gap between theory and experiment is the largest. From the computational point of view, there is no molecular dynamics (MD) software devoted to the simulation of electrochemical systems while other fields such as biochemistry (GROMACS) or material science (LAMMPS) have dedicated tools. This is due to the difficulty of accounting for complex effects arising from (i) the degree of metallicity of the electrode (i.e. from semimetals to perfect conductors), (ii) the mutual polarization occurring at the electrode/electrolyte interface and (iii) the redox reactivity through explicit electron transfers. Current understanding therefore relies on standard theories that derive from an inaccurate molecular-scale picture. My objective is to fill this gap by introducing a whole set of new methods for simulating electrochemical systems. They will be provided to the computational electrochemistry community as a cutting-edge MD software adapted to supercomputers. First applications will aim at the discovery of new electrolytes for energy storage. Here I will focus on (1) ‘‘water-in-salts’’ to understand why these revolutionary liquids enable much higher voltage than conventional solutions (2) redox reactions inside a nanoporous electrode to support the development of future capacitive energy storage devices. These selected applications are timely and rely on collaborations with leading experimental partners. The results are expected to shed an unprecedented light on the importance of polarization effects on the structure and the reactivity of electrode/electrolyte interfaces, establishing MD as a prominent tool for solving complex electrochemistry problems.

1 588 769 €

Start date: 2018-04-01, End date: 2023-03-31

This proposal is devoted to the applications of a new hypoelliptic Dirac operator, whose analytic properties have been studied by Lebeau and myself. Its construction connects classical Hodge theory with the geodesic flow, and more generally any geometrically defined Hodge Laplacian with a dynamical system on the cotangent bundle. The proper description of this object can be given in analytic, index theoretic and probabilistic terms, which explains both its potential many applications, and also its complexity.

1 112 400 €

Start date: 2012-02-01, End date: 2017-01-31

"During the past twenty years, we have witnessed profound technological changes, summarised under the terms of digital revolution or entering the information age. It is evident that these technological changes will have a deep societal impact, and questions of privacy and security are primordial to ensure the survival of a free and open society. Cryptology is a main building block of any security solution, and at the heart of projects such as electronic identity and health cards, access control, digital content distribution or electronic voting, to mention only a few important applications. During the past decades, public-key cryptology has established itself as a research topic in computer science; tools of theoretical computer science are employed to “prove” the security of cryptographic primitives such as encryption or digital signatures and of more complex protocols. It is often forgotten, however, that all practically relevant public-key cryptosystems are rooted in pure mathematics, in particular, number theory and arithmetic geometry. In fact, the socalled security “proofs” are all conditional to the algorithmic untractability of certain number theoretic problems, such as factorisation of large integers or discrete logarithms in algebraic curves. Unfortunately, there is a large cultural gap between computer scientists using a black-box security reduction to a supposedly hard problem in algorithmic number theory and number theorists, who are often interested in solving small and easy instances of the same problem. The theoretical grounds on which current algorithmic number theory operates are actually rather shaky, and cryptologists are generally unaware of this fact. The central goal of ANTICS is to rebuild algorithmic number theory on the firm grounds of theoretical computer science."

1 453 507 €

Start date: 2012-01-01, End date: 2016-12-31

Single-photon sources (SPSs) are systems capable of emitting photons one by one. These sources are of major importance for quantum-information science and applications. SPSs experiments generally rely on the optical excitation of two level systems of atomic-scale dimensions (single-molecules, vacancies in diamond…). Many fundamental questions related to the nature of these sources and the impact of their environment remain to be explored: Can SPSs be addressed with atomic-scale spatial accuracy? How do the nanometer-scale distance or the orientation between two (or more) SPSs affect their emission properties? Does coherence emerge from the proximity between the sources? Do these structures still behave as SPSs or do they lead to the emission of correlated photons? How can we then control the degree of entanglement between the sources? Can we remotely excite the emission of these sources by using molecular chains as charge-carrying wires? Can we couple SPSs embodied in one or two-dimensional arrays? How does mechanical stress or localised plasmons affect the properties of an electrically-driven SPS? Answering these questions requires probing, manipulating and exciting SPSs with an atomic-scale precision. This is beyond what is attainable with an all-optical method. Since they can be confined to atomic-scale pathways we propose to use electrons rather than photons to excite the SPSs. This unconventional approach provides a direct access to the atomic-scale physics of SPSs and is relevant for the implementation of these sources in hybrid devices combining electronic and photonic components. To this end, a scanning probe microscope will be developed that provides simultaneous spatial, chemical, spectral, and temporal resolutions. Single-molecules and defects in monolayer transition metal dichalcogenides are SPSs that will be studied in the project, and which are respectively of interest for fundamental and more applied issues.

1 996 848 €

Start date: 2018-06-01, End date: 2023-05-31

The project ARTHUS aims at determining the physical origin of Dark Energy: in addition to the energy sources of the standard model of cosmology, effective terms arise through spatially averaging inhomogeneous cosmological models in General Relativity. It has been demonstrated that these additional terms can play the role of Dark Energy on large scales (but they can also mimic Dark Matter on scales of mass accumulations). The underlying rationale is that fluctuations in the Universe generically couple to spatially averaged intrinsic properties of space, such as its averaged scalar curvature, thus changing the global evolution of the effective (spatially averaged) cosmological model. At present, we understand these so- called backreaction effects only qualitatively. The project ARTHUS is directed towards a conclusive quantitative evaluation of these effects by developing generic and non-perturbative relativistic models of structure formation, by statistically measuring the key-variables of the models in observations and in simulation data, and by reinterpreting observational results in light of the new models. It is to be emphasized that there is no doubt about the existence of backreaction effects; the question is whether they are even capable of getting rid of the dark sources (as some models discussed in the literature suggest), or whether their impact is substantially smaller. The project thus addresses an essential issue of current cosmological research: to find pertinent answers concerning the quantitative impact of inhomogeneity effects, a necessary, worldwide recognized step toward high-precision cosmology. If the project objectives are attained, the results will have a far-reaching impact on theoretical and observational cosmology, on the interpretation of astronomical experiments such as Planck and Euclid, as well as on a wide spectrum of particle physics theories and experiments.

2 091 000 €

Start date: 2017-09-01, End date: 2022-08-31

The ERC starting grant GECOMETHODS, on which this POC is based, tackled problems of diffusion equations via geometric control methods. One of the most striking achievements of the project has been the development of an algorithm of image reconstruction based mainly on non-isotropic diffusion. This algorithm is bio-mimetic in the sense that it replicates the way in which the primary visual cortex V1 of mammals processes the signals arriving from the eyes. It has performances that are at the state of the art in image processing. These results together with others obtained in the ERC project show that image processing algorithms based on the functional architecture of V1 can go very far. However, the exceptional performances of the primary visual cortex V1 rely not only on the particular algorithm used, but also on the fact that such algorithm “runs” on a dedicated hardware having the following features: 1. an exceptional level of parallelism; 2. connections that are well adapted to transmit information in a non-isotropic way as it is required by the algorithms of image reconstruction and recognition. The idea of this POC is to create a dedicated hardware (called ARTIV1) emulating the functional architecture of V1 and hence having on one hand a huge degree of parallelism and on the other hand connections among the CPUs that reflect the non-isotropic structure of the visual cortex V1. Such a hardware that we plan to build as an integrated circuit with an industrial partner will be a veritable artificial visual cortex. It will be fully programmable and it will be able to perform many biomimetic image processing tasks that we expect to be exceptionally performant. ARTIV1 will come to the marked accompanied by some dedicated software for image reconstruction and image recognition. However we expect that other applications will be developed by customers, as for instance softwares for optical flow estimation or for sound processing.

149 937 €

Start date: 2017-04-01, End date: 2018-09-30

Which molecules are present in the atmosphere of exoplanets? What are their mass, radius and age? Do they have clouds, convection (atmospheric turbulence), fingering convection, or a circulation induced by irradiation? These questions are fundamental in exoplanetology in order to study issues such as planet formation and exoplanet habitability. Yet, the impact of fingering convection and circulation induced by irradiation remain poorly understood: - Fingering convection (triggered by gradients of mean-molecular-weight) has already been suggested to happen in stars (accumulation of heavy elements) and in brown dwarfs and exoplanets (chemical transition e.g. CO/CH4). A large-scale efficient turbulent transport of energy through the fingering instability can reduce the temperature gradient in the atmosphere and explain many observed spectral properties of brown dwarfs and exoplanets. Nonetheless, this large-scale efficiency is not yet characterized and standard approximations (Boussinesq) cannot be used to achieve this goal. - The interaction between atmospheric circulation and the fingering instability is an open question in the case of irradiated exoplanets. Fingering convection can change the location and magnitude of the hot spot induced by irradiation, whereas the hot deep atmosphere induced by irradiation can change the location of the chemical transitions that trigger the fingering instability. This project will characterize the impact of fingering convection in the atmosphere of stars, brown dwarfs, and exoplanets and its interaction with the circulation in the case of irradiated planets. By developing innovative numerical models, we will characterize the reduction of the temperature gradient of the atmosphere induced by the instability and study the impact of the circulation. We will then predict and interpret the mass, radius, and chemical composition of exoplanets that will be observed with future missions such as the James Webb Space Telescope (JWST).

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31

The role of experience in language acquisition has been the focus of heated theoretical debates, between proponents of nativist views according to whom experience plays a minimal role and advocates of empiricist positions holding that experience, be it linguistic, social or other, is sufficient to account for language acquisition. Despite more than a half century of dedicated research efforts, the problem is not solved. The present project brings a novel perspective to this debate, combining hitherto unconnected research in language acquisition with recent advances in the neurophysiology of hearing and speech processing. Specifically, it claims that prenatal experience with speech, which mainly consists of prosody due to the filtering effects of the womb, is what shapes the speech perception system, laying the foundations of subsequent language learning. Prosody is thus the cue that links genetically endowed predispositions present in the initial state with language experience. The proposal links the behavioral and neural levels, arguing that the hierarchy of the neural oscillations corresponds to a unique developmental chronology in human infants’ experience with speech and language. The project uses state-of-the-art brain imaging techniques, EEG & NIRS, with monolingual full term newborns, as well as full-term bilingual, preterm and deaf newborns to investigate the link between prenatal experience and subsequent language acquisition. It proposes to follow the developmental trajectories of these four populations from birth to 6 and 9 months of age.

1 621 250 €

Start date: 2018-06-01, End date: 2023-05-31

Although the T cell antigen receptor (TCR) occupies a central place in T cell physiology, it does not work in isolation and the signals it triggers are tuned by receptors that convey positive (costimulators) and negative (coinhibitors) informations. We lack a satisfying comprehension of the way T cells integrate such multiple inputs to make informed decisions. The proteomics-based methodology we developed around the TCR places us in a favorable situation to decode at systems-level the crosstalk between the TCR, the CD28 costimulator and the PD-1 coinhibitor signaling pathways. The novelty of our approach stems from (1) its use of primary T cells, (2) its capacity to probe the architecture and dynamics of signalosomes resulting from T cell-antigen presenting cell encounters, (3) the attention we pay to the stoichiometry of the studied signalosomes, a key parameter largely ignored in previous studies, and (4) its multidisciplinary nature straddling molecular and organismal scales. Our specific aims are: Aim 1. To understand how the TCR and CD28 signaling pathways cooperate to achieve optimal T cell responses. Aim 2. To determine whether CD28 is the sole target of the PD-1 coinhibitor. Aim 3. To determine how under inflammatory conditions CD28 functions can be superseded by those of OX40, a costimulator of the TNFR superfamily. Aim 4. To unveil how malfunctions of LAT, a key signaling hub used by the TCR, disrupt the TCR-CD28 crosstalk and result in unique pathogenic T cells that by becoming ‘autistic’ to TCR signals and addicted to CD28 signals lead to severe immunopathologies. We think that combining genetic, epigenomics, proteomics, and computational approaches creates ideal experimental conditions to understand at system-levels how TCR, costimulatory, coinhibitory and inflammatory signals are integrated during T cell clonal expansion. Although of fundamental nature, our project should help understanding the harmful role PD-1 plays during anti-tumoral responses.

2 000 000 €

Start date: 2018-08-01, End date: 2022-07-31

Diabetes has become one of the most widespread metabolic disorders with epidemic dimensions affecting almost 6% of the world’s population. Despite modern treatments, the life expectancy of patients with Type 1 diabetes remains reduced as compared to healthy subjects. There is therefore a need for alternative therapies. Towards this aim, using the mouse, we recently demonstrated that the in vivo forced expression of a single factor in pancreatic alpha-cells is sufficient to induce a continuous regeneration of alpha-cells and their subsequent conversion into beta-like cells, such converted cells being capable of reversing the consequences of chemically-induced diabetes in vivo (Collombat et al. Cell, 2009). The PI and his team therefore propose to further decipher the mechanisms involved in this alpha-cell-mediated beta-cell regeneration process and determine whether this approach may be applied to adult animals and whether it would efficiently reverse Type 1 diabetes. Furthermore, a major effort will be made to verify whether our findings could be translated to human. Specifically, we will use a tri-partite approach to address the following issues: (1) Can the in vivo alpha-cell-mediated beta-cell regeneration be induced in adults mice? What would be the genetic determinants involved? (2) Can alpha-cell-mediated beta-cell regeneration reverse diabetes in the NOD Type 1 diabetes mouse model? (3) Can adult human alpha-cells be converted into beta-like cells? Together, these ambitious objectives will most certainly allow us to gain new insight into the mechanisms defining the identity and the reprogramming capabilities of mouse and human endocrine cells and may thereby open new avenues for the treatment of diabetes. Similarly, the determination of the molecular triggers implicated in the beta-cell regeneration observed in our diabetic mice may lead to exciting new findings, including the identification of “drugable” targets of importance for human diabetic patients.

1 500 000 €

Start date: 2012-01-01, End date: 2016-12-31

This proposal addresses a pressing need from emerging big data applications such as genomics and data center monitoring: besides the scale of processing, big data systems must also enable perpetual, low-latency processing for a broad set of analytical tasks, referred to as big and fast data analysis. Today’s technology falls severely short for such needs due to the lack of support of complex analytics with scale, low latency, and strong guarantees of user performance requirements. To bridge the gap, this proposal tackles a grand challenge: “How do we design an algorithmic foundation that enables the development of all necessary pillars of big and fast data analysis?” This proposal considers three pillars: 1) Parallelism: There is a fundamental tension between data parallelism (for scale) and pipeline parallelism (for low latency). We propose new approaches based on intelligent use of memory and workload properties to integrate both forms of parallelism. 2) Analytics: The literature lacks a large body of algorithms for critical order-related analytics to be run under data and pipeline parallelism. We propose new algorithmic frameworks to enable such analytics. 3) Optimization: To run analytics, today's big data systems are best effort only. We transform such systems into a principled optimization framework that suits the new characteristics of big data infrastructure and adapts to meet user performance requirements. The scale and complexity of the proposed algorithm design makes this project high-risk, at the same time, high-gain: it will lay a solid foundation for big and fast data analysis, enabling a new integrated parallel processing paradigm, algorithms for critical order-related analytics, and a principled optimizer with strong performance guarantees. It will also broadly enable accelerated information discovery in emerging domains such as genomics, as well as economic benefits of early, well-informed decisions and reduced user payments.

2 472 752 €

Start date: 2017-09-01, End date: 2022-08-31

Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange. Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion. Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.

1 499 901 €

Start date: 2018-08-01, End date: 2023-07-31

The detection of primordial gravity waves created during the Big Bang ranks among the greatest potential intellectual achievements in modern science. During the last few decades, the instrumental progress necessary to achieve this has been nothing short of breathtaking, and we today are able to measure the microwave sky with better than one-in-a-million precision. However, from the latest ultra-sensitive experiments such as BICEP2 and Planck, it is clear that instrumental sensitivity alone will not be sufficient to make a robust detection of gravitational waves. Contamination in the form of astrophysical radiation from the Milky Way, for instance thermal dust and synchrotron radiation, obscures the cosmological signal by orders of magnitude. Even more critically, though, are second-order interactions between this radiation and the instrument characterization itself that lead to a highly non-linear and complicated problem. I propose a ground-breaking solution to this problem that allows for joint estimation of cosmological parameters, astrophysical components, and instrument specifications. The engine of this method is called Gibbs sampling, which I have already applied extremely successfully to basic CMB component separation. The new and ciritical step is to apply this method to raw time-ordered observations observed directly by the instrument, as opposed to pre-processed frequency maps. While representing a ~100-fold increase in input data volume, this step is unavoidable in order to break through the current foreground-induced systematics floor. I will apply this method to the best currently available and future data sets (WMAP, Planck, SPIDER and LiteBIRD), and thereby derive the world's tightest constraint on the amplitude of inflationary gravitational waves. Additionally, the resulting ancillary science in the form of robust cosmological parameters and astrophysical component maps will represent the state-of-the-art in observational cosmology in years to come.

1 999 205 €

Start date: 2018-04-01, End date: 2023-03-31

"Many physical models involve nonlinear dispersive problems, like wave or laser propagation, plasmas, ferromagnetism, etc. So far, the mathematical under- standing of these equations is rather poor. In particular, we know little about the detailed qualitative behavior of their solutions. Our point is that an apparent com- plexity hides universal properties of these models; investigating and uncovering such properties has started only recently. More than the equations themselves, these univer- sal properties are essential for physical modelisation. By considering several standard models such as the nonlinear Schrodinger, nonlinear wave, generalized KdV equations and related geometric problems, the goal of this pro- posal is to describe the generic global behavior of the solutions and the profiles which emerge either for large time or by concentration due to strong nonlinear effects, if pos- sible through a few relevant solutions (sometimes explicit solutions, like solitons). In order to do this, we have to elaborate different mathematical tools depending on the context and the specificity of the problems. Particular emphasis will be placed on - large time asymptotics for global solutions, decomposition of generic solutions into sums of decoupled solitons in non integrable situations, - description of critical phenomenon for blow up in the Hamiltonian situation, stable or generic behavior for blow up on critical dynamics, various relevant regularisations of the problem, - global existence for defocusing supercritical problems and blow up dynamics in the focusing cases. We believe that the PI and his team have the ability to tackle these problems at present. The proposal will open whole fields of investigation in Partial Differential Equations in the future, clarify and simplify our knowledge on the dynamical behavior of solutions of these problems and provide Physicists some new insight on these models."

2 079 798 €

Start date: 2012-04-01, End date: 2017-03-31

"During their first year of life, infants become attuned to the phonemes, words and phonological rules of their language, with little or no adult supervision. After 30 years of accumulated experimental results, we are still lacking an account for the puzzling fact that these 3 interdependent components of language are acquired not sequentially, but in parallel. Drawing tools from Machine Learning and Automatic Speech Recognition, we construct a model of this early process, test it on 2 large spontaneous speech databases (Japanese, French and Dutch) and test its predictions in infants using behavioral, EEGs and fNIRS techniques. 1. Coding. We study different ways of defining coding features for speech, from fine-grained to coarse grained, in view of the automatic discovery of a hierarchy of linguistic units. We compare this with a systematic study of the units of speech coding as they unfold in 6, 9 and 12 month old infants.. 2. Lexicon. Infants recognize some words before they know the phonemes of their language; we modify existing word segmentation algorithms so they can work on raw speech. We test the unique prediction that infants start with a large lexicon that’s quite different from the adult one. 3. Rules. Phonemes are produced as overlapping, coarticulated gestures. To untangle these context effects, we use a predictive model of coarticulation in auditory space and invert it. We test when and how infants perform reverse coarticulation. 4. Integration. The above subprojects provide only an initial bootstrapping into approximate phonemes, words, and contextual rules. We show how to iteratively integrate these approximate representations to derive better ones. The outcome will be numerically assessed on an adult directed and infant directed speech database, and compared to those of to state-of-the-art supervized phoneme recognizers. The predictions will be tested in infants learning artificial languages and in a longitudinal study."

2 194 557 €

Start date: 2012-11-01, End date: 2017-10-31

The brain is composed of a set of areas specialized in specific computations whose outputs need to be transferred to other specialized areas for cognition to emerge. To account for context-dependent behaviors, the information has to be flexibly routed through the fixed anatomy of the brain. The aim of my proposal is to test a general framework for flexible communication between brain areas based on nested oscillations which I recently developed. The general idea is that internally-driven slow oscillations (<20Hz) either set-up or prevent the communication between brain areas. Stimulus-driven gamma oscillations (>30Hz), nested in the slow oscillations, can then be directed to task-relevant areas of the network. I plan to use a multimodal, multi-scale and transversal (human and monkey) approach in experiments manipulating visual processing, attention and memory to test core predictions of my framework. The theoretical approach and the methodological development used in my project will provide the basis for future fundamental and clinical research.

1 333 718 €

Start date: 2017-02-01, End date: 2022-01-31

Mobile data traffic sharply increases each year, due to the rich multi-media applications, video streaming, social networks, and billions of connected users and devices. This increasing mobile data traffic is expected to reach by 2018 roughly 60% of total network traffic. In this regard, caching contents at the edge of the network, namely at the base station and user terminals, is a promising way of offloading the backhaul (especially crucial in dense network deployments) and decreasing the end-to-end content access delays, since the requested contents become very close to the users. Therefore, caching has the potential to become the third key technique for wireless systems sustainability. The goal of this proof of concept is to realize a prototype of such an architecture which enables caching at the edge of the network, and called as “CacheMire”. In particular, we shall focus on development of the first version of CacheMire, which aims to 1) provide an application programming interface (API) to website developers (or content providers); 2) build a set of software/hardware tools to track/collect users' content access statistics under privacy constraints and regulations; 3) and design a storage unit/box for caching strategic contents (i.e., images, videos, files, news) at the base stations and access points. In addition, we aim to combine advanced physical layer techniques with caching so that resources in the uplink/downlink of next generation 5G wireless networks can be further optimized.

149 683 €

Start date: 2017-06-01, End date: 2018-11-30

Topology provides mathematical tools to sort objects according to global properties regardless of local details, and manifests itself in various fields of physics. In solid-state physics, specific topological properties of the band structure, such as a band inversion, can for example robustly enforce the appearance of spin-polarized conducting states at the boundaries of the material, while its bulk remains insulating. The boundary states of these ‘topological insulators’ in fact provide a support system to encode information non-locally in ‘topological quantum bits’ robust to local perturbations. The emerging ‘topological quantum computation’ is as such an envisioned solution to decoherence problems in the realization of quantum computers. Despite immense theoretical and experimental efforts, the rise of these new materials has however been hampered by strong difficulties to observe robust and clear signatures of their predicted properties such as spin-polarization or perfect conductance. These challenges strongly motivate my proposal to study two-dimensional topological insulators, and in particular explore the unknown dynamics of their topological edge states in normal and superconducting regimes. First it is possible to capture information both on charge and spin dynamics, and more clearly highlight the basic properties of topological edge states. Second, the dynamics reveals the effects of Coulomb interactions, an unexplored aspect that may explain the fragility of topological edge states. Finally, it enables the manipulation and characterization of quantum states on short time scales, relevant to quantum information processing. This project relies on the powerful toolbox offered by radiofrequency and current-correlations techniques and promises to open a new field of dynamical explorations of topological materials.

1 499 940 €

Start date: 2018-02-01, End date: 2023-01-31

How variations in whole chromosome number impact organism homeostasis remains an open question. Variations to the normal euploid genome content are frequently found in healthy animals and are thought to contribute with phenotypic variability in adverse situations. Yet they are also at the basis of several human diseases, including neuro-developmental disorders and cancer. Our preliminary data shows that physiological aneuploidy can be identified in certain cells during development. Moreover, we have observed that when induced through mutations, non-euploid cells are effectively eliminated from the cycling population. A quantitative view of the frequency of non-euploid karyotypes and the mechanisms underlying their genesis is lacking in the literature. Further, the tissue specific responses at play to eliminate non-euploid cells, when induced through mutations are not understood. The objectives of this proposal are to quantitatively assess the occurrence of physiological chromosome number variations gaining insight into mechanisms involved in generating it. Additionally, we will identify the tissue-specific pathways involved in maintaining organism homeostasis through the elimination of non-euploid cells. We will use a novel genetic approach to monitor individual chromosome loss at the level of the entire organism, combine it with quantitative methods and state-of-the art-microscopy, and focus on two model organisms - Drosophila and mouse - during development and adulthood. We predict that the findings resulting from this proposal will significantly impact the fields of cell, developmental and animal physiology, generating novel concepts that will bridge the existing gaps in the field, and expand our understanding of the links between karyotype variations, animal development and disease establishment.

2 000 000 €

Start date: 2017-07-01, End date: 2022-06-30

The failure of metallic materials caused by corrosion strongly impacts our society with cost, safety, health and performance issues. The mechanisms of corrosion propagation are fairly well understood, and various means of mitigation are known even if research is still necessary to improve this knowledge or to develop corrosion protection for the application of new materials. The vision of CIMNAS is that a major breakthrough for corrosion protection lies in a deep understanding and control of the initiation stage triggering corrosion. Corrosion initiation takes place at the atomic/molecular scale or at a scale of a few nanometres (the nanoscale) on metal and alloy surfaces, metallic, oxidised or coated, and interacting with the corroding environment. The mission of CIMNAS is to challenge the difficulty of understanding corrosion initiation at the nanometric/atomic scale on such complex interfaces, ultimately aiming at designing more robust metallic surfaces via the understanding of corrosion mechanisms. The project is constructed on new ideas to achieve three knowledge breakthroughs, each answering a key question for the understanding of corrosion initiation on metal and alloy surfaces. It is envisioned that the model approach used and the achieved breakthroughs will open up a new horizon for research on corrosion initiation mechanisms at the nanoscale, and new opportunities for a knowledge-based design of novel corrosion protection technologies. Technologies presently at low TRL (Technology Readiness Level) will benefit from these breakthroughs. Resources will include a team of highly experienced and recognised researchers headed by the PI, a unique apparatus recently installed at the PI’s lab, integrating surface spectroscopy, microscopy, and electrochemistry for in situ measurements in a closed system, novel experimental approaches, and a strong complementarity of experiments and modelling.

1 657 056 €

Start date: 2017-09-01, End date: 2021-08-31

Specific recruitment of different proteins to distinct intracellular membranes is fundamental in the biology of eukaryotic cells, but the molecular basis for specificity is incompletely understood. This proposal investigates the hypothesis that coincidence detection of proteins and lipids constitutes a major mechanism for specific recruitment of proteins to intracellular membranes in order to control cellular membrane dynamics. CODE will establish and validate mathematical models for coincidence detection, identify and functionally characterise novel coincidence detectors, and engineer artificial coincidence detectors as novel tools in cell biology and biotechnology.

2 500 000 €

Start date: 2019-01-01, End date: 2023-12-31

Bacteria are tiny; yet their collective dynamics generate large-scale flows and profoundly modify a fluid’s viscosity or diffusivity. So do autophoretic microswimmers, an example of active microscopic particles that draw their motion from physico-chemical exchanges with their environment. How do such ``active fluids'' turn individual microscopic propulsion into macroscopic fluid dynamics? What controls this self-organization process? These are fundamental questions for biologists but also for engineers, to use these suspensions for mixing or chemical sensing and, more generally, for creating active fluids whose macroscopic physical properties can be controlled precisely. Self-propulsion of autophoretic swimmers was reported only recently. Major scientific gaps impair the quantitative understanding of their individual and collective dynamics, which is required to exploit these active fluids. Existing models scarcely account for important experimental characteristics such as complex hydrodynamics, physico-chemical processes and confinement. Thus, these models cannot yet be used as predictive tools, even at the individual level. Further, to use phoretic suspensions as active fluids with microscopically-controlled properties, quantitatively-predictive models are needed for the collective dynamics. Instead of ad-hoc interaction rules, collective models must be built on a detailed physico-mechanical description of each swimmer’s interaction with its environment. This project will develop these tools and validate them against experimental data. This requires overcoming several major challenges: the diversity of electro-chemical processes, the confined geometry, the large number of particles, and the plurality of interaction mechanisms and their nonlinear coupling. To address these issues, rigorous physical, mathematical and numerical models will be developed to obtain a complete multi-scale description of the individual and collective dynamics of active particles.

1 497 698 €

Start date: 2017-09-01, End date: 2022-08-31

"The purpose of this project is to use the ubiquitous nature of certain combinatorial topological objects called maps in order to unveil deep connections between several areas of mathematics. Maps, that describe the embedding of a graph into a surface, appear in probability theory, mathematical physics, enumerative geometry or graph theory, and different combinatorial viewpoints on these objects have been developed in connection with each topic. The originality of our project will be to study these approaches together and to unify them. The outcome will be triple, as we will: 1. build a new, well structured branch of combinatorics of which many existing results in different areas of enumerative and algebraic combinatorics are only first fruits; 2. connect and unify several aspects of the domains related to it, most importantly between probability and integrable hierarchies thus proposing new directions, new tools and new results for each of them; 3. export the tools of this unified framework to reach at new applications, especially in random graph theory and in a rising domain of algebraic combinatorics related to Tamari lattices. The methodology to reach the unification will be the study of some strategic interactions at different places involving topological expansions, that is to say, places where enumerative problems dealing with maps appear and their genus invariant plays a natural role, in particular: 1. the combinatorial theory of maps developped by the "French school" of combinatorics, and the study of random maps; 2. the combinatorics of Fermions underlying the theory of KP and 2-Toda hierarchies; 3; the Eynard-Orantin "topological recursion" coming from mathematical physics. We present some key set of tasks in view of relating these different topics together. The pertinence of the approach is demonstrated by recent research of the principal investigator."

1 086 125 €

Start date: 2017-03-01, End date: 2022-02-28

I propose for funding to construct a spectrometer to map in 3-D the intensity due to line emission, a technique known as Intensity Mapping. Instead of detecting individual galaxies, this emerging technique measures signal fluctuations produced by the combined emission of the galaxy population on large regions of the sky in a wide frequency (i.e. redshift) band, and thus increases sensitivity to faint sources. Capitalizing on a recent technology breakthrough, our intensity mapping experiment will measure the 3-D fluctuations of the [CII] line at redshifts 4.5<z<8.5. [CII] is one of the most valuable star formation tracers at high redshift. My project will answer the outstanding questions of whether dusty star-formation contributes to early galaxy evolution, and whether dusty galaxies play an important role in shaping cosmic reionization. My team will first build, test, and finally install the instrument on the APEX antenna following an agreement with APEX partners. The spectrometer will be based on the state-of-the-art development of new arrays in the millimeter using Kinetic Inductance Detectors. Spectra (200-360 GHz) will be obtained by a fast Martin-Puplett interferometer. Then, we will observe with CONCERTO a few square degrees and offer a straight forward alternative for probing star formation and dust build-up in the early Universe. Finally, CONCERTO will set to music the various cosmic evolution probes. Cross-correlation of the signals will be used in particular to capture the topology of the end of reionization era. CONCERTO will be one of two instruments in the world to perform intensity mapping of the [CII] line in the short term. The novel methodology is extremely promising as it targets an unexplored observable touching on some of the fundamental processes building the early universe. In the flourishing of new ideas in the intensity-mapping field, CONCERTO lies at the forefront.

3 499 942 €

Start date: 2019-01-01, End date: 2023-12-31

Developing minimalistic biological neural networks and observing their functional activity is crucial to decipher the information processing in the brain. This project aims to address two major challenges: to design and fabricate in vitro biological neural networks that are organized in physiological relevant ways and to provide a label-free monitoring platform capable of observing neural activity both at the neuron resolution and at large fields of view. To do so, the project will develop a unique microfluidic compartmentalized chips where populations of primary neurons will be seeded in deposition chambers with physiological relevant number and densities. Chambers will be connected by microgrooves in which neurites only can grow and whose dimensions will be tuned according to the connectivity pattern to reproduce. To observe the activity of such complex neural networks, we will develop a disruptive observation technique that will transduce the electrical activity of spiking neurons into optical differences observed on a lens-free platform, without calcium labelling and constantly in-incubo. By combining neuro-engineering patterning and the lens-free platform, we will compare individual spiking to global oscillators in basic neural networks under localized external stimulations. Such results will provide experimental insight into computational neuroscience current approaches. Finally, we will design an in vitro network that will reproduce a neural loop implied in major neurodegenerative diseases with physiological relevant neural types, densities and connectivities. This circuitry will be manipulated in order to model Huntington and Parkinson diseases on the chip and assess the impact of known drugs on the functional activity of the entire network. This project will engineer microfluidics chips with physiological relevant neural network and a lensfree activity monitoring platform to answer fundamental and clinically relevant issues in neuroscience.

1 727 731 €

Start date: 2016-11-01, End date: 2021-10-31

According to the Centre for Research on the Epidemiology of Disasters (CRED), earthquakes are responsible for more than half of the total human losses due to natural disasters from 1994 to 2003. There is no doubt that earthquakes are lethal and costly. CoQuake proposes an alternative, ground-breaking approach for avoiding catastrophic earthquakes by inducing them at a lower energetic level. Earthquakes are a natural phenomenon that we cannot avoid, but –for the first time– in CoQuake I will show that it is possible to control them, hence reducing the seismic risk, fatalities and economic cost. CoQuake goes beyond the state-of-the-art by proposing an innovative methodology for investigating the effect and the controllability of various stimulating techniques that can reactivate seismic faults. It involves large-scale, accurate simulations of fault systems based on constitutive laws derived from micromechanical, grain-by-grain simulations under Thermo-Hydro-Chemo-Mechanical couplings (THMC), which are not calibrated on the basis of ad-hoc empirical and inaccurate constitutive laws. A pioneer experimental research programme and the design and construction of a new apparatus of metric scale, will demonstrate CoQuake’s proof-of-principle and it will help to explore the transition from aseismic to seismic slip. CoQuake is an interdisciplinary project as it takes knowledge from various fields of engineering, computational mechanics, geomechanics, mathematics and geophysics. CoQuake opens a new field and new line of research in earthquake mechanics and engineering, with a direct impact on humanity and science.

1 499 999 €

Start date: 2018-06-01, End date: 2023-05-31

Music performance is considered by many to be one of the most breath taking feats of human intelligence. That music performance is a creative act is no longer a disputed fact, but the very nature of this creative work remains illusive. Taking the view that the creative work of performance is the making and shaping of music structures, and that this creative thinking is a form of problem solving, COSMOS proposes an integrated programme of research to transform our understanding of the human experience of performed music, which is almost all music that we hear, and of the creativity of music performance, which addresses how music is made. The research themes are as follows: i) to find new ways to represent, explore, and talk about performance; ii) to harness volunteer thinking (citizen science) for music performance research by focussing on structures experienced and problem solving; iii) to create sandbox environments to experiment with making performed structures; iv) to create theoretical frameworks to discover the reasoning behind the structures perceived and made; and, v) to foster community engagement by training experts to provide feedback on structure solutions so as to increase public understanding of the creative work in music performance. Analysis of the perceived and designed structures will be based on a novel duality paradigm that turns conventional computational music structure analysis on its head to reverse engineer why a perceiver or a performer chooses a particular structure. Embedded in the approach is the use of computational thinking to optimise representations and theories to ensure accuracy, robustness, efficiency, and scalability. The PI is an established performer and a leading authority in music representation, music information research, and music perception and cognition. The project will have far reaching impact, reconfiguring expert and public views of music performance and time-varying music-like sequences such as cardiac arrhythmia.

2 495 776 €

Start date: 2019-06-01, End date: 2024-05-31

With COVOPRIM I propose to reconstruct the recent evolutionary history of one often overlooked component of speech and language: voice perception. Perceptual and neural mechanisms of voice perception will be compared between humans, macaques and marmosets –two highly vocal and extensively studied monkey species–to quantify cross-species differences and infer mechanisms potentially inherited from a common ancestor. Two key building blocks of vocal communication detailed in my past research in humans will be compared across species: (1) the sensitivity to conspecific vocalizations, and (2) the processing of speaker/caller identity. COVOPRIM is organized in three workpackages (WPs). WP1 will use large-scale behavioural testing based on ad-lib access of monkeys to automated test systems (following the highly successful model developed locally with baboons). Two main behavioural experiments will establish psychometric response functions for robust cross-species comparison. WP2 will use functional magnetic resonance imaging (fMRI) to measure cerebral activity during auditory stimulation in the three species. I will compare across brains the organization of what I hypothesize constitutes a “voice patch system” similar to the face patch system of visual cortex and broadly conserved in primates. I will also take advantage of the monkey models and use long-term, subject-specific enrichments of the auditory stimulation to probe the experience-dependence of neural coding in the voice patch system—an outstanding issue in human voice perception. WP3 will use fMRI-guided microstimulation in monkeys and transcranial magnetic stimulation in humans to establish the effective connectivity within the voice patch system and test the causal relation between voice patch neuronal activity and voice perception behaviour. COVOPRIM is expected to generate considerable advances in our understanding of the recent evolution in primates of the perceptual and neural mechanisms of voice perception.

2 900 000 €

Start date: 2019-01-01, End date: 2023-12-31

Low temperature matter exhibits a spectacular variety of highly ordered states that occur through phase transitions. In quantum systems, phase transitions and associated critical phenomena constitute a central issue of modern physics. Wilson’s theory of renormalization showed that very different physical systems could be unified under the same universality class characterized by critical exponents. The high degree of control offered by ultracold atom experiments sets them as an ideal platform for the investigation of phase transitions and critical phenomena. CRITISUP2 aims at exploring criticality in superfluid spin ½ Fermi gases where the interplay between temperature spin polarization and interactions is at the origin of a rich phase diagram and a variety of phase transitions. We will measure the corresponding static and dynamic critical exponents, and search for the long-sought Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase predicted over 50 years ago. We will also study the phase diagram and critical counterflow of dual Bose-Fermi superfluids which have emerged as a new paradigm of quantum matter. Cutting-edge Bold Diagrammatic Monte Carlo and new resummation methods, developed in-house, will be confronted to the experiments on the one hand, and provide answers to debated questions on the other. The expected outcomes of CRITISUP2 will constitute a major leap forward relevant for several fields of modern physics, ranging from condensed-matter to astrophysics, nuclear physics, and high energy physics.

2 246 536 €

Start date: 2017-05-01, End date: 2022-04-30

Emergence of a large number of distributed decision and control systems (e.g., in health care, transportation, and energy management), combined with increasing demands of traditional communications (e.g., due to multiview videos), create an imminent need for highly improved communication systems. We advocate that—combined with improvements in battery, antenna, and chip technologies—context- and/or task-oriented communication techniques will bring the desired breakthrough. Specifically, context- oriented techniques will greatly improve performance, because future networks have complex infrastructures (with cache-memories, cloud-RANs, etc.) allowing the terminals to collect side-informations about other terminals’ data or signals, and because many distributed decision systems rely on numerous devices with correlated measurements. Task-oriented techniques promise even larger gains, especially in distributed decision systems where decisions take value on a small range, and thus the traditional approach of communicating sequences of observed signals results in a huge overhead. Information theory, and in particular distributed joint source-channel coding, provides a general framework for designing context-oriented communication techniques. Such a general framework is missing for task-oriented communication. Previous results indicate that creative usages of information theory on its frontier to statistics and decision theory are well-suited for designing task-oriented communication techniques for applications as diverse as coordination of smart devices, distributed hypothesis testing, and clustering of data. Our goal is to design context- and/or task-oriented communication techniques for these three applications and for cache-aided communication. Besides the high gains that our new techniques bring directly to these applications, the complementarity of our applications and obtained results will facilitate a future general framework for context- and task-oriented communication.

1 495 288 €

Start date: 2017-05-01, End date: 2022-04-30

Designers draw extensively to externalize their ideas and communicate with others. However, drawings are currently not directly interpretable by computers. To test their ideas against physical reality, designers have to create 3D models suitable for simulation and 3D printing. However, the visceral and approximate nature of drawing clashes with the tediousness and rigidity of 3D modeling. As a result, designers only model finalized concepts, and have no feedback on feasibility during creative exploration. Our ambition is to bring the power of 3D engineering tools to the creative phase of design by automatically estimating 3D models from drawings. However, this problem is ill-posed: a point in the drawing can lie anywhere in depth. Existing solutions are limited to simple shapes, or require user input to “explain” to the computer how to interpret the drawing. Our originality is to exploit professional drawing techniques that designers developed to communicate shape most efficiently. Each technique provides geometric constraints that help viewers understand drawings, and that we shall leverage for 3D reconstruction. Our first challenge is to formalize common drawing techniques and derive how they constrain 3D shape. Our second challenge is to identify which techniques are used in a drawing. We cast this problem as the joint optimization of discrete variables indicating which constraints apply, and continuous variables representing the 3D model that best satisfies these constraints. But evaluating all constraint configurations is impractical. To solve this inverse problem, we will first develop forward algorithms that synthesize drawings from 3D models. Our idea is to use this synthetic data to train machine learning algorithms that predict the likelihood that constraints apply in a given drawing. In addition to tackling the long-standing problem of single-image 3D reconstruction, our research will significantly tighten design and engineering for rapid prototyping.

1 482 761 €

Start date: 2017-02-01, End date: 2022-01-31

Dark matter (DM) is a ubiquitous yet invisible presence in our universe. It dictated how galaxies formed in the first place, and now moves stars around them at puzzling speeds. The DM mass in the universe is known to be five times that of ordinary matter; yet its true nature remains elusive. Weakly interacting massive particles (WIMPs), relics from the early universe, are a compelling explanation chased by sensitive experiments in deep underground laboratories. However, searches for heavy WIMPs (≈100 times the proton mass), the most theoretically natural candidates, have been so far unsuccessful. Nor has evidence for such heavy particles yet been found at the CERN Large Hadron Collider. Alternative scenarios are now under scrutiny, such as the existence of a hidden sector of lighter DM particles that interact, differently than WIMPs, also with electrons. DAMIC-M (Dark Matter In CCDs at Modane) will search beyond the heavy WIMP paradigm by detecting nuclear recoils and electrons induced by light DM in charge-coupled devices (CCDs). The 0.5 kg detector will be installed at the Laboratoire Souterrain de Modane, France. In this novel and unconventional use of CCDs, which are commonly employed for digital imaging in astronomical telescopes, the ionization charge will be detected in the most massive CCDs ever built with exquisite spatial resolution (15 μm x 15 μm pixel). The crucial innovation in these devices is the non-destructive, repetitive measurement of the pixel charge, which results in the high-resolution detection of a single electron and unprecedented sensitivity to light DM (≈ eV energies are enough to free an electron in silicon). By counting individual charges in a detector with extremely low leakage current – a combination unmatched by any other DM experiment – DAMIC-M will take a leap forward of several orders of magnitude in the exploration of the hidden sector, a jump that may be rewarded by serendipitous discovery.

3 349 563 €

Start date: 2018-09-01, End date: 2023-08-31

The switch from parchment to paper had a fundamental impact on later medieval universities, equivalent to the shift to Open Access today, hindering some intellectual practices while encouraging others. The DEBATE project identifies a neglected genre of latin texts that flourished on paper, the Principia, which record the public confrontations between candidates (socii) for the title of doctor. These debates, imposed by university statutes throughout Europe as annual exercises linked to lectures on the Sentences (the medieval parallel to our PhD thesis), forced the candidate to reveal his innovative theories (sheets of papers were exchanged among the socii beforehand), display his erudition and prove his intellectual prowess before a large audience. The futuristic discussion usually exceeded the confines of one discipline and allowed the bachelor to indulge his interdisciplinary interests, employing science, theology, mathematics, politics, literature, and rhetoric in his polemics against his colleagues. Principia thus reveal the cutting edge method of fostering science in later medieval universities. The DEBATE team intends to identify new manuscripts, edit the texts, establish authorship for anonymous fragments and propose an interpretation that will help explain how innovation was a primordial target in medieval academia. Putting together all the surviving texts of Principia produced in various cultural contexts, this project will provide a wealth of material that will bring about a basic change in our understanding of the mechanism of the production of academic knowledge in the early universities all around Europe.The project is designed to promote erudition by combining a palaeographical, codicological, editorial and hermeneutical approach, aiming to open an advanced area of inquiry focusing on an intellectual practice that bound together medieval universities from different geographical and cultural regions: Paris, Bologna, Vienna, Prague, Krakow and Cologne.

1 997 976 €

Start date: 2018-08-01, End date: 2023-07-31

We are designing molecular networks - based on DNA programing- to detect extremely dilute molecular signals and robustly separate them from background noise. This could have relevant applications in the field of molecular diagnostics, in particular in the area of ultra-sensitive testing of nucleic acids from liquid biopsy for example for the detection of circulating microRNA. MicroRNA are difficult targets for standard ultra sensitive techniques such as quantitative PCR, but, because of their presence in the blood stream, they also represent an emerging class of important biomarkers for a wide range of diseases, including cancer. This project will allow us to put together a proof of principle, based of clinically relevant targets and sample, that will clearly demonstrate the benefit of our approach for the molecular diagnostic of microRNA, in terms of sensibility, multiplexing, robustness, modularity and simplicity in sample preparation.

149 852 €

Start date: 2017-12-01, End date: 2019-05-31

We propose a program that aims at providing new developments and new applications of shifted symplectic and Poisson structures. It is formulated in the language and framework of derived algebraic geometry after Toën–Vezzosi and Lurie. On the foundational side, we will introduce the new notion of shifted symplectic groupoids and prove that they provide an alternative approach to shifted Poisson structures (as they were defined by the PI together with Tony Pantev, Bertrand Toën, Michel Vaquié and Gabriele Vezzosi). Along the way, we shall be able to prove several conjectures that have recently been formulated by the PI and other people. Applications are related to mathematical physics. For instance: - We will provide an interpretation of the Batalin–Vilkovisky formalism in terms of derived symplectic reduction. - We will show that the semi-classical topological field theories with values in derived Lagrangian correspondences that were previously introduced by the PI are actually fully extended topological field theories in the sense of Baez–Dolan and Lurie. - We will explain how one may use this formalism to rigorously construct a 2D topological field theory that has been discovered by Moore and Tachikawa. Quantization problems will also be discussed at the end of the proposal. This project proposal lies at the crossroads of algebraic geometry, mathematical physics (in its algebraic and geometric aspects) and higher algebra.

1 385 247 €

Start date: 2018-09-01, End date: 2023-08-31

"Diatoms are the most successful group of eukaryotic phytoplankton in the modern ocean. Recently completed whole genome sequences have revealed a wealth of information about the evolutionary origins and metabolic adaptations that may have led to their ecological success. A major finding is that they have acquired genes both from their endosymbiotic ancestors and by horizontal gene transfer from marine bacteria. This unique melting pot of genes encodes novel and largely unexplored capacities for metabolic management. The project will address the current gap in knowledge about the physiological functions of diatom gene products and about the evolutionary mechanisms that have led to diatom success in contemporary oceans. We will exploit genome-enabled approaches to pioneer new research topics addressing: 1. How has diatom evolution enabled interactions between chloroplasts and mitochondria that have provided diatoms with physiological and metabolic innovations? 2. What are the relative contributions of DNA sequence variation and epigenetic processes in diatom adaptive dynamics? By combining these questions, we will uniquely be able to identify sentinel genes that have driven major physiological and metabolic innovations in diatoms, and will explore the mechanisms that have selected and molded them during diatom evolution. We will focus our studies largely on diatom responses to nutrients, in particular nitrate and iron, and will exploit the advantages of Phaeodactylum tricornutum as a model diatom species for reverse genetics. The proposed studies will revisit textbook understanding of photosynthesis and nitrogen metabolism, and will refine hypotheses about why diatoms dominate in contemporary ocean settings. By placing our studies in evolutionary and ecological contexts, in particular by examining the contribution of epigenetic processes in diatoms, our work will furthermore provide insights into how the environment selects for fitness in phytoplankton."

2 423 320 €

Start date: 2012-06-01, End date: 2017-05-31

Discrete subgroups of Lie groups, whose study originated in Fuchsian differential equations and crystallography at the end of the 19th century, are the basis of a large aspect of modern geometry. They are the object of fundamental theories such as Teichmüller theory, Kleinian groups, rigidity theories for lattices, homogeneous dynamics, and most recently Higher Teichmüller theory. They are closely related to the notion of a geometric structure on a manifold, which has played a crucial role in geometry since Thurston. In summary, discrete subgroups are a meeting point of geometry with Lie theory, differential equations, complex analysis, ergodic theory, representation theory, algebraic geometry, number theory, and mathematical physics, and these fascinating interactions make the subject extremely rich. In real rank one, important classes of discrete subgroups of semisimple Lie groups are known for their good geometric, topological, and dynamical properties, such as convex cocompact or geometrically finite subgroups. In higher real rank, discrete groups beyond lattices remain quite mysterious. The goal of the project is to work towards a classification of discrete subgroups of semisimple Lie groups in higher real rank, from two complementary points of view. The first is actions on Riemannian symmetric spaces and their boundaries: important recent developments, in particular in the theory of Anosov representations, give hope to identify a number of meaningful classes of discrete groups which generalise in various ways the notions of convex cocompactness and geometric finiteness. The second point of view is actions on pseudo-Riemannian symmetric spaces: some very interesting geometric examples are now well understood, and recent links with the first point of view give hope to transfer progress from one side to the other. We expect powerful applications, both to the construction of proper actions on affine spaces and to the spectral theory of pseudo-Riemannian manifolds

1 049 182 €

Start date: 2017-09-01, End date: 2022-08-31

DISCRETION aims to unlock the black box of discretionary decision-making in child protection cases by a comparative-empirical study of how discretionary decisions are made and justified in the best interests of the child. There are huge research gaps in this important area of the welfare state, with a great deal of uncertainty concerning how, when and why discretionary decisions about the child´s best interests are different between decision-makers within and between child protection systems. The main objectives for this project are to reveal the mechanisms for exercising discretion, and improve the understanding of the principle of the child´s best interests. These objectives will be reached by systematically examining the role of institutional, organisational and individual factors including regulations of best interest principles; professions involved; type of courts; type of child protection system; demographic factors and individual values; and the populations’ view on children and paternalism. DISCRETION employs an innovative methodological approach, with multilevel and cross-country studies. DISCRETION will, by conducting the largest cross-national study on decision-making in child protection to date, lift our understanding of international differences in child protection to a new level. By conducting randomized survey experiments with both decision-makers in the system and the general population, DISCRETION generates unique data on the causal mechanisms explaining differences in discretionary decisions. The outcomes of DISCRETION are important because societies are at a crossroad when it comes to how children are treated and how their rights are respected, which creates tensions in the traditional relationship between the family and the state. DISCRETION will move beyond the field of child protection and provide important insights into the exercise of discretion in all areas where the public interest as well as national interest must be interpreted.

1 997 918 €

Start date: 2017-06-01, End date: 2022-05-31

The molecular mechanisms that serve to couple DNA replication, chromosome segregation and cell division are largely unknown in bacteria. This led a considerable interest to the study of Escherichia coli FtsK, an essential cell division protein that assembles into DNA-pumps to transfer chromosomal DNA between the two daughter cell compartments during septation. Indeed, our recent work suggests that FtsK might regulate the late stages of septation to ensure DNA is fully cleared from the septum before it is allowed to close. This would be the first example of a cell cycle checkpoint in bacteria. FtsK-mediated DNA transfer is required in 15% of the cells at each generation in E. coli, in which it serves to promote the resolution of topological problems arising from the circularity of the chromosome by Xer recombination. However, the FtsK checkpoint could be a more general feature of the bacterial cell cycle since FtsK is highly conserved among eubacteria, including species that do not possess a Xer system. Indeed, preliminary results from the lab indicate that DNA transfer by FtsK is required independently of Xer recombination in Vibrio cholerae. To confirm the existence and the generality of the FtsK checkpoint in bacteria, we will determine the different situations that lead to a requirement for FtsK-mediated DNA transfer by studying chromosome segregation and cell division in V. cholerae. In parallel, we will apply new fluorescent microscopy tools to follow the progression of cell division and chromosome segregation in single live bacterial cells. PALM will notably serve to probe the structure of the FtsK DNA-pumps at a high spatial resolution, FRET will be used to determine their timing of assembly and their interactions with the other cell division proteins, and TIRF will serve to follow in real time their activity with respect to the progression of chromosome dimer resolution, chromosome segregation, and septum closure.

1 565 938 €

Start date: 2012-02-01, End date: 2017-01-31

DREAM, Drafting and Enacting the Revolutions in the Arab Mediterranean, seeks to write the history of the revolutions in the Arab Mediterranean since the independences. It aims to write a transnational history of often forgotten struggles, recall facts and original forms of resistance. We know very few about the revolts that occurred in this period, and even less about the memory that they left in the societies, the way these memories circulated. This rediscovery of revolutions in the shadows must be done through the collection of original material, specifically “poor archives” of the ordinary and the production of Archives – through a combination of classical interviews and innovative methods that involve researchers, archivists, artists and the actors themselves. The objective is to write a history that focuses on emotions and paths of revolts, telling us more about the link between all dimensions of human lives in these territories (religion, gender, social positions) and the articulation of these dimensions in the revolutionary projects. DREAM aims to write a history that doesn’t produce heroes or big figures, doesn’t discuss success or failure, but tries to understand the motivations and the potentialities that were at stake in different episodes and moments, during the uprisings and in between them. It aims to explore the historical signification and the concrete aspects of the call for dignity (Karama/sharaf) in a space that, after liberating itself from the colonial domination, was trapped into the illusion of a common faith (being it the Arab nation or the Islamic umma) and the concrete oppression of authoritarian regimes. This period needs urgently to be explored and history, with its modern tools and patterns, can embrace and trace the particular conditions in which Arab people lived for more than six decades, and specifically the frames of their dreams and projections.

1 941 050 €

Start date: 2018-09-01, End date: 2023-08-31