ERC FUNDED PROJECTS

"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

In cryptographic protocol theory, we consider a situation where a number of entities want to solve some problem over a computer network. Each entity has some secret data it does not want the other entities to learn, yet, they all want to learn something about the common set of data. In an electronic election, they want to know the number of yes-votes without revealing who voted what. For instance, in an electronic auction, they want to find the winner without leaking the bids of the losers. A main focus of the project is to develop new techniques for solving such protocol problems. We are in particular interested in techniques which can automatically construct a protocol solving a problem given only a description of what the problem is. My focus will be theoretical basic research, but I believe that advancing the theory of secure protocol compilers will have an immense impact on the practice of developing secure protocols for practice. When one develops complex protocols, it is important to be able to verify their correctness before they are deployed, in particular so, when the purpose of the protocols is to protect information. If and when an error is found and corrected, the sensitive data will possibly already be compromised. Therefore, cryptographic protocol theory develops models of what it means for a protocol to be secure, and techniques for analyzing whether a given protocol is secure or not. A main focuses of the project is to develop better security models, as existing security models either suffer from the problem that it is possible to prove some protocols secure which are not secure in practice, or they suffer from the problem that it is impossible to prove security of some protocol which are believed to be secure in practice. My focus will again be on theoretical basic research, but I believe that better security models are important for advancing a practice where protocols are verified as secure before deployed.

1 171 019 €

Start date: 2011-12-01, End date: 2016-11-30

Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity. Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer. The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.

1 692 737 €

Start date: 2011-11-01, End date: 2017-04-30

"Wave propagation in complex (disordered) media stretches our knowledge to the limit in many different fields of physics. It has important applications in seismology, acoustics, radar, and condensed matter. It is a problem of large fundamental interest, notably for the study of Anderson localization. In optics, it is of great importance in photonic devices, such as photonic crystals, plasmonic structures or random lasers. It is also at the heart of many biomedical-imaging issues: scattering ultimately limits the depth and resolution of all imaging techniques. We have recently demonstrated that wavefront shaping –i.e. adaptive optics applied to complex media- is the tool of choice to match and address the huge complexity of this problem in optics. The COMEDIA project aims at developing a novel wavefront shaping toolbox, addressing both spatial and spectral degrees of freedom of light. Thanks to this toolbox, we plan to fulfill the following objectives: 1) A full spatiotemporal control of the optical field in a complex environment, 2) Breakthrough results in imaging and nano-optics, 3) Original answers to some of the most intriguing fundamental questions in mesoscopic physics."

1 497 000 €

Start date: 2011-11-01, End date: 2016-10-31

"NK cells are innate lymphocytes that play a role in the early response against intracellular pathogens and against tumors. Several NK cell subsets have been described in peripheral organs that correspond to discrete stages of in vivo maturation. How NK cells differentiate from early precursors and what are the specific functions of each NK cell subset are unresolved issues. Here, we propose a three-aim program to address these questions. First, we want to revisit the partition of the NK cell population that is currently based on surface markers of undefined function by looking at the expression of transcription factors (TF) essential for NK cell development and maturation, such as T-bet and Eomes, using novel TF reporter mice. This strategy should also allow us to identify very early steps of NK cell development (NK cell progenitors) that remain ill defined. Second, we will try and identify molecular mechanisms that induce transition between NK cell maturation stages. For this we will take advantage of a previous gene profiling analysis that pointed at several pathways and TF that were highly regulated during NK cell maturation. The role of these pathways and TF in the differentiation of NK cells will be measured using a novel Cre/lox system allowing NK-specific gene deletion. Detailed analysis of mouse mutants will be used to delineate the role of selected genes and pathways in NK cell differentiation. Third, we will compare patterns of migration, cytokine secretion, in vivo cytotoxicity and global gene expression by individual NK cell subsets during an airway infection by Influenza to get insight on the specific functions of NK cell subsets during immune responses. Altogether, the results of this study should provide developmental, molecular and functional evidences to support the physiological relevance of NK cell subsets. This may improve strategies that aim at manipulating NK cell function for the benefit of patients with cancer or chronic infectious diseases"

1 340 757 €

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

"The aim of my research project is to build a mathematical model for the quantitative assessment of the effects of demographic changes on economic activity. It is an ambitious project as it involves the integration of the latest developments in demographic and economic models. It is also highly innovative as it proposes an original treatment of demographic uncertainty. Most existing models consider demographics as a deterministic variable and foresee a set of scenarios. At best, the models incorporate demographics as a risk variable and assume that agents know the stochastic process underlying the demographic dynamics. In the present research project, I wish to build a demographic-economic model in which the future demographics are uncertain. This will have three consequences. First, individual decisions are different and depend on the individuals' attitudes towards uncertainty. Second, the aggregation of individual decisions is more complex, especially because of the fact that the latter are not necessarily temporally consistent. Third, the approach to economic policy is renewed. The government is not necessarily perceived as an omniscient being who corrects market dysfunctions, but rather, it is itself under uncertainty and must compromise with the choices made by agents."

1 000 000 €

Start date: 2012-03-01, End date: 2017-02-28

Comparative studies of inbreeding and evolution in non-model animal populations: a research proposal directed towards integrating ecological and evolutionary research on inbreeding. Specifically, my aim is to apply novel ecogenomics tools in the study of evolutionary consequences of inbreeding in non-model animal populations. At present, our understanding of inbreeding is dominated by studies of a small number of model organisms. I will undertake comparative studies on inbreeding effects in a genus of spiders containing independently evolved naturally inbreeding species as well as outcrossing sister species. The study of a naturally inbreeding animal species will provide unique insights to consequences of inbreeding for population genetic structure, genome-wide genetic diversity, and evolution of life history traits. Social spiders are not only unique because they naturally inbreed, but also by being cooperative and showing allomaternal brood care including self-sacrifice, and they evolve highly female-biased sex-ratios, a trait that is not well understood in diploid species. My research objectives are 1) to establish a robust phylogeny for comparative studies; 2) to quantify the effects of inbreeding on the genetic diversity within and between populations; 3) to estimate gene flow among inbred lineages to determine whether inbred lineages diversify but retain the potential for gene exchange, or undergo cryptic speciation; 4) to determine effects of inbreeding on gene expression; 5) to investigate the mechanism underlying the genetic sex determination system that cause female biased sex-ratios; and finally 6) to determine whether sex-ratio is under adaptive parental control in response to genetic relatedness and ecological constraints. Addressing these objectives will generate novel insights and expand current knowledge on the evolutionary ecology of inbreeding in wild animal populations.

1 497 248 €

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

The goal of this project is to discover the first galaxies that formed after the Big Bang. The astrophysics of galaxy formation is deeply fascinating. From tiny density fluctuations of quantum mechanical nature believed to have formed during an inflationary period a tiny fraction of a second after the Big Bang during structure slowly formed through gravitational collapse. This process is strongly dependent on the nature of the dominant, but unknown form of matter - the dark matter. In the project proposed here I will study the epoch of first galaxy formation and the subsequent few billion years of cosmic evolution using gamma-ray bursts and Lyman-α (Lyα) emitting galaxies as probes. I am the principal investigator on two observational projects utilizing these probes. In the first project, I will over three years starting October 2009 be using the new X-shooter spectrograph on the European Southern Observatory Very Large Telescope to build a sample of ~100 gamma-ray bursts with UV/optical/near-IR spectroscopic follow-up. The objective of this project is to measure primarily metallicities, molecular content, and dust content of the gamma-ray burst host galaxies. I am primarily interested in the redshift range from 9 to 2 corresponding to about 500 million years to 3 billions years after the Big Bang. In the 2nd project we will use the new European Southern Observatory survey telescope VISTA. I am co-PI of the Ultra-VISTA project that over the next 5 years starting December 2009 will create an ultradeep image (about 2000 hr of total integration time) of a piece of sky known as the COSMOS field. I am responsible for the part of the project that will use a narrow-band filter to search for Lyα emitting galaxies at a redshift of 8.8 (corresponding to about 500 million years after the Big Bang) - believed to correspond to the epoch of formation of some of the very first galaxies.

1 002 000 €

Start date: 2011-11-01, End date: 2016-10-31

The objective of the project Environmental Effects and Risk Evaluation of Engineered Nanoparticles (EnvNano) is to elucidate the particle specific properties that govern the ecotoxicological effects of engineered nanoparticles and in this way shift the paradigm for environmental risk assessment of nanomaterials. While current activities in the emerging field of nano-ecotoxicology and environmental risk assessment of nanomaterials are based on the assumption that the methodologies developed for chemicals can be adapted to be applicable for nanomaterials, EnvNano has a completely different starting point: The behaviour of nanoparticles in suspension is fundamentally different from that of chemicals in on solution. Therefore, all modifications of existing techniques that do not take this fact into account are bound to have a limited sphere of application or in the worst case to be invalid. By replacing the assumption of dissolved chemicals with a particle behaviour assumption, the traditional risk assessment paradigm will be so seriously impaired that a shift of paradigm will be needed. EnvNano is based on the following hypotheses: 1. The ecotoxicity and bioaccumulation of engineered nanoparticles will be a function of specific physical and chemical characteristics of the nanoparticles; 2. The environmental hazards of engineered nanoparticles cannot be derived from hazard identifications of the material in other forms; 3. Existing regulatory risk assessment procedures for chemicals will not be appropriate to assess the behaviour and potential harmful effects of engineered nanoparticles on the environment. These research hypotheses will be addressed in the four interacting research topics of EnvNano: Particle Characterization, Ecotoxicty, Bioaccumulation, and Framework for Risk Evaluation of Nanoparticles aimed to form the foundation for a movement from coefficient-based to kinetic-based environmental nanotoxicology and risk assessment.

1 196 260 €

Start date: 2011-12-01, End date: 2016-03-31

Recent genome-wide association studies have successfully identified rare and common variants that correlate with complex traits. However, they have provided us with little insight into the nature of the genetic, biological and evolutionary relationships underlying such complex phenotypes. There is thus a growing need for approaches that provide a mechanistic understanding of how genetic variants function to impact phenotypic variation and why they have been substrates of natural selection. One set of traits that displays considerable heterogeneity and that has undoubtedly been shaped by natural selection is the host response to microorganisms. By integrating cutting-edge knowledge and technology in the fields of genomics, population genetics, immunology and bioinformatics, our aim is to establish a thorough understanding of how variable the human immune response is in the natural setting and how this phenotypic variation is under genetic control. Specifically, we aim (i) to characterise the genetic architecture of two populations differing in their ethnic background; (ii) to define individual and population-level variation in immune responses, in the same individuals, by establishing an ex vivo cell-based model to study levels of transcript abundance of both mRNA and miRNA, before and after activation with various immune stimuli; (iii) to map expression quantitative trait loci associated with variation in immune responses; and (iv) to identify adaptive immunological phenotypes. This study will increase our understanding of how genotypes influence the heterogeneity of immune response phenotypes at the level of the human population, and reveal immunological mechanisms under genetic control that have been crucial for our past and present survival against infection. In doing so, we will provide the foundations to define perturbations in these responses that correlate with the occurrence of various infectious and non-infectious diseases as well as with vaccine success.

1 494 756 €

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

Förster fluorescence resonance energy transfer (FRET) is one of the most popular methods to measure distance, structure, association, and dynamics at the single molecule level. However, major challenges are limiting FRET in several fields of physical and analytical sciences: (i) a short distance range below 8 nm, (ii) a concentration range in the nanomolar regime, and (iii) generally weak detected signals. At the interface between physical chemistry and nano-optics, the proposal objective is to extend the effectiveness of single molecule FRET using plasmonic nanocircuits to: (i) perform FRET on a range up to 20 nm, (ii) detect a single FRET pair in a solution of micromolar concentration, and (iii) improve the statistical distribution in FRET measurements. To meet its ambitious goals, the proposal introduces plasmonic nanocircuits to tailor the light-molecule interaction at the nanoscale. Energy transfer between donor and acceptor fluorophores is efficiently mediated through intense surface plasmon modes to extend the FRET distance range and improve the fluorescence signal. Moreover, the nanocircuits will be combined with recent innovations in biophotonics: stimulated emission of acceptor fluorescence, full dynamic analysis, and fluidic nanochannels. The scientific breakthroughs and project impacts will open new horizons for proteomics, enzymology, genomics and photonics. For elucidating molecular structure, the long range FRET will enable understanding the folding structure of large DNA or protein molecules. For assessing chemical reactions, achieving single molecule analysis at micromolar concentration is essential to monitor relevant kinetics, reveal sample heterogeneity, and detect rare and/or transient species. For analytical chemistry, nanocircuits are ideal for sensitive biosensing on a chip. For photonics, nanocircuits can realize key components for optical information processing at the nanoscale.

1 477 942 €

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

The freezing of colloids is an amazingly common phenomenon encountered in many natural and engineering processes such as the freezing of soils, food engineering or cryobiology. It can also be used as a bioinspired, versatile and environmentally-friendly processing route for bioinspired porous materials and composites exhibiting breakthroughs in functional properties. Yet, it is still a puzzling phenomenon with many unexplained features, due to the complexity of the system, the space and time scales at which the process should be investigated and the multidisciplinary approach required to completely apprehend it. The objective is to progress towards a deep understanding of the freezing of colloids through novel in situ observations approaches and mathematical modelling, to exert a better control on the processing route and achieve the full potential of this novel class of bioinspired materials. Materials will be processed and their structure/properties relationships investigated and optimized. This project offers a unique integration of approaches, competences and resources in materials science, chemistry, physics, mathematics and technological developments of observation techniques. For materials science only, the versatility of the process and its control could yield potential breakthroughs in numerous key applications of tremendous human, technological, environmental and economical importance such as catalysis, biomaterials or energy production, and open a whole new field of research. Far-reaching implications beyond materials science are expected, both from the developments in mathematics and physics, and from the implications of colloids freezing in many situations and fields of research.

1 469 034 €

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

In Europe and all over the world, genocide and mass violence have been a structural feature of the 20th century. This project aims at questioning the social legacy of mass violence by studying how different societies have coped with the first consequence of mass destruction: the mass production of cadavers. What status and what value have indeed been given to corpses? What political, social or religious uses have been made of dead bodies in occupied Europe, Soviet Union, Serbia, Spain but also Rwanda, Argentina or Cambodia, both during and after the massacres? Bringing together perspectives of social anthropology, history and law, and raising the three main issues of destruction, identification and reconciliation, our project will enlighten how various social and cultural treatments of dead bodies simultaneously challenge common representations, legal practices and moral. Project outputs will therefore open and strengthen the field of genocide studies by providing proper intellectual and theoretical tools for a better understanding of mass violence’s aftermaths in today societies.

1 197 367 €

Start date: 2012-02-01, End date: 2016-01-31

"The goal of this project is to develop new numerical methods for the approximation of evolution equations possessing strong geometric properties such as Hamiltonian systems or stochastic differential equations. In such situations the exact solutions endow with many physical properties that are consequences of the geometric structure: Preservation of the total energy, momentum conservation or existence of ergodic invariant measures. However the preservation of such qualitative properties of the original system by numerical methods at a reasonable cost is not guaranteed at all, even for very precise (high order) methods. The principal aim of geometric numerical integration is the understanding and analysis of such problems: How (and to which extend) reproduce qualitative behavior of differential equations over long time? The extension of this theory to partial differential equations is a fundamental ongoing challenge, which require the invention of a new mathematical framework bridging the most recent techniques used in the theory of nonlinear PDEs and stochastic ordinary and partial differential equations. The development of new efficient numerical schemes for geometric PDEs has to go together with the most recent progress in analysis (stability phenomena, energy transfers, multiscale problems, etc..) The major challenges of the project are to derive new schemes by bridging the world of numerical simulation and the analysis community, and to consider deterministic and stochastic equations, with a general aim at deriving hybrid methods. We also aim to create a research platform devoted to extensive numerical simulations of difficult academic PDEs in order to highlight new nonlinear phenomena and test numerical methods."

971 772 €

Start date: 2011-09-01, End date: 2016-08-31

Historians have good reasons to be highly suspicious of the “rational choice” methodologies that hold sway in economics, political science or sociology and that find a new lease on life today with the rise of the cognitive sciences. On the other hand, researchers using these methodologies show usually very little interest in history. The result is that we know very little about the historical development of “rational choice” as a way to define rationality in action, while this intellectual paradigm has become pervasive and reshaped the way we do science and the way we think about politics. This project will follow the problem of decision-making through the 20th century and weave into a single historical narrative its different disciplinary formulations. It starts with a puzzle: while the “decisionist” critiques of legality of the 1920s associated the decision with an anti-rationalist vision of politics, this notion gradually morphed into the epitome of “rational choice” after 1945. How did this transformation occur? The project will reconstruct this shift from a paradigm in which Law was the instrument that would make political decisions rational, to another in which the power of rationalization was vested in Science. It asks how the post-1945 efforts at specifying conditions of rationality for political decisions changed the meaning of “rationality.” It connects these developments to the interdisciplinary set of “decision sciences” that emerged in the 1950s around issues of strategic and political behavior and spawned our contemporary instruments of “conflict-resolution” or automated models of decision-making. The project suggests that “rationality” in political decision-making is not a transcendental norm, but a historically contingent benchmark dependent on its technical instrumentations. Democratizing political decision-making, then, means opening these models and instruments of rationalization to scholarly debate and public scrutiny.

628 004 €

Start date: 2011-12-01, End date: 2016-11-30

Imagine lighter and more fuel economic cars with improved crashworthiness that help save lives, aircrafts and wind-turbine blades with significant weight reductions that lead to large savings in material costs and environmental impact, and light but efficient armour that helps to protect against potentially deadly blasts. These are the future perspectives with a new generation of advanced structures and micro-structured materials. The goal of INNODYN is to bring current design procedures for structures and materials a significant step forward by developing new efficient procedures for integrated analysis and design taking the nonlinear dynamic performance into account. The assessment of nonlinear dynamic effects is essential for fully exploiting the vast potentials of structural and material capabilities, but a focused endeavour is strongly required to develop the methodology required to reach the ambitious goals. INNODYN will in two interacting work-packages develop the necessary computational analysis and design tools using 1) reduced-order models (WP1) that enable optimization of the overall topology of structures which is today hindered by excessive computational costs when dealing with nonlinear dynamic systems 2) multi-scale models (WP2) that facilitates topological design of the material microstructure including essential nonlinear geometrical effects currently not included in state-of-the-art methods. The work will be carried out by a research group with two PhD-students and a postdoc, led by a PI with a track-record for original ground-breaking research in analysis and optimization of linear and nonlinear dynamics and hosted by one of the world's leading research groups on topology optimization, the TOPOPT group at the Technical University of Denmark.

823 992 €

Start date: 2012-02-01, End date: 2016-01-31

This research project will focus on the area of the Sino-Tibetan borderlands situated within the People’s Republic of China, and referred to as Kham by Tibetans who make up most of the population of this region divided between the provinces of Sichuan to the east, Yunnan to the south and the Tibet Autonomous Region to the west. This research project intends to explore from a comparative perspective the possible definitions of this entity called Kham, which in the course of history has never strictly corresponded to any administrative unit or coherent whole, and which ultimately should be considered as a land of encounters, a place of métissage (cultural exchanges). By addressing a regional area virtually overlooked by Western research in social science, this project aims to strengthen international academic exchanges and to produce a strong network of collaboration on Kham studies. The multidisciplinary team will undertake ethnographic field studies and documentary research including archival research and contribute fresh, first-hand material to the socio-cultural diversity of Kham. In-depth investigation of the internal diversity of Tibet and its connection with the outside remains sketchy and thus a particular focus of this project is to delve into the complexities of Tibetan society in China. This pioneering work will provide new materials on four complementary cross-disciplinary themes: 1) trade and commerce, 2) ethnicity, religion and local identities, 3) political entities and social organization, and 4) representations and cultural politics, each of which in its own way will improve our understanding of the particular historical, social and political context of the Kham region. Finally, this multi-tiered and multi-scalar approach, with an emphasis on networks, will enhance work on historical mapping, which is still practically non-existent in this region.

651 722 €

Start date: 2012-03-01, End date: 2016-02-29

The goal of the MARCHES project is to rationalise and optimize the interplay between electronically excited-states in complex molecular architectures. The simulation of the properties of large conjugated architectures is to be performed with ab initio tools explicitly taking into account environmental effects. Though efficient methods able to tackle such task are to be conceived during this project, we aim to enlighten coupled excited-states so to pave the way towards chemically-intuitive designs of new molecules. Indeed, the rationalisation and optimisation of the excited-state properties of large compounds is not only one of the major challenges of computational chemistry and physics, it also opens new horizons for emergent properties. In that framework, this project will allow to design molecular switches usable as building blocks for complex logic gates, subsequently unlocking crucial steps towards more efficient storage materials. To this end, compounds containing several photochromic switches coupled at the excited state have to be designed: this is an important challenge. Indeed, photochromes are actually limited to uncoupled or simply additive systems: emergent multi-addressable features are impossible to achieve.

1 500 000 €

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

Every year, software bugs cost hundreds of millions of euros to compagnies and administrations. A number of disasters such as the Ariane 5 first flight failure can are due to faulty softwares. Static analysis aims at computing automatically properties of softwares, so as to prove they are exempt from some class of bugs. In the last ten years, static analysis of numeric intensive applications improved dramatically so that the certification of safety properties like the absence of runtime errors in industrial size control-command, numeric intensive applications, such as Airbus fly-by-wire softwares is now feasible. By contrast, the situation is much worse for memory intensive softwares. Existing static analyzers for such softwares do not scale to large scale softwares, and fail to prove strong invariants on large classes of softwares. These limitations stem from the fact they use a monolithic algebra of logical formulas (or abstract domain). Our proposal is based on the observation that the complex memory properties that need be reasoned about should be decomposed in combinations of simpler properties. Therefore, in static analysis, a powerful memory abstract domain could be designed by combining several simpler domains, specific to common memory usage patterns. The benefit of this novel vision is twofold: first it would make it possible to simplify drastically the design of complex abstract domains required to reason about complex softwares, hereby allowing certification of complex memory intensive softwares by automatic static analysis; second, it would enable to split down and better control the cost of the analyses, thus significantly helping scalability. This shift of focus will bring both theoretical and practical improvements to the program certification field. We propose to build a static analysis framework for reasoning about memory properties, and put it to work on important classes of applications, including large safety critical memory intensive softwares.

1 489 663 €

Start date: 2011-10-01, End date: 2017-09-30

A common form of gene transfer is the vertical gene transfer between one organism and its offspring during sexual reproduction. However, some organisms, such as bacteria, are able to acquire genetic material independently of sexual reproduction by horizontal gene transfer (HGT). Three mechanisms mediate HGT in bacteria: conjugation, transduction and natural transformation. HGT and the selective pressure exerted by the widespread use antibiotics (in medicine, veterinary medicine, agriculture, animal feeding, etc) are responsible for the rapid spread of antibiotic resistance genes among pathogenic bacteria. In this proposal, we focus on bacterial transformation systems, also named competence systems. Natural transformation is the acquisition of naked DNA from the extracellular milieu. It is the only programmed process for generalized genetic exchange found in bacteria. This highly efficient and regulated process promotes bacterial genome plasticity and adaptive response of bacteria to changes in their environment. It is essential for bacterial survival and/or virulence and greatly limits efficiency of treatments or vaccine against some pathogenic bacteria. The architecture and functioning of the membrane protein complexes mediating DNA transfer through the cell envelope during bacterial transformation remain elusive. We want to decipher the molecular mechanism of this transfer. To attain this goal, we will carry out structural biology studies (X-ray crystallography and high resolution electron microscopy) as well as functional and structure-function in vivo studies. We have the ambition to make major contributions to the understanding of bacterial transformation. Ultimately, we hope that our results will also help to find compounds that could block natural transformation in bacterial pathogens.

1 405 149 €

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

There exist very few techniques for studying a group of cells containing a large number compared to a single cell but small compared to a whole tissue. This implies that statistics are exceedingly difficult to obtain from measurements of individual cells. Microfluidics provides a way to amend this by allowing ways to observe individual cells and automate such measurements. The aim in this project is to develop a cell manipulation platforms based on microfluidics techniques developed in our lab, while answering relevant biological questions. The first question concerns Sickle Cell Anemia, a genetic disease for which no treatment exists. We will study the polymerization of hemoglobin within red blood cells, as they are submitted to cycles of oxygenation and deoxygenation. Quantitative measurements of the response of the cells to oxygen variations will allow physiological conditions to be simulated, including in the presence of therapeutic candidates or other biological agents. The second question concerns the motility of adherent cells in a three-dimensional environment. This question will be to understand the migration of cells in a 3D gradient of chemo-attractant, as well as gradients of rigidity of the environment. This part will require the development of new technological tools which can later be applied to a wide range of biological problems. The long term aim is to replace the current tools of biological labs with miniaturized and integrated lab on a chip devices.

1 494 744 €

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

Accurate adaptation to stimuli predicting threatening outcome is critical to survival. An insufficient fear reaction may lead the animal to overlook future signs of danger, whereas overreacting may lead the animal to failure to explore and miss opportunities for feeding or mating. Numerous data indicate that the medial prefrontal cortex (mPFC) plays a key role in the control of fear behavior and that distinct prefrontal areas differentially regulate the expression/inhibition of fear responses. Whereas lesions/inactivations of the mPFC infralimbic (IL) area promote fear expression, lesions/inactivations of the mPFC prelimbic area (PL) promote fear inhibition. Moreover, PL and IL receive segregated inputs from functionally distinct amygdala circuits activated during high and low fear states. These data suggest that a key function of mPFC circuits might be to integrate inputs from the amygdala to ultimately gate fear expression via projections to specific neuronal circuits. However, little is known about the underlying neuronal circuits. Is the rapid switch between expression/suppression of fear behaviors mediated by the same circuits or does the mPFC contain distinct circuits dedicated to the control of opposite behaviors? Is there an organization in terms of afferents and efferent at the level of mPFC neuronal circuits? To address these questions we will use a cross-level approach combining in vivo electrophysiological optogenetic and behavioral approaches to elucidate the anatomical/physiological properties of mPFC circuits and to address their functional role in the control of fear behavior. We will first examine the activation and connectivity of mPFC circuits using in vivo extracellular recordings and extracellular stimulations. We will next selectively manipulate these circuits during behavior using light-activated proteins to establish causal relationships. Finally we will study their plasticity and anatomical properties using in vivo intracellular recordings.

1 496 300 €

Start date: 2011-11-01, End date: 2016-10-31

Aerospace and communication engineering technologies are in constant need of microwaves with extremely high spectral purity and stability. Unfortunately, the generation of such ultra-pure microwaves with compact, versatile and transportable sources is still a very complex challenge. In aerospace engineering, ultra-stable quartz oscillators are overwhelmingly dominant as key components for both navigation and detection systems. However, it is unanimously recognized today that their frequency stability performance is reaching its floor, and will not improve significantly anymore. In the search for an alternative standard for the next generation of ultra-pure microwave sources in aerospace technology, we propose the exploration of an elegant and promising solution relying on optical resonators with ultra-high Q factors (Q ~ 1E10). In these quasi-perfectly shaped cavities, nonlinear effects are significantly enhanced and microwave generation is performed through the extraction of the intermodal frequency. This approach has several advantages over existing or other prospective methods: conceptual simplicity, higher robustness, smaller power consumption, longer lifetime, immunity to interferences, very compact volume, frequency versatility, easy chip integration, as well as a strong potential for integrating the mainstream of standard photonic components for both microwave and lightwave technologies. Our ambition in the NextPhase project is to significantly outperform quartz oscillators and demonstrate performances comparable to cryogenic sapphire oscillators, with a compact (< 100 cm3), versatile (up to at least 200 GHz) and ultra-stable (Allan variance ~ 1E-15 at 1 s; phase noise floor < -160 dBc/Hz) microwave photonic generator. We also expect our work to open new opportunities of research in optical communications (photonic components for full-optical processing, carrier synthesis), as well as in fundamental aspects of condensed matter and quantum physics.

1 384 628 €

Start date: 2011-11-01, End date: 2016-10-31

The high prevalence of Chlamydia infections and the heavy burden they inflict on public health justify the search for novel therapeutic approaches directed against this pathogen. Research on this obligate intracellular bacterium is very difficult, due to substantial technical impediments. One current challenge is to identify bacterial proteins that are required for Chlamydia to survive and proliferate in the host and that could serve as targets in novel therapeutic strategies. In particular, the identification of bacterial proteins implicated in the microbe’s ability to persist in host cells is highly desirable, since current treatments fail to erradicate the resulting chronic infections. Our project is focused on the bacterial proteins that are secreted into the host cell during infection and translocate into the nucleus. Our preliminary work has already identified some of these “nuclear effectors” of Chlamydia. Targetting the “central system” of the host, these proteins are likely essential for infection. We will (i) identify all Chlamydia trachomatis nuclear effectors and define their frame of action (in time and space) during infection, (ii) identify the targets of the nuclear effectors and their roles in infection and (iii) test the hypothesis that nuclear effectors are necessary for the entry into and/or maintenance of the persistent state of infection. Addressing for the first time the full repertoire of “nuclear weapons” of an intracellular bacterium, we will uncover new interactions between the pathogen and the host. This work will lead to the development of rationally-designed drugs that inhibit the activity of the nuclear effectors, thereby disrupting the microbe’s ability to survive in the host. Beyond this medical aim, our study, which lies at the interface between microbiology, cell biology and genome biology, will provide new angles of study to each of these three disciplines and improve our understanding of fundamental cellular processes.

1 491 660 €

Start date: 2012-07-01, End date: 2018-06-30

"A quantum dot (QD) in a microcavity is an ideal single spin-single photon interface: the spin of a carrier trapped inside a QD can be used as a quantum bit and the coupling to photons can allow remote spin entanglement. A QD in a cavity can also generate single photons or entangled photon pairs, often referred to as flying quantum bit. Controlling the QD spontaneous emission is crucial to ensure optimal coupling of the photon and spin states. The present project relies on a unique and original technology we have developed which allows us to deterministically control the QD-cavity system. With this technique, we can fabricate a large number of identical coupled QD-cavity devices operating either in the weak or strong coupling regime. The potential of the technique has been proven by the fabrication of the brightest source of entangled photon pairs to date (Nature 2010). The objective of the present project is to build up a platform for basic quantum operations using QDs in cavities. The first aim is to develop highly efficient light emitting devices emitting indistinguishable single photons and entangled photon pairs. The mechanisms leading to quantum decoherence in QD based sources will be investigated. We will also explore a new generation of devices where QDs are coupled to plasmonic nano-antenna. The second objective is to implement basic quantum operations ranging from entanglement purification to quantum teleportation using QD based sources. The third objective of the project is to control the spin-photon interface. We first aim at demonstrating quantum non-demolition spin measurement through highly sensitive off-resonant Faraday rotation. We then aim at entangling two spins separated by macroscopic distances, using their controlled interaction with photons. This will be obtained either by making a single photon interact with two spin in cavities or by interfering indistinguishable photons emitted by two independent charged QDs."

1 482 000 €

Start date: 2011-11-01, End date: 2016-10-31

Polycomb Group (PcG) proteins are pivotal for the specification and maintenance of cell identity by preventing inappropriate gene activation. They function mostly through the regulation of chromatin structure and, in particular, the post-translational modification of histones. Although the enzymatic activities of the main PcG complexes has been described, lots remain to be discovered in terms of how these chromatin modifying activities are regulated. Genome wide analysis uncovered genes that are targeted by PcG proteins in various model cell lines, however it still very unclear how PcG proteins are targeted to a specific set of genes depending on the cell type. Finally, PcG proteins are frequently fund deregulated in diseases among which cancer but whether the alteration of their expression is a causative event to pathologies requires further investigation. This proposal is focused on the Polycomb Repressive Complex 2 (PRC2) whose function is pivotal to the polycomb machinery. In the first two aims of this proposal, we will investigate mechanistically how transcription factors, non-coding RNAs and chromatin structure might independently or in conjunction establish the conditions conducive to gene targeting by PRC2 and regulate its activity. In the third and fourth aims of this proposal, we will investigate what is the function of PRC2 during tumorigenesis and cell reprogramming and how its function is regulated during these processes.

1 499 815 €

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

The complexity by which genotypes modulate phenotypic variation has been a major obstacle in understanding the basis of inter-individual differences. In the particular case of disease susceptibility, enormous efforts have been conducted among large consortia of quantitative geneticists, and a recent wealth of results showed both victories and frustrations. Victories because many genetic factors could successfully be linked to diabetes, heart failure, cancer, infectivity, and many other common diseases. Frustrations as it is becoming more and more apparent that genetic dissections are far from completion, with many unsolved questions especially regarding gene x environment interactions and incomplete penetrance. In this context, I propose to revisit the molecular basis of phenotypic diversity by addressing fundamental questions in a simple and powerful model organism: the yeast S. cerevisiae. Combining experimental biology and bioinformatics into a ‘systems’ approach, I propose 1) To reconsider our current view of genetic determinism. By examining the effect of genetic variation on single-cells, we will visualise how they shape probability laws underlying phenotypic outcomes. This will prepare us to the upcoming era of generalized single-cell analysis. 2) To investigate how chromatin epigenotypes affect phenotypic variations. We will characterize nucleosomal epi-polymorphisms and study their impact on transcriptional and phenotypic responses to environmental changes. This will establish whether and how individual epigenomes should be considered when planning trait dissections. This ambitious project is grounded on solid preliminary results and can be achieved thanks to my dual expertise in numerical science and experimental genetics. The questions addressed are fundamental for our understanding of living systems and the innovative methodology will help us integrate upcoming technologies into the construction of personalized medicine.

1 499 660 €

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

The innate immune response is the first line of defence against pathogens, which is initiated by the detection of pathogen-derived signatures referred to as Pathogen-Associated Molecular Patterns (PAMPs). Plants and animals sense PAMPs and in turn differentially regulate a large set of immune response genes, among which microRNAs (miRNAs) were recently identified. In the model plant Arabidopsis thaliana, dozens of miRNAs are PAMP-responsive, among them we found that a conserved miRNA contributes to antibacterial resistance. More recently, we have reported a major role of the Arabidopsis miRNA pathway in antibacterial defence and, as a corollary, have identified a series of bacterial-derived suppressors of the miRNA pathway. This pioneering work represents an important contribution to the understanding of virulence strategies employed by pathogenic bacteria and suggests that analogous strategies may also be used by human pathogenic bacteria. In the proposed project, we will first aim to investigate the extent to which an RNA silencing suppression strategy employed by a phytopathogenic bacterial effector is also used by effectors from human pathogenic bacteria. We will additionally aim to generate a comprehensive view of small RNA repertoires produced in the course of bacterial infection using both a human and a plant pathogenic bacteria. The second aspect of our proposal is directed toward a better understanding of the influence of PAMPs and bacterial effectors on Arabidopsis transcriptional gene silencing (TGS), a pathway that silences transposable elements and repeats through the establishment and maintenance of cytosine DNA methylation. Finally, we will aim to identify and characterize bacterial effectors that interfere with TGS. Overall, these studies should reveal completely novel bacterial virulence strategies and contribute to a better understanding of the mechanisms underlying post-transriptional- and transcriptional- gene silencing in different organisms.

1 499 955 €

Start date: 2011-12-01, End date: 2017-11-30

Pancreatic ductal adenocarcinoma (PDAC) is the most intractable of human malignancies. Survival rate at 5 years is very low (less than 5%). Patients are most of the time diagnosed while the disease has already spread out and benefits from surgical resection is often cut off due to local recurrence and lack of efficient chemotherapy. Indeed, it is urgent to develop new tools to be used by clinicians in order to propose better management of the disease. This project is based on two specific characteristics of PDAC. First, the existence of a prominent tumor stroma compartment (desmoplasia) consisting of non-neoplastic myofibroblastic pancreatic stellate cells, vascular, nerve and immune cells surrounded by immense quantities of ECM, from far exceeding that found in most other tumor types. Second, the very specific and almost unique PDAC associated neural compartment remodeling (PANR) correlated with the intense neuropathic pain observed in this disease. PANR consists in a modification of nerve fiber structure/density and presence of tumoral cell within nerve fibers, a phenomenon called peri-neural invasion which is highly correlated to local recurrence of primary PDAC tumor. We and others hypothesized that, by dialoguing with cancer cells, non-tumoral stromal cells impact on PDAC tumor biology by modeling the own tumoral structure and fostering the tumor development. Regarding this concept we suppose that the intra-tumoral micro-environment has an active and efficient role on the neural compartment remodeling, its associated pain and local recurrence. By integrating preliminary and ongoing results from transcriptomic and proteomic analysis of human PDAC and endogenous mice model developing PDAC, as well as multiples cell lines co-culture studies, we aim to determine this “stromal PDAC signature” and its specific components involved in the PANR. Such improvement could permit to unravel novel diagnostic, prognostic, and therapeutic options for this deadly malignancy.

952 686 €

Start date: 2011-12-01, End date: 2016-11-30

The development of better vaccines against cancer or intracellular pathogens is a major challenge of immunological research. Novel approaches are needed to induce efficient, long-lasting memory CD8 T cell (CTL) responses. The CD8α subset of mouse dendritic cells (mDC) is specialized in this function, excelling at antigen cross-presentation. Their targeting in vivo for vaccination yielded encouraging results. How to translate this strategy for human health was not obvious, because no human DC (hDC) subset equivalent to CD8α mDC had been discovered. Investigating the relationships between mDC and hDC subsets was hampered by the use of different markers for their identification. To overcome this problem, we used comparative genomics to unravel potential equivalences between mDC and hDC subsets based on the similarities of their gene expression programs. This led us to demonstrate that BDCA3 hDC are professional cross-presenting DC equivalent to CD8α mDC. However, we still do not know what the extent of the physiological functions of different DC subsets is, and we largely ignore how they are regulated. We propose a major and innovative effort to investigate in parallel in mouse and human the biology of two DC subsets thought to be important for antiviral and antitumoral defence: plasmacytoid DC and professional cross-presenting DC. We designed a Systems Biology approach to uncover key functions and regulatory pathways conserved in these cells. We will investigate DC subset functions and their regulation in vivo during infectious challenges, by using state-of-the-art technology to generate and analyse novel high throughput data and innovative mutant mice. We will directly translate to human the knowledge obtained in the mouse, through comparative genomics and in vitro experiments on hDC. This approach is the first of this kind, at the forefront of creating new knowledge to understand the pivotal role of DC subsets in immunity and to manipulate them for promoting health.

1 498 822 €

Start date: 2012-02-01, End date: 2017-07-31

Given the contemporary biodiversity crisis, effective conservation strategies that offset the threats to ecosystem integrity are crucial for maintaining biodiversity. The development of sound biodiversity scenarios is thus a major challenge for the scientific community. However, current biodiversity models rarely incorporate recent advances in ecological and evolutionary theory like: (i) how evolution shapes species’ niches and ranges; (ii) how community assembly rules shape species' ranges; and (iii) how these two processes interact to drive the response of populations and communities to environmental changes. Since the considered processes act on the opposing ends of an organisational hierarchy, they have rarely been combined and no model integrating all these processes yet exists. The task of bridging the gap between local processes and macroecological species range dynamics is to build upon theoretical and empirical approaches from evolutionary ecology and community ecology, to extract the processes relevant for higher-scale dynamics and to account for their interactions to generate biodiversity scenarios and associated services. The key-idea of the proposed project TEEMBIO is thus to fill this gap through four interrelated research axes: 1- Improve our understanding on how evolution shapes species ranges at micro- and macro-evolutionary scales. 2- Improve our understanding on how community assembly rules shape biodiversity and species. 3- Develop, analyze and parameterize comprehensive projection tools (EEM-models) that incorporate both evolutionary dynamics and community assembly rules to predict global change impacts on biodiversity. 4- Develop a set of quantitative scenarios of plant biodiversity and associated ecosystem services using two case studies (forest in European Alps and grasslands in French Alps) with a comprehensive assessment of protected area networks

1 482 705 €

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

Widely advertised as a discovery machine, the LHC proton collider at CERN will also provide large samples of standard particles, allowing the final, most precise experimental determination of some fundamental parameters of particle physics theory. Together with the expected discoveries, these measurements will allow to elucidate the dynamics of electroweak symmetry breaking. The aim of the present project is to organize and realize a precise measurement of the W resonance parameters, and in particular the W boson mass with a target precision below 0.01%. Most LHC measurements aim at a precision of order 1%, and can be performed on a time scale of about one year, within a small group of collaborators. The measurement of the W boson mass is a special case, as its aimed precision requires perfect understanding of the experimental and physical environment. It therefore requires careful planning. Intermediate measurements of standard processes need to be performed, synchronized, and will play a key role in the final result. The primary tools serving this purpose are the study of the production properties of the J/Psi, W and Z particles in the uncertain LHC environment. These studies will allow to understand the performance of the ATLAS detector and to constrain the dynamics of proton-proton interactions, which represent a major source of uncertainty. Once the above properties are firmly established, the distributions sensitive to the W boson mass can be precisely predicted, and the fundamental parameters can be determined. The coordinator of this project has recognized expertise on electroweak physics, and has led the ATLAS Collaboration's research in this field since 2007. As argued above, the preparation of the measurement of mW requires to build and coordinate a team devoted to the realization of this difficult measurement over the next years. The present grant would provide a unique opportunity to gather all necessary conditions for the success of this project.

1 259 760 €

Start date: 2011-10-01, End date: 2016-09-30