ERC FUNDED PROJECTS

Multiple myeloma (MM) is a cancer of plasma cells, that is incurable, and the second most common form of blood cancer. Proteasome inhibitors (PIs) are considered a mainstay in the treatment of MM and mantle cell lymphoma (MCL). Current drugs, based on PIs however, target the chymotrypsin-like activity of the 20S proteasome, and inhibit the activities of both the 20S and 26S proteasomes. Thus, it is possible that selective drug intervention specifically inhibiting only the 20S proteasomes will reduce toxicity, and minimize the deleterious side effects of the current therapeutic regimens. Our preliminary work revealed a family of 20S proteasome inhibitors, which we termed Catalytic Core Regulators (CCRs) that selectively target the 20S proteasome rather than the 26S complex. Based on sequence motif and structural elements of the CCRs we have designed an artificial protein that is capable of inhibiting the 20S proteasome. We anticipate that these findings will lead to the design of synthetic proteins, peptides or peptidomimetic compounds targeting cancer cells more specifically. This specificity will pose the compounds in an attractive light for using them in various therapeutic applications. What is exciting from the commercialization perspective, is that pharmaceutical research has switched to revisit the use of peptides as therapeutics. Pharmaceutical companies have seen the development of peptides as a promising direction to lower their risk position. Overall, peptide therapeutics have a 20% chance of receiving regulatory approval, a probability that is 50% higher than that for the approval of small molecules, which form the basis of so called traditional drugs. In the project, we will carry out actions, which will equip us with the sufficient IP protection strategy, business strategy, industry networks and initial contacts for taking the innovation out from the laboratory to next phase in developing therapy first for MM and MCL later on.

150 000 €

Start date: 2019-04-01, End date: 2020-09-30

The paradigm of the structure-function relationship in proteins is outdated.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

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

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

In the coming few decades, two major global grand challenges will continue to attract the attention of scientists and engineers in academia and industry: achieving clean water and clean energy. This PoC establishes the development of two prototypes, water oxidation catalyst and water purification filter, by creating inexpensive, abundant and versatile hierarchical structures of inorganic nanomaterials (HSINs). The formation of HSINs has been one of the major obstacles toward achieving a technological progress in various applications. Presently, fabrication of well-defined 3-D structures can be achieved either by photo/electro lithography, assembly, 3D printing or template-mediated methods. Various structures with high quality/yield can be obtained through those techniques, however, these methods suffer from high cost, difficulty of fabrication of free-standing structures, and sometime the throughput is limited. On the other hand, the templated approaches usually are facile, low cost and offer several and complex structures in particular the ones obtained from nature. Our invention is based on forming the HSINs using fossil templates from nature. We propose to harness the naturally designed morphologies of the fossil templates to rationally form hierarchical structures of nanomaterials. These structures have many advantageous, compared to the current state-of-the-art catalyst and filter, for example high surface area, high porosity, confined space (nano-reactor) and divers functionalities obtained by controlling the chemical composition of the inorganic material shell. Since these properties are important for achieving high performance, we propose HSINs as next generation water oxidation electrocatalyst and water purification filter.

150 000 €

Start date: 2017-03-01, End date: 2018-08-31

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

1 500 000 €

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

What is responsible for the emergence of homochirality, the almost exclusive use of one enantiomer over its mirror image? And what led to the evolution of life’s homochiral biopolymers, DNA/RNA, proteins and lipids, where all the constituent monomers exhibit the same handedness? Based on in-situ observations and laboratory studies, we propose that this handedness occurs when chiral biomolecules are synthesized asymmetrically through interaction with circularly polarized photons in interstellar space. The ultimate goal of this project will be to demonstrate how the diverse set of heterogeneous enantioenriched molecules, available from meteoritic impact, assembles into homochiral pre-biopolymers, by simulating the evolutionary stages on early Earth. My recent research has shown that the central chiral unit of RNA, ribose, forms readily under simulated comet conditions and this has provided valuable new insights into the accessibility of precursors of genetic material in interstellar environments. The significance of this project arises due to the current lack of experimental demonstration that amino acids, sugars and lipids can simultaneously and asymmetrically be synthesized by a universal physical selection process. A synergistic methodology will be developed to build a unified theory for the origin of all chiral biological building blocks and their assembly into homochiral supramolecular entities. For the first time, advanced analyses of astrophysical-relevant samples, asymmetric photochemistry triggered by circularly polarized synchrotron and laser sources, and chiral amplification due to polymerization processes will be combined. Intermediates and autocatalytic reaction kinetics will be monitored and supported by quantum calculations to understand the underlying processes. A unified theory on the asymmetric formation and self-assembly of life’s biopolymers is groundbreaking and will impact the whole conceptual foundation of the origin of life.

1 500 000 €

Start date: 2019-04-01, End date: 2024-03-31

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 rupture of an Aortic Aneurysm (AA), which is often lethal, is a mechanical phenomenon that occurs when the wall stress state exceeds the local strength of the tissue. Our current understanding of arterial rupture mechanisms is poor, and the physics taking place at the microscopic scale in these collagenous structures remains an open area of research. Understanding, modelling, and quantifying the micro-mechanisms which drive the mechanical response of such tissue and locally trigger rupture represents the most challenging and promising pathway towards predictive diagnosis and personalized care of AA. The PI's group was recently able to detect, in advance, at the macro-scale, rupture-prone areas in bulging arterial tissues. The next step is to get into the details of the arterial microstructure to elucidate the underlying mechanisms. Through the achievements of AArteMIS, the local mechanical state of the fibrous microstructure of the tissue, especially close to its rupture state, will be quantitatively analyzed from multi-photon confocal microscopy and numerically reconstructed to establish quantitative micro-scale rupture criteria. AArteMIS will also address developing micro-macro models which are based on the collected quantitative data. The entire project will be completed through collaboration with medical doctors and engineers, experts in all required fields for the success of AArteMIS. AArteMIS is expected to open longed-for pathways for research in soft tissue mechanobiology which focuses on cell environment and to enable essential clinical applications for the quantitative assessment of AA rupture risk. It will significantly contribute to understanding fatal vascular events and improving cardiovascular treatments. It will provide a tremendous source of data and inspiration for subsequent applications and research by answering the most fundamental questions on AA rupture behaviour enabling ground-breaking clinical changes to take place.

1 499 783 €

Start date: 2015-04-01, End date: 2020-03-31

Chronic Obstructive Pulmonary Disease (COPD) is a group of chronic diseases characterized by airflow limitations in the lung. COPD is a critical international health problem. It is estimated to affect up to 600 million people worldwide and by 2020 it will become the third most frequent cause of death. In Europe alone, COPD affects up to 10% of people (i.e. more people than breast cancer and diabetes) and it takes the life of around 300,000 Europeans each year. Up to date, COPD has no cure as current treatments fail to halt the long-term decline in lung function. They are only able to delay its progression. Those treatments however, are associated with a variety of side effects some of which can be acute and even life threatening. Thus, COPD remains a disease with a significant unmet medical need. In this project (acronymed AbCURE_COPD) we intend to carry out a set of necessary activities for the evaluation of a potentially groundbreaking approach for treating COPD. Our approach is focusing on antibody-mediated clearance of senescent cells which accumulate in tissues with age and contribute to multiple age-related diseases, including COPD. The goal of the PoC project is two-fold. (1) The first goal is to establish the technical feasibility of our idea by testing the effect of senescence-specific antibodies on COPD development and progression by implementing COPD mouse model we developed. (2) The second goal is to establish the business feasibility of our revolutionary approach by taking the necessary steps towards its commercialization, focusing on the creation of strategic alliances with key private sector companies. We firmly believe that with our approach we can significantly extend the health span and improve the quality of life of COPD patients. Equally important, our approach will pave the way for the development of novel treatment strategies applicable to other age-related diseases, such as osteoarthritis, cardiovascular, and neurodegenerative diseases.

150 000 €

Start date: 2018-11-01, End date: 2020-04-30

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

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

3 000 000 €

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

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

2 500 000 €

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

In tissues, cells have their physical space constrained by neighbouring cells and extracellular matrix. In the PROMICO ERC project, our team proposed to specifically address the effect of physical confinement on normal and cancer cells that are dividing and migrating, using new pathophysiologically relevant in vitro approaches based on innovative micro-fabrication techniques. One of the devices we developed was meant to quantitatively control two key parameters of the cell environment: its geometry and its surface chemical properties. The main technical breakthrough was achieved using micro-fabricated elastomeric structures bound to a hard substrate (Le Berre Integrative Biology, 2012). The method led to important fundamental discoveries in cell biology (Lancaster Dev Cell 2013, Le Berre PRL 2013, Liu Cell 2015, Raab Science 2016). In part based on our findings, the notion that confinement is a crucial parameter for cell physiology has spread through the cell biology. Based on this, our idea is that cell confinement could be used as a powerfull cell conditioning technology, to change the cell state and offer new opportunities for fundamental research in cell biology, but also in cell therapies and drug screening. However, our current method to confine cells is not adapted to large scale cell conditioning applications, because the throughput and reliability of the device is still too low and because the recovery of cells after confinement remain poorly controlled. It is thus now timely to develop a robust and versatile cell confiner adapted to use in any cell biology lab, in academy and in industry, with no prior experience in micro-fabrication. Achieving this goal involves a complete change of technology compared to the ‘homemade’ PDMS device we have been using so far. We will also perform proofs of concept of its use for its application in cell based therapies, such as cancer immunotherapy, by testing the possibility to mechanically activate dendritic cells.

150 000 €

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

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

1 497 420 €

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

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

1 476 882 €

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

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

1 761 000 €

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

The human kind is witnessing an escalation of obesity-related health problems such as cardiovascular diseases and type 2 diabetes. A recent groundbreaking study revealed adiponectin receptors (ADIPOR) as key targets for treating such obesity-related diseases. Indeed, the modulation of this integral membrane protein by small molecules agonists ameliorates diabetes and prolongs lifespan of genetically obese rodent model. Despite these exciting results and the importance of ADIPOR in human physiology, there is a complete lack of knowledge of ADIPOR mechanisms of action and pharmacology. This is mainly due to the challenges associated with the characterization of membrane protein structure and function. To fill this gap of knowledge and based on my extensive experience in membrane protein biology, I propose here to characterize the the proximal signaling pathways associated with ADIPOR activation as well as the molecular and structural mechanisms of ADIPOR activation. We will develop an innovative integrated strategy combining state-of-the-art molecular and structural pharmacology approaches including 1) molecular analyses of ADIPOR network of interaction using resonance energy transfer measurement in living cells and a proteomic analysis and 2) structural analyses of ADIPOR and signaling complexes using biophysics and X-ray crystallography. Our data will have a major impact on drug discovery for treating obesity-related diseases as it will enable the application of structure-based drug design and in silico screening for the molecular control of ADIPOR activity. The proposed high-risk endeavor of obtaining structural data on these atypical membrane signaling complexes is a new direction both for my career and for the field of adiponectin biology; the exceptionally high gain from these studies fully justifies the risks; the feasibility of this project is supported by my recent success in membrane protein pharmacology, biochemistry, biophysics and crystallography.

1 989 518 €

Start date: 2015-07-01, End date: 2020-06-30

The understanding of spatial, social and dynamical organization of large numbers of agents is presently a fundamental issue in modern science. ADORA focuses on problems motivated by biology because, more than anywhere else, access to precise and many data has opened the route to novel and complex biomathematical models. The problems we address are written in terms of nonlinear partial differential equations. The flux-limited Keller-Segel system, the integrate-and-fire Fokker-Planck equation, kinetic equations with internal state, nonlocal parabolic equations and constrained Hamilton-Jacobi equations are among examples of the equations under investigation. The role of mathematics is not only to understand the analytical structure of these new problems, but it is also to explain the qualitative behavior of solutions and to quantify their properties. The challenge arises here because these goals should be achieved through a hierarchy of scales. Indeed, the problems under consideration share the common feature that the large scale behavior cannot be understood precisely without access to a hierarchy of finer scales, down to the individual behavior and sometimes its molecular determinants. Major difficulties arise because the numerous scales present in these equations have to be discovered and singularities appear in the asymptotic process which yields deep compactness obstructions. Our vision is that the complexity inherent to models of biology can be enlightened by mathematical analysis and a classification of the possible asymptotic regimes. However an enormous effort is needed to uncover the equations intimate mathematical structures, and bring them at the level of conceptual understanding they deserve being given the applications motivating these questions which range from medical science or neuroscience to cell biology.

2 192 500 €

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

Fundamental interactions in nature are well described by quantum gauge fields in 4 space-time dimensions (4d). When the strength of gauge interaction is weak the Feynman perturbation techniques are very efficient for the description of most of the experimentally observable consequences of the Standard model and for the study of high energy processes in QCD. But in the intermediate and strong coupling regime, such as the relatively small energies in QCD, the perturbation theory fails leaving us with no reliable analytic methods (except the Monte-Carlo simulation). The project aims at working out new analytic and computational methods for strongly coupled gauge theories in 4d. We will employ for that two important discoveries: 1) the gauge-string duality (AdS/CFT correspondence) relating certain strongly coupled gauge Conformal Field Theories to the weakly coupled string theories on Anty-deSitter space; 2) the solvability, or integrability of maximally supersymmetric (N=4) 4d super Yang-Mills (SYM) theory in multicolor limit. Integrability made possible pioneering exact numerical and analytic results in the N=4 multicolor SYM at any coupling, effectively summing up all 4d Feynman diagrams. Recently, we conjectured a system of functional equations - the AdS/CFT Y-system – for the exact spectrum of anomalous dimensions of all local operators in N=4 SYM. The conjecture has passed all available checks. My project is aimed at the understanding of origins of this, still mysterious integrability. Deriving the AdS/CFT Y-system from the first principles on both sides of gauge-string duality should provide a long-awaited proof of the AdS/CFT correspondence itself. I plan to use the Y-system to study the systematic weak and strong coupling expansions and the so called BFKL limit, as well as for calculation of multi-point correlation functions of N=4 SYM. We hope on new insights into the strong coupling dynamics of less supersymmetric gauge theories and of QCD.

1 456 140 €

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

Aeroelastic instabilities are at the origin of large deformations of structures and are limiting the capacities of products in various industrial branches such as aeronautics, marine industry, or wind electricity production. If suppressing aeroelastic instabilities is an ultimate goal, a paradigm shift in the technological development is to take advantage of these instabilities to achieve others objectives, as reducing the drag of these flexible structures. The ground-breaking challenges addressed in this project are to design fundamentally new theoretical methodologies for (i) describing mathematically aeroelastic instabilities, (ii) suppressing them and (iii) using them to reduce mean drag of structures at a low energetic cost. To that aim, two types of aeroelastic phenomena will be specifically studied: the flutter, which arises as a result of an unstable coupling instability between two stable dynamics, that of the structures and that the flow, and vortex-induced vibrations which appear when the fluid dynamics is unstable. An aeroelastic global stability analysis will be first developed and applied to problems of increasing complexity, starting from two-dimensional free-vibrating rigid structures and progressing towards three-dimensional free-deforming elastic structures. The control of these aeroelastic instabilities will be then addressed with two different objectives: their suppression or their use for flow control. A theoretical passive control methodology will be established for suppressing linear aeroelastic instabilities, and extended to high Reynolds number flows and experimental configurations. New perturbation methods for solving strongly nonlinear problems and adjoint-based control algorithm will allow to use these aeroelastic instabilities for drag reduction. This project will allow innovative control solutions to emerge, not only in flutter or vortex-induced vibrations problems, but also in a much broader class of fluid-structure problems.

1 377 290 €

Start date: 2015-07-01, End date: 2020-06-30

Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease. We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do. Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.

2 574 819 €

Start date: 2019-04-01, End date: 2024-03-31

The scientific motivation of this project is the significant presence of organic compounds at the surface of the ocean. They form the link between ocean biogeochemistry through the physico-chemical processes near the water-air interface with primary and secondary aerosol formation and evolution in the air aloft and finally to the climate impact of marine boundary layer aerosols. However, their photochemistry and photosensitizer properties have only been suggested and discussed but never fully addressed because they were beyond reach. This project suggests going significantly beyond this matter of fact by a combination of innovative tools and the development of new ideas. This project is therefore devoted to new laboratory investigations of processes occurring at the air sea interface to predict emission, formation and evolution of halogenated radicals and aerosols from this vast interface between oceans and atmosphere. It progresses from fundamental laboratory measurements, marine science, surface chemistry, photochemistry … and is therefore interdisciplinary in nature. It will lead to the development of innovative techniques for characterising chemical processing at the air sea interface (e.g., a multiphase atmospheric simulation chamber, a time-resolved fluorescence technique for characterising chemical processing at the air-sea interface). It will allow the assessment of new emerging ideas such as a quantitative description of the importance of photosensitized reactions in the visible at the air/sea interface as a major source of halogenated radicals and aerosols in the marine environment. This new understanding will impact on our ability to describe atmospheric chemistry in the marine environment which has strong impact on the urban air quality of coastal regions (which by the way represent highly populated regions ) but also on climate change by providing new input for global climate models.

2 366 276 €

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

The goal of this project is to investigate two conjectures in arithmetic geometry pertaining to the geometry of projective varieties over finite and number fields. These two conjectures, formulated by Tate and Grothendieck in the 1960s, predict which cohomology classes are chern classes of line bundles. They both form an arithmetic counterpart of a theorem of Lefschetz, proved in the 1940s, which itself is the only known case of the Hodge conjecture. These two long-standing conjectures are one of the aspects of a more general web of questions regarding the topology of algebraic varieties which have been emphasized by Grothendieck and have since had a central role in modern arithmetic geometry. Special cases of these conjectures, appearing for instance in the work of Tate, Deligne, Faltings, Schneider-Lang, Masser-Wüstholz, have all had important consequences. My goal is to investigate different lines of attack towards these conjectures, building on recent work on myself and Jean-Benoît Bost on related problems. The two main directions of the proposal are as follows. Over finite fields, the Tate conjecture is related to finiteness results for certain cohomological objects. I want to understand how to relate these to hidden boundedness properties of algebraic varieties that have appeared in my recent geometric proof of the Tate conjecture for K3 surfaces. The existence and relevance of a theory of Donaldson invariants for moduli spaces of twisted sheaves over finite fields seems to be a promising and novel direction. Over number fields, I want to combine the geometric insight above with algebraization techniques developed by Bost. In a joint project, we want to investigate how these can be used to first understand geometrically major results in transcendence theory and then attack the Grothendieck period conjecture for divisors via a number-theoretic and complex-analytic understanding of universal vector extensions of abelian schemes over curves.

1 222 329 €

Start date: 2016-12-01, End date: 2021-11-30

A massive and ever growing amount of digital image and video content is available today, on sites such as Flickr and YouTube, in audiovisual archives such as those of BBC and INA, and in personal collections. In most cases, it comes with additional information, such as text, audio or other metadata, that forms a rather sparse and noisy, yet rich and diverse source of annotation, ideally suited to emerging weakly supervised and active machine learning technology. The ALLEGRO project will take visual recognition to the next level by using this largely untapped source of data to automatically learn visual models. The main research objective of our project is the development of new algorithms and computer software capable of autonomously exploring evolving data collections, selecting the relevant information, and determining the visual models most appropriate for different object, scene, and activity categories. An emphasis will be put on learning visual models from video, a particularly rich source of information, and on the representation of human activities, one of today's most challenging problems in computer vision. Although this project addresses fundamental research issues, it is expected to result in significant advances in high-impact applications that range from visual mining of the Web and automated annotation and organization of family photo and video albums to large-scale information retrieval in television archives.

2 493 322 €

Start date: 2013-04-01, End date: 2019-03-31

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

149 236 €

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

The field of disordered quantum gases is developing rapidly. Dramatic progress has been achieved recently and first experimental observation of one-dimensional Anderson localization (AL) of matterwaves has been reported using Bose-Einstein condensates in controlled disorder (in our group at Institut d'Optique and at LENS; Nature, 2008). This dramatic success results from joint theoretical and experimental efforts, we have contributed to. Most importantly, it opens unprecedented routes to pursue several outstanding challenges in the multidisciplinary field of disordered systems, which, after fifty years of Anderson localization, is more active than ever. This theoretical project aims at further developing the emerging field of disordered quantum gases towards novel challenges. Our aim is twofold. First, we will propose and analyze schemes where experiments on ultracold atoms can address unsolved issues: AL in dimensions higher than one, effects of inter-atomic interactions on AL, strongly-correlated disordered gases and quantum simulators for spin systems (spin glasses). Second, by taking into account specific features of ultracold atoms, beyond standard toy-models, we will raise and study new questions which have not been addressed before (eg long-range correlations of speckle potentials, finite-size effects, controlled interactions). Both aspects would open new frontiers to disordered quantum gases and offer new possibilities to shed new light on highly debated issues. Our main concerns are thus to (i) study situations relevant to experiments, (ii) develop new approaches, applicable to ultracold atoms, (iii) identify key observables, and (iv) propose new challenging experiments. In this project, we will benefit from the original situation of our theory team: It is independent but forms part of a larger group (lead by A. Aspect), which is a world-leader in experiments on disordered quantum gases, we have already developed close collaborative relationship with.

985 200 €

Start date: 2011-01-01, End date: 2015-12-31

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

Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out. The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding. To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity. Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...

1 499 948 €

Start date: 2015-03-01, End date: 2020-02-29

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

I propose to use large clouds of cold Ytterbium atoms to observe Anderson localization of light in three dimensions, which has challenged theoreticians and experimentalists for many decades. After the prediction by Anderson of a disorder-induced conductor to insulator transition for electrons, light has been proposed as ideal non interacting waves to explore coherent transport properties in the absence of interactions. The development in experiments and theory over the past several years have shown a route towards the experimental realization of this phase transition. Previous studies on Anderson localization of light using semiconductor powders or dielectric particles have shown that intrinsic material properties, such as absorption or inelastic scattering of light, need to be taken into account in the interpretation of experimental signatures of Anderson localization. Laser-cooled clouds of atoms avoid the problems of samples used so far to study Anderson localization of light. Ab initio theoretical models, available for cold Ytterbium atoms, have shown that the mere high spatial density of the scattering sample is not sufficient to allow for Anderson localization of photons in three dimensions, but that an additional magnetic field or additional disorder on the level shifts can induce a phase transition in three dimensions. The role of disorder in atom-light interactions has important consequences for the next generation of high precision atomic clocks and quantum memories. By connecting the mesoscopic physics approach to quantum optics and cooperative scattering, this project will allow better control of cold atoms as building blocks of future quantum technologies. Time-resolved transport experiments will connect super- and subradiant assisted transmission with the extended and localized eigenstates of the system. Having pioneered studies on weak localization and cooperative scattering enables me to diagnostic strong localization of light by cold atoms.

2 490 717 €

Start date: 2019-10-01, End date: 2024-09-30

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

2 307 800 €

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

Heart disease and particularly myocardial infarction, i.e. heart attack, is the leading cause of death in the Western world today. The diminished regenerative potential of the heart begins shortly after birth, when most CardioMyocytes (CMs) cease to proliferate and make a transition from hyperplastic to hypertrophic growth. The Tzahor lab has been intensively exploring novel molecules, compounds as well as the molecular mechanisms that facilitate CM cell division in the adult heart of mammals as a strategy for eliciting heart regeneration. These efforts, had led to the identification of novel compounds which significantly increased the proliferation of adult CMs. Drawing upon these findings, the aim of the aNtHESIS project is two-fold. First, to (i) validate the pre-clinical application of our two novel compounds by conducting comprehensive in-vitro and in-vivo tests in mice as well as by carrying out experiments using human CMs. The second aim is (ii) to establish the business feasibility of our cardiac regenerative therapy concept by taking the necessary steps towards the commercialization of our novel compounds, focusing on the creation of strategic alliances with key private sector companies.

150 000 €

Start date: 2016-01-01, End date: 2017-06-30

"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

Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses. ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify. In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen. Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.

1 499 794 €

Start date: 2017-12-01, End date: 2022-11-30

Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems. We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes. This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.

2 000 000 €

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

This proposal proceeds from an anomaly. Apartheid routinely breached the separation that it names. Whereas the South African regime was deeply isolationist in international terms, new research links it to the Cold War and decolonization. Yet this trend does not consider sufficiently that the global contest over the meaning of apartheid and resistance to it occurs on the terrain of culture. My project argues that studying the global circulation of South African cultural formations in the apartheid era provides novel historiographic leverage over Western liberalism during the Cold War. It recasts apartheid as an apparatus of transnational cultural production, turning existing historiography inside out. This study seeks: • To provide the first systematic account of the deterritorialization of “apartheid”—as political signifier and as apparatus generating circuits of transnational cultural production. • To analyze these itinerant cultural formations across media and national borders, articulating new intersections. • To map the itineraries of major South African exiles, where exile is taken to be a system of interlinked circuits of affiliation and cultural production. • To revise the historiography of states other than South Africa through the lens of deterritorialized apartheid-era formations at their respective destinations. • To show how apartheid reveals contradictions within Western liberalism during the Cold War, with special reference to racial inequality. Methodologically, I introduce the model of thick convergence to analyze three periods: 1. Kliptown & Bandung: Novel possibilities, 1948-1960. 2. Sharpeville & Memphis: Drumming up resistance, 1960-1976. 3. From Soweto to Berlin: Spectacle at the barricades, 1976-1990. Each explores a cultural dominant in the form of texts, soundscapes or photographs. My work stands at the frontier of transnational research, furnishing powerful new insights into why South Africa matters on the stage of global history.

1 861 238 €

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

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

1 797 840 €

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

Arboviruses infect millions of people each year, however, mechanisms that drive viral emergence and maintenance remain largely unknown. A combination of host factors (e.g., human mobility), mosquito factors (e.g., abundance) and viral factors (e.g., transmissibility) interconnect to drive spread. Further, for endemic arboviruses, complex patterns of population immunity, built up over many years, appear key to the emergence of particular lineages. To disentangle the contribution of these different drivers, we need detailed data from the same pathogen system over a long time period from the same location. In addition, we need new methods, which can integrate these different data sources and allow appropriate mechanistic inferences. In this project, I will use the most globally prevalent arbovirus, dengue virus, as a case study. I will focus on Thailand where all four dengue serotypes have circulated endemically for decades and excellent long-term data and isolates exist, to address two fundamental questions: i) How do population-level patterns of immunity evolve over time and what is their impact on strain dynamics? I will use mechanistic models applied to historic serotype-specific case data to reconstruct the evolving immune profile of the population and explore the impact of immunity on viral diversity using sequences from archived isolates from each year over a 50-year period. ii) How do human behaviors, vector densities interact with immunity to dictate spread? I will work with geolocated full genome sequences from across Thailand and use detailed data on how people move, their contact patterns, their immunity profiles and mosquito distributions to study competing hypotheses of how arboviruses spread. I will compare the key drivers of dengue spread with that found for outbreaks of Zika and chikungunya. This proposal addresses fundamental questions about the mechanisms that drive arboviral emergence and spread that will be relevant across disease systems.

1 499 896 €

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

The goal of this project is to prepare in a deterministic way, and then to characterize, various entangled states of up to 25 individual atoms held in an array of optical tweezers. Such a system provides a new arena to explore quantum entangled states of a large number of particles. Entanglement is the existence of quantum correlations between different parts of a system, and it is recognized as an essential property that distinguishes the quantum and the classical worlds. It is also a resource in various areas of physics, such as quantum information processing, quantum metrology, correlated quantum systems and quantum simulation. In the proposed design, each site is individually addressable, which enables single atom manipulation and detection. This will provide the largest entangled state ever produced and fully characterized at the individual particle level. The experiment will be implemented by combining two crucial novel features, that I was able to demonstrate very recently: first, the manipulation of quantum bits written on long-lived hyperfine ground states of single ultra-cold atoms trapped in microscopic optical tweezers; second, the generation of entanglement by using the strong long-range interactions between Rydberg states. These interactions lead to the so-called dipole blockade , and enable the preparation of various classes of entangled states, such as states carrying only one excitation (W states), and states analogous to Schrödinger s cats (GHZ states). Finally, I will also explore strategies to protect these states against decoherence, developed in the framework of fault-tolerant and topological quantum computing. This project therefore combines an experimental challenge and the exploration of entanglement in a mesoscopic system.

1 449 600 €

Start date: 2009-12-01, End date: 2014-11-30

Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.

1 900 000 €

Start date: 2012-09-01, End date: 2018-08-31

Redox chemistry provides the fundamental basis for numerous energy-related electrochemical devices, among which Li-ion batteries (LIB) have become the premier energy storage technology for portable electronics and vehicle electrification. Throughout its history, LIB technology has relied on cationic redox reactions as the sole source of energy storage capacity. This is no longer true. In 2013 we demonstrated that Li-driven reversible formation of (O2)n peroxo-groups in new layered oxides led to extraordinary increases in energy storage capacity. This finding, which is receiving worldwide attention, represents a transformational approach for creating advanced energy materials for not only energy storage, but also water splitting applications as both involve peroxo species. However, as is often the case with new discoveries, the fundamental science at work needs to be rationalized and understood. Specifically, what are the mechanisms for ion and electron transport in these Li-driven anionic redox reactions? To address these seminal questions and to widen the spectrum of materials (transition metal and anion) showing anionic redox chemistry, we propose a comprehensive research program that combines experimental and computational methods. The experimental methods include structural and electrochemical analyses (both ex-situ and in-situ), and computational modeling will be based on first-principles DFT for identifying the fundamental processes that enable anionic redox activity. The knowledge gained from these studies, in combination with our expertise in inorganic synthesis, will enable us to design a new generation of Li-ion battery materials that exhibit substantial increases (20 -30%) in energy storage capacity, with additional impacts on the development of Na-ion batteries and the design of water splitting catalysts, with the feasibility to surpass current water splitting efficiencies via novel (O2)n-based electrocatalysts.

2 249 196 €

Start date: 2015-10-01, End date: 2020-09-30

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

Recent trends in computing have prompted users and organizations to store an increasingly large amount of sensitive data at third party locations in the cloud outside of their direct control. Storing data remotely poses an acute security threat as these data are outside our control and could potentially be accessed by untrusted parties. Indeed, the reality of these threats have been borne out by the Snowden leaks and hundreds of data breaches each year. In order to protect our data, we will need to encrypt it. Functional encryption is a novel paradigm for public-key encryption that enables both fine-grained access control and selective computation on encrypted data, as is necessary to protect big, complex data in the cloud. Functional encryption also enables searches on encrypted travel records and surveillance video as well as medical studies on encrypted medical records in a privacy-preserving manner; we can give out restricted secret keys that reveal only the outcome of specific searches and tests. These mechanisms allow us to maintain public safety without compromising on civil liberties, and to facilitate medical break-throughs without compromising on individual privacy. The goals of the aSCEND project are (i) to design pairing and lattice-based functional encryption that are more efficient and ultimately viable in practice; and (ii) to obtain a richer understanding of expressive functional encryption schemes and to push the boundaries from encrypting data to encrypting software. My long-term vision is the ubiquitous use of functional encryption to secure our data and our computation, just as public-key encryption is widely used today to secure our communication. Realizing this vision requires new advances in the foundations of functional encryption, which is the target of this project.

1 253 893 €

Start date: 2015-06-01, End date: 2020-05-31

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

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

2 492 561 €

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