ERC FUNDED PROJECTS

"AIME is an inquiry to make more precise what is lumped together into the confusing word ""modernization"". The work done in the field of science studies (STS) on the progress and practice of science and technology has had the consequence of deeply modifying the definition of ""modernity"", resulting into the provocative idea that ""we (meaning the Europeans) have never been modern"". This is, however only a negative definition. To obtain a positive rendering of the European current situation, it is necessary to start an inquiry in the complex and conflicting set of values that have been invented. This inquiry is possible only if there is a clear and shareable way to judge the differences in the set of truth-conditions that make up those conflicting sets of values. AIME offers a grammar of those differences based on the key notion of modes of existence. Then it builds a procedure and an instrument to test this grammar into a selected set of situations where the definitions of the differing modes of existence is redefined and renegotiated. The result is a set of shareable definitions of what modernization has been in practice. This is important just at the moment when Europe has lost its privileged status and needs to be able to present itself in a new ways to the other cultures and civilizations which are making up the world of globalization with very different views on what it is to modernize themselves."

1 334 720 €

Start date: 2011-09-01, End date: 2015-06-30

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

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

Understanding the establishment and persistence of bacterial infections in the gut requires integrating an ensemble of factors including bacterial and host components and the presence of other microorganisms. We will capitalize on 25 years of studies on the bacterium Listeria monocytogenes used as a model, to focus on three objectives which will significantly increase our knowledge of the bacterium, of the cell biology of infection and of the epigenetic reprogramming upon infection. Our aims are: - at the bacterial level : to describe for the first time, the proteomic landscape of a bacterium during switch from saprophytism to virulence. We will use a proteogenomic approach together with ribosome profiling, to analyze the translation of the whole transcriptome after bacterial growth in several conditions, including in vivo, in order to barcode all the proteins which play a role in infection. This will open the way to assess the role of 1) small proteins; 2) internal translation initiation sites ; 3) the coupling of transcription and translation. - at the host cell level : To decipher the molecular mechanisms underlying the dynamics and role in infection of host intracellular organelles, starting with mitochondria. - At the host epigenetic level : To explore how the microbe reprograms host transcription and how tolerance to a commensal such as Akkermansia muciniphila differs from responsiveness to a pathogen insult, at the level of histones and mRNA modifications by studying 1) chromatin remodeling, in particular histones modifications during infection ; 2) modifications of the epitranscriptome during Listeria infection and colonization with Akkermansia ; 3) whether there is an epigenetic memory of infection and colonization. This ambitious multidisciplinary project will not only generate new concepts in infection biology but also will unravel fundamental mechanisms in microbiology, cell biology, and epigenetics opening new avenues for further research.

1 147 500 €

Start date: 2015-10-01, End date: 2019-09-30

The main objective nowadays in the field of biomaterials is to design highly performing bioinspired materials learning from natural processes. Importantly, biochemical and physical cues are key parameters that can affect cellular processes. Controlling processes that occur at the cell/material interface is also of prime importance to guide the cell response. The main aim of the current project is to develop novel functional bio-nanomaterials for in vitro biological studies. Our strategy is based on two related projects. The first project deals with the rational design of smart films with foreseen applications in musculoskeletal tissue engineering. We will gain knowledge of key cellular processes by designing well defined self-assembled thin coatings. These multi-functional surfaces with bioactivity (incorporation of growth factors), mechanical (film stiffness) and topographical properties (spatial control of the film s properties) will serve as tools to mimic the complexity of the natural materials in vivo and to present bioactive molecules in the solid phase. We will get a better fundamental understanding of how cellular functions, including adhesion and differentiation of muscle cells are affected by the materials s surface properties. In the second project, we will investigate at the molecular level a crucial aspect of cell adhesion and motility, which is the intracellular linkage between the plasma membrane and the cell cytoskeleton. We aim to elucidate the role of ERM proteins, especially ezrin and moesin, in the direct linkage between the plasma membrane and actin filaments. Here again, we will use a well defined microenvironment in vitro to simplify the complexity of the interactions that occur in cellulo. To this end, lipid membranes containing a key regulator lipid from the phosphoinositides familly, PIP2, will be employed in conjunction with purified proteins to investigate actin regulation by ERM proteins in the presence of PIP2-membranes.

1 499 996 €

Start date: 2011-06-01, End date: 2016-05-31

How can simple molecules self-organize into a growing synthetic reaction network like biochemical metabolism? This proposal takes a novel synthesis-driven approach to the question by mimicking a central self-amplifying CO2-fixing biochemical reaction cycle known as the reductive tricarboxylic acid cycle. The intermediates of this cycle are the synthetic precursors to all major classes of biomolecules and are built from CO2, an anhydride and electrons from simple reducing agents. Based on the nature of the reactions in the cycle and the specific structural features of the intermediates that comprise it, we propose that the entire cycle may be enabled in a single reaction vessel with a surprisingly small number of simple, mutually compatible catalysts from the recent synthetic organic literature. However, since one of the required reactions does not yet have an efficient synthetic equivalent in the literature and since those that do have not yet been carried out sequentially in a single reaction vessel, we will first independently develop the new reaction and sequences before attempting to combine them into the entire cycle. The new reaction and sequences will be useful green synthetic methods in their own right. Most significantly, this endeavour could provide the first experimental evidence of an exciting new alternative model for early biochemical evolution that finally illuminates the origins and necessity of biochemistry’s core reactions.

1 500 000 €

Start date: 2015-09-01, End date: 2020-08-31

CD8 T lymphocytes have a fundamental role in ensuring the control of different types of intracellular pathogens including bacteria, parasites and most viruses. This control may fail due to several reasons. The current aggressive anti-cancer therapies (or rarely certain congenital immune deficiencies) induce CD8 depletion. After bone-marrow transplantation, long time periods are required to ensure T cell reconstitution particularly in the adult. This long lag-time is due to the long-time periods required for hematopoietic precursors to generate T lymphocytes and to a thymus insufficiency in the adult. However, even when CD8 T cells are present CD8 immune responses are not always adequate. Certain chronic infections, as HIV, induce CD8 dysfunction and it is yet unclear how to generate efficient CD8 memory responses conferring adequate protection. To address these questions this project aims 1) To find strategies ensuring the rapid reconstitution of the peripheral and the gut CD8 T cell compartments a) by studying the mechanisms involved HSC division and T cell commitment; b) by isolating and characterizing progenitors we previously described that are T cell committed and able of an accelerated CD8 reconstitution c) by developing new strategies that may allow stable thymus transplantation and continuous thymus T cell generation. 2) To determine the mechanics associated to efficient CD8 memory generation a) by evaluating cellular modifications that ensure the efficient division and the remarkable accumulation and survival of CD8 T cells during the adequate immune responses as compared to inefficient responses b) by studying CD8 differentiation into effector and memory cells in both conditions. These studies will use original experiment mouse models we develop in the laboratory, that allow to address each of these aims. Besides state of the art methods, they will also apply unique very advanced approaches we introduced and are the sole laboratory to perform.

1 969 644 €

Start date: 2009-02-01, End date: 2014-05-31

Each year, civil wars cause hundreds of thousands of deaths, millions of refugees, ecological disruptions, regional instability. These conflicts encompass many players and their effects are felt not only at the regional level but also within Western societies (refugees, terrorism, sectarian tensions). Despite this, no systematic comparison of civil wars have been conducted using a qualitative method. Social scientists are struggling to understand these breakdowns of the social order, which are fertile from a theoretical perspective because they de-trivialize the social functioning. In civil war, the partial or total institutional collapse marks the end of the (imperfect) monopoly of the state with regards to violence and justice, challenges the social and ethnic hierarchies and also provokes fluctuation of the economic and social capital. Accordingly, we will address three questions. First, the sudden and non-anticipated reconfiguration of modes of accumulation and conversion of capitals and the relationship between social fields. Next, the formation of competing institutions by politico-military movements involved in the construction of an alternative political order. Finally, individual adaptations to risks and uncertainty affecting the ability of actors to anticipate the consequences of their actions and reassess their own values and engagement. The implementation of this program of comparative sociology of civil wars will draw on extensive fieldwork. This requires an adapted methodology for researchers faced with unpredictable situations, where quantitative methods fall short. Prosopography, semi- or unstructured interviews and participant observation are therefore prioritised. The creation of an interdisciplinary team of sociologists, political scientists and anthropologists will be able to carry out research based on thick description, following 25 years of experience by the PI in collecting data and supervising researchers in areas afflicted by civi

2 500 000 €

Start date: 2016-01-01, End date: 2020-12-31

The application's unifying theme is cognition. Any decision reflects the information that comes to the decision-maker's awareness at the moment of making the decision. In turn, this information is the stochastic outcome of a sequence of more or less conscious choices and of awareness manipulation by third parties. The three parts of this application all are concerned with two factors of limited awareness (cognitive costs and motivated beliefs) and with the application of imperfect cognition to economics. The various projects can be subsumed into three themes, each with different subprojects: 1. Self-serving beliefs, laws, norms and taboos (expressive function of the law, taboos, dignity and contracts). 2. Cognition, markets, and contracts (mechanism design under costly cognition, directing attention in markets and politics). 3. Cognition and individual decision-making (foundations of some non-standard preferences). The methodology for this research will be that of formal economic modeling and welfare analysis, enriched with important insights from psychology and sociology. It will also include experimental (laboratory) investigations. The output will first take the form of a series of articles in economics journals, as well as, for the research described in Part 1, a book to disseminate the research to broader, multidisciplinary and non-specialized audiences.

1 910 400 €

Start date: 2010-04-01, End date: 2016-03-31

Cancer related inflammation (CRI) is a well-established hallmark of cancer. We recently demonstrated that the DNA damage repair SLX4 complex suppresses spontaneous and human immunodeficiency virus (HIV)-dependent pro-inflammatory cytokine production, revealing a role for this DNA repair complex in controlling innate immune responses. Bi-allelic mutations in SLX4 are involved in the onset of Fanconi Anemia (FA), a syndrome characterized, besides heightened cancer susceptibility, by severe defects of the immune system, resulting from increased pro-inflammatory cytokine levels and progressive bone marrow failure. Within this proposal, using SLX4-deficiency as a working model, I aim at investigating the molecular process underlying CRI. Based on our previous observation that the SLX4 complex binds to HIV-derived reverse-transcripts and promotes their degradation, my working hypothesis is that CRI results from the accumulation of endogenous pathological nucleic acids that are recognized by the innate immune system in the absence of SLX4. The present project should unveil the relationship between repression of pro-inflammatory cytokine production by proteins involved in DNA repair, DNA damage, and CRI, thereby opening unforeseen perspectives in the treatment of cancer patients.

1 500 000 €

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

T cell cross priming (the initiation of CD8+ T cell responses to antigen that are not expressed by dendritic cells, DCs) requires the phagocytosis of antigens by DCs and their presentation on MHC class I molecules, a process referred to as “cross presentation”. Here, we propose a series of integrated approaches to address the most fundamental mechanisms of cross presentation and explore the use of this process for translational purposes in human cancer. This proposal will pursue three main objectives: 1) To analyze the mechanisms of control of antigen cross presentation and phagocytic functions in DCs. We will use genome wide screens and conditional KO mice, associated to quantitative assays for phagosomal functions and cross presentation, to investigate the molecular mechanisms of cross presentation in vitro and in vivo. 2) To study the epigenetic programing of cross presentation during the ontogeny of mouse DC subpopulations. We will define a “cross presentation gene signature” that will be validated by systematic gene silencing in vitro and we will analyze the epigenetic basis of control of cross presentation-related genes developing DCs. 3) To investigate the regulation of cross presentation in human primary DCs and to develop translational approaches in cancer. We will study cross presentation and phagosome functions in primary human DC subpopulations and its regulation by innate receptors for the development of original immunomodulation and vaccination strategies. We will explore the use of DCs cross presentation abilities in solid tumor infiltrating DCs and their use for prognosis in cancer. The results of this project will unravel fundamental mechanisms of phagocytosis and its control by innate signals in mice and humans. The proposal also aims at defining new possible strategies for cancer treatment and prognosis.

2 500 000 €

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

"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

This project studies dynamic mechanisms. By “dynamic mechanisms”, we mean policies to which a principal (e.g., a seller, an employer, or a regulator) can commit to induce the agents (e.g., buyers, employees, or regulated firms) to take the desired actions over time. Several components of the project are envisaged: - Competition in dynamic mechanisms. o I propose a competitive setting in which agents (e.g., buyers or workers) learn about the offers of different principals over time. Agents may receive more than one offer at a time, leading to direct competition between mechanisms. Received offers are agents’ private information, permitting strategic delay of acceptance (for instance, an agent may want to wait to evaluate new offers that received in the future). - Robust predictions for a rich class of stochastic processes. o We study optimal dynamic mechanisms for agents whose preferences evolve stochastically with time. We develop an approach to partially characterizing these mechanisms which (unlike virtually all of the existing literature) does not depend on ad-hoc restrictions on the stochastic process for preferences. - Efficient bilateral trade with budget balance: dynamic arrival of traders o I study bilateral trade with budget balance, when traders (i) arrive over time, and (ii) have preferences which evolve stochastically with time. The project aims at an impossibility result in this setting: contrary to the existing literature which does not account for dynamic arrivals, budget-balanced efficient trade is typically impossible, even for very patient traders. - Pre-event ticket sales and complementary investments o We provide a rationale for the early allocation of capacity to customers for events such as flights and concerts based on customers’ demand for pre-event complementary investments (such as booking a hotel or a babysitter). We examine efficient and profit-maximizing mechanisms.

1 321 625 €

Start date: 2017-01-01, End date: 2021-12-31

This project offers a theoretical and empirical investigation of matching markets. Matching is, broadly speaking, the study of complementarities, which explains the formation of coalitions. Matching models are found in many applied fields within Economics: Labour Economics, Family Economics, Consumer theory of differentiated goods (hedonic models), Trade, etc. Desirable properties of these coalitions, such as stability, lead to testable implications of the surplus that individuals generate in a match, allowing for structural estimation of matching models. The goal of this proposal is to expand the frontiers of the theory of matching to design a very general and highly flexible model of matching that will lend itself to estimation and thus lead to empirical findings in various fields of Economics. Based on promising work initiated by the PI, this proposal seeks to bridge the gap between the theory and the empirics of matching markets that was traditionally observed in this literature. Particular focus will be given to situations where stable outcomes may not exist (such as unipartite, or one-to-many matching models), frictions, taxes. In these cases, a thorough investigation is carried on what solution concept should be used, and what are the testable implications. Applications will be given to various empirical issues or policy relevant questions such as: - The nature of the complementarities between senior and junior employees within teams, - The role played by the marriage market in the problem of rural depletion in China, - The impact of CEO risk aversion on assignment to firms, and on the CEO compensation package, - The pricing of attributes of French wines.

1 119 000 €

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

A common strategy of bacterial pathogens is active or passive uptake into host cells. There, they can localize within a bacterial containing vacuole (BCV) or access the host cytoplasm through BCV rupture. Hence, intracellular pathogens are often classified as vacuole-bound or cytoplasmic. Recently, this definition has been challenged by the discovery that many vacuole-bound pathogens, including Mycobacterium tuberculosis and Salmonella enterica, access the host cytoplasm, and by the insight that cytoplasmic bacteria, like Shigella flexneri or Listeria monocytogenes, do not always escape the BCV. Despite this increasing complexity, a precise understanding lacks for why and how a pathogen “chooses” between a BCV or the cytoplasm and yet this is very important: because of differential pathogen sensing in membrane-bound and cytoplasmic compartments, intracellular localization leads to induction of different host responses. Therefore, a comprehensive understanding of the processes controlling BCV integrity is not only essential, but can provide new therapeutic targets. Our previous research has implemented innovative fluorescence microscopy to track the invasion steps of pathogenic bacteria. We have further integrated a large-volume, correlative, light/electron microscopy (CLEM) workflow via focused ion beam scanning electron microscopy. This uncovered the subversion of host Rab cascades by Shigella to rupture its BCV. Starting with the Shigella model of epithelial cell invasion, we will delineate the precise molecular mechanisms controlling BCV integrity in different host cell types. We will analyze (i) the scaffolds of host pathways for membrane remodeling, (ii) their subversion by various pathogens, and (iii) their differential regulation depending on pathophysiological conditions. Together, this will allow development of novel, rational antimicrobial strategies and will yield fundamental insight into understudied cell biological mechanisms of membrane trafficking.

2 000 000 €

Start date: 2017-01-01, End date: 2021-12-31

Economics provides decision-makers with powerful tools to analyse a wide range of issues. The methodological unity of the discipline and its quest for a general understanding of market as well as non-market interactions have given the discipline great influence on policy. A core component of economics is its assumption that individuals act as if they each had some goal function that they seek to maximise, under the constraints they face and the information they have. Despite significant advances in behavioural economics, there still is no consensus as to whether and why certain preferences are more likely than others. Further progress could be made if the factors that shape human motivation in the first place were understood. The aim of this project is to produce novel insights about such factors, by establishing evolutionary foundations of human motivation.The project's scope is ambitious. First, it will study two large classes of interactions: strategic interactions, and interactions within the realm of the family. Second, to obtain both depth and breadth of insights, it will consist of four different, but inter-related, components (three theoretical and one empirical), the ultimate goal being to significantly enhance our overall understanding of the factors that shape human motivation. The methodology is ground-breaking in that it is strongly interdisciplinary. Parts of the body of knowledge built by biologists and evolutionary anthropologists in the past decades will be combined with state-of-the-art economics to produce insights that cannot be obtained within any single discipline. Focus will nonetheless be on addressing issues of importance for economists.The proposed research builds on extensive work done by the PI in the past decade. It will benefit from the years that the PI has invested in understanding the biology and the evolutionary anthropology literatures, and in contributing towards building an interdisciplinary research ecosystem in Toulouse, France

1 550 891 €

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

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

753 393 €

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

There is mounting evidence that firms are becoming more fragmented; production is less often made “in-house”. Firms buy inputs from abroad. Tasks are often split in parts. Some are offshored, others are subcontracted. Hence, firms buy services from other, local or international, firms. But they also supply inputs to other firms. Technical change, the internet, and globalization, all facilitate this transformation. In order to better understand how firms thrive in the new global environment, the proposed research aims to construct a networks view of the firm. Fragmentation offers new opportunities: firms may specialize in what they make best, hence creating a business network of customers and suppliers. Networks are also useful to secure provision of fragmented tasks. The firms’ suppliers of goods and services – accountants, logisticians, consultants… -- may well be related to the firm through its workers’ social networks: family ties, boardroom relations… These social networks should be useful when times are tough -- board members could help find financing in banks where their schoolmates have a job – or when times are unusually good -- employees could help in spotting the right hires among their former co-workers. The proposed research will focus on how firms social and business networks help firms to be resilient in the face of shocks. Resilience will be measured using the firms’ and workers’ outcomes – value-added, wages, employment, or occupations. The research will have a theoretical component using general equilibrium models with heterogeneous firms, an empirical component with unique data sources from at least two countries (France, Sweden), and an “econometric theory” component which will seek to develop techniques for the study of many-to-one matches in the presence of networks. The research will speak to the labor economics community but also to the international trade community, the management community, as well as the econometrics community.

1 753 288 €

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

We propose to undertake a new challenge: the control of gene expression systems by physico-chemical means to achieve the following objectives: i) developing robust tools for spatio-temporal control of protein expression; ii) understanding the role of micro-environmental factors in gene regulation; and iii) constructing and implementing in vivo smart nanomachines able to express active molecules in response to a stimulus and deliver them to a targeted cell. First, various biochemical processes (transcription, translation) will be controlled by light in vitro, based on photo-induced conformational changes of nucleic acids (DNA, RNA) and chromatin. Based on conformational changes rather than specific template-protein interaction, and combined with microfluidic methodologies, this novel approach will provide a ubiquitous tool to address gene expression using light regardless of the sequence, with unique control and spatio-temporal resolution. Second, by reconstituting photo-responsive gene expression systems in well-defined giant liposomes, we will study the dynamics of gene expression in response to light stimulation. This will allow us to establish the respective roles of the membrane (surface charge, permeability) and of the inner micro-environment composition (viscosity, molecular crowding). Third, we will develop stable, long-circulating polymer nanocapsules (polymersomes) encapsulating a gene expression material that can be triggered by light and/or molecules of biological interest. In response to the signal, an exogenous, potentially immunogenic enzyme will be expressed inside the protecting nanocapsule to locally and catalytically convert a non toxic precursor present in the medium into a cytotoxic drug that will be delivered to a cell (e.g., a cancer cell). This new concept of triggerable gene-carrying nanomachines with unique amplification capacity of drug secretion shall open new horizons for the development of smart biological probes and future therapeutics.

1 450 320 €

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

"Pharmaceutical drugs provide an ideal window into studying contemporary societies. With dimensions that are simultaneously scientific, therapeutic, popular and commercial, these drugs are central to various issues. ACTs, the new recommended treatment for malaria in Africa, crystallize these issues and provide a case study to investigate the global drug market. This project proposes to use ACTs as a lens to study the realities affecting this market, both in terms of supply and demand in two African countries where the pharmaceutical systems differ significantly. This will involve analyzing the globalizing processes affecting drugs in Benin and Ghana and to study their consequences on public health. To further compare the drug systems and to address the serious issue of the spread of resistances to ACTs from Asia to Africa, the project also proposes conducting a study on the drug system in Cambodia. The central discipline is anthropology, which is extremely relevant to the study of formal and informal pharmaceutical supply and to the analysis of drug use (WP1 and WP2). However, since a multidisciplinary approach is advised for drug studies, the PI will work with an epidemiologist who will study the scope of ACT consumption (WP3) and a sociologist specializing in pharmaceutical legislation who will analyze local production and ACT regulations (WP4). Opening into Asia will occur through WP5. A WP6 is devoted to project management, dissemination of results, organizing two symposiums and institutional twofold impacts: (1) to foster reflection so that more efficient pharmaceutical systems are established in Africa, and (2) to provide critical information to prevent the spread of resistances to ACTs from Asia to Africa. The project includes a substantial training component: 8 master students, 2 PhD and 1 post-doct. The PI’s skills in methodology and theory and the solid partnerships she has developed in Benin and Ghana will support the project’s feasibility."

927 034 €

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

Over the past decade, distributed computing has experienced a dramatic scale shift, with respect to size, geographical spread and volume of data. Meanwhile, Internet has moved into homes, creating tremendous opportunities to exploit the huge amount of resources at the edge of the network. Search engines that navigate this universe are astonishingly powerful and rely on sophisticated tools to scan and index the network. However, the network contains far more than just the pages such systems can index. There is a tremendous potential in leveraging these new kinds of information to empower individuals in ways that Internet search will never be able to offer. This reveals striking evidence that navigating the Internet goes beyond traditional search engines. Complementary and different means to navigate the digital world are now required. The objective of GOSSPLE is to provide an innovative and fully decentralized approach to navigate the digital information universe by placing users affinities and preferences at the heart of the search process. GOSSPLE will turn the network into a self-organizing federation of overlapping sub-networks, capturing on the fly the interactions and affinities observed in real life and fully leveraging the huge resource potential available on edge nodes. GOSSPLE will provide a set of fully decentralized algorithms to efficiently search, dynamically index and asynchronously disseminate information to interested users based on their preferences and (implicit) recommendations. Building up upon the peer to peer communication paradigm and harnessing the power of gossip-based algorithms, GOSSPLE will yield a disruptive way of programming distributed collaborative applications. Our goal is ambitious: impose the GOSSPLE approach as a fully decentralized, collaborative and scalable, yet complementary, alternative to traditional search engines to fully exploit the capabilities of the digital universe.

1 250 000 €

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

Accounting for firms' heterogeneity in trade patterns is probably one of the key innovations of international trade that occurred during the last decade. The impact of initial papers such as Melitz (2003) and Bernard and Jensen (1999) is so large in the field that it is considered to have introduced a new paradigm. Apart from providing a convincing framework for a set of empirical facts, the main motivation of this literature was that there are new gains to be expected from trade liberalization. Those come from a selection process, raising aggregate productivity through the reallocation of output among heterogeneous firms. It initially seemed that the information requirements for trade policy evaluations had become much more demanding, in particular requiring detailed micro data. However, the recent work of Arkolakis et al. (2011) suggests that two aggregate ``sufficient statistics'' may be all that is needed to compute the welfare changes associated with trade liberalization. More, they show that those statistics are the same when evaluating welfare changes in representative firm models. The project has three parts. The first one starts by showing that the sufficient statistics approach relies crucially on a specific distributional assumption on heterogeneity, the Pareto distribution. When distributed non-Pareto, heterogeneity does matter, i.e. aggregate statistics are not sufficient to evaluate welfare changes and predict trade patterns. The second part of the project specifies which type of firm-level heterogeneity matters. It shows how to identify which sectors are characterized by ``productivity sorting'' and in which ones ``quality sorting'' is more relevant. Extending the analysis to multiple product firms, the third part shows that heterogeneity inside the firm also matters for welfare changes following trade shocks. It considers how the change in the product mix of the firm following trade liberalization alters the measured productivity of the firm.

1 119 040 €

Start date: 2012-11-01, End date: 2018-07-31

The molecular cross talks occuring at the interface between the intestinal epithelium and bacterial flora will be studied at two levels : (i) how commensals and pathogens affect innate immune signalling, thereby leading to tolerance of the resident microbiota, and inflammatory rejection of the pathogens. The theme of commensals and pathogens regulating this innate response, particularly how they respectively strengthen or weaken the network of humoral and cellular epithelial defense systems will be central here. (ii) How, in molecular and cellular terms, bacteria affect epithelial renewal. The gut of a germ-free mouse and of a conventional mouse show dramatic differences marked by global immaturity and slow epithelial renewal in absence of flora. In front of pathogens, the actual role plaid in the disease in altering the kinetics of epthelial repair is unknown. The aim of this project is to study how commensals and pathogens affect intestinal epithelial renewal, particularly the key steps of the whole developmental process such as lineages decisions, entry in cycle and proliferation, migration and final differentiation, decision to engage in cell death. In order to address these fundamental questions, we will study a commensal microorganism : Lactobacillus casei, and a pathogenic microorganism : Shigella flexneri as model organism, and will develop several novel systems such as reverse genetics of Lactobacilli, development of intestinal crypt models in vitro to study bacterial interactions, and development of a mouse model showing susceptibility to human-specific enteroinvasive pathogens. This project aims at interfacing microbiology, cell biology, and development biology around the concept of microbes manipulating intestinal epithelial homeostaesis. It also includes a strong component of therapeutic development aimed at identifying novel anti-infectious strategies and options to speed up epithelial restitution upon infectious-inflammatory damages.

2 356 350 €

Start date: 2009-02-01, End date: 2014-03-31

"""Making the sea more human."" The project focuses on rebuilding the concepts of maritime and ocean law, given the expansion of human activities at sea. The sea is one of our new frontiers. The development of human activities at sea has led to a transformation of the Law of the Sea and Maritime Law. The main purpose of law is to civilize the new activities opened up by technological innovations. But maritime law remains centred on the concept of the ship, and does not take into account the new marine vessels and their workers. The development of illegal activities at sea questions the competence of States and their cooperation. The HUMAN SEA project will provide critical assessment and perspectives on legal framework related to merchant navy globalisation, illegal activities at sea, and offshore activities. It will summarize the current law concerning international maritime labour in the merchant navy; then consider how the fight against illegal activities led to monitoring of marine areas, thanks to new technologies and through the cooperation of states; then bring the look on ways of managing oil and gas offshore platforms and large liners. Future activities, such as living on the sea, will be considered. Technical innovations predict the development of such use, but the legal framework remains to conceive. The final, overarching task, of the project consists in a conceptual synthesis to define the common principles to be applied for a new maritime law that takes into account activities at sea in their human, environmental, economical and technological dimensions. Such an ambitious project calls for expertise in various domains of law, i.e. Social Law, Economic Law and Environmental Law. The development of human activities at sea requires rethinking concepts rooted in the history of maritime navigation and the very notion of ship and sea, for example. How should we view the twenty-first century civilization through the laws of these new activities at sea?"

1 761 720 €

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

This research project will confort theory and data to deepen our understanding of the mechanisms and policies of innovation, and the relationship between innovation, growth and social mobility. The underlying framework is the Schumpeterian theory of economic growth, where: (i) growth is generated by innovative entrepreneurs; (ii) entrepreneurial investments respond to incentives that are themselves shaped by economic policies and institutions; (iii) new innovations involves creative destruction. This project will explore new extensions of the Schumpeterian growth paradigm together with new firm-level and individual datasets to analyze the following questions : (a) the measurement of productivity growth and the extent to which measured TFP growth factors is correctly accounting for new innovation; (b) the relashionship between innovation and trade and more specifically the causal links from export and import to innovation, and the main channels through wich export and import affect innovation; (c) the effect of fiscal and institutional changes on entrepreneurship: in particular, how recent changes in the French legislation on self-employement have affected individual incentives to become self-employed, and differently so for different social or regional groups of individuals; (d) the relationship between creative destruction, inequality, and wellbeing: in particular, how does creative destruction (mesured by job or firm turnover) impact on social mobility (e.g measured by the probability of making it to top income brackets conditional upon a low initial income or a low parental income) and health. This approach can shed new light on important aspects of the growth process such as: the middle income trap, secular stagnation, the recent rise in top income inequality, and firm dynamics. Moreover, the paradigm can be used to think (or rethink) about growth policy design.

1 968 588 €

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

Innate lymphoid cells (ILC) are a newly described family of hematopoietic cells that lack antigen-specific receptors but can be activated to promptly produce large amounts of cytokines (including interleukin (IL)-5, -13, -17A, -22, TNF-α and interferon-γ) and thereby contribute to the immediate, first-line immune defense against viral, bacterial, and parasitic infections. ILCs include the previously described natural killer (NK) cells and have a similar 'natural' effector function which is immediately available during immune responses and prior to that of adaptive immunity. Three groups of ILC (ILC1, ILC2, ILC3) have been described that share biological activities of T helper (Th)1, Th2 and Th17/22 subsets and CTL. ILCs are active during both fetal and adult life and play important roles in the homeostasis of mucosal and non-mucosal tissues. Nevertheless, how ILCs are integrated into ongoing immune responses remains unclear and this knowledge is a prerequisite for harnessing the clinical potential of these immune effector cells. This proposal will investigate critical checkpoints that can regulate ILC reactivity for immune responses in humans and mice. The four proposed objectives will be addressed using a combination of cutting-edge technologies including innovative mouse models that can report on ILC biology in vivo, single cell transcriptional and functional analysis of diverse circulating and tissue human and mouse ILC subsets, ‘digital’ pathogen-dependent ILC activation approaches and computational analysis of large immunological datasets from healthy, normal human individuals. Collectively, these complementary studies will shed new light on the biological determinants which condition ILC reactivity in humans and mice. Understanding how the threshold of ILC responsiveness is set prior to and during immune responses will have important implications for disease intervention.

1 899 375 €

Start date: 2016-08-01, End date: 2021-07-31

"The INCLUSIVE project aims at challenging our very perspective of property by adding an innovative notion, the ‘inclusive right’, in the toolbox of legal and economic theory. Whereas exclusivity is conventionally considered as the core element and purpose of property right, sharing and collectively using resources, either tangible or intellectual, is an increasing practice and a new field of research in the legal, sociological, cultural and economic academy. From public domain in copyright, the open access or copyleft licensing to the multiple and complex authorship resulting from online wiki creation and new forms of cohousing based on common spaces and property, all rely on the lack or limitation of exclusive rights and the accommodation of symmetric entitlements of other individuals. All share a sense of ‘inclusivity’ that can be defined by (1) the absence of a power to exclude others, which leads to inclusion of others in the use and (2) the collectiveness and interdependency of privileges to use a resource. Yet, no legal tool is available to comprehend such inclusivity, but the notion of ‘commons’ devoid of any normative content. The INCLUSIVE project will study allocation of resources grounded on inclusivity and the issues raised by such legal vacuum or inadequate application of exclusivity-based rules. INCLUSIVE will elaborate a legal model of ‘inclusive right’ allowing for organised collectiveness, enforceability and sustainability and assess its applicability in selected fields. Instead of forcing exclusive rights on situations organised around inclusivity, the project radically innovates by rethinking the categories of legal interests, with new conceptual and methodological frameworks and adapted normative criteria. This legal concept could have discrete applications and play a role in two major challenges of our times: the sustainability of natural or informational resources and the connected agency of individuals in the digital environment."

1 361 382 €

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

Inflammasomes are intracellular multi-protein complexes that play essential functions in immunity against microbial pathogens. Upon microbial sensing, inflammasomes induce protease caspase-1-dependent maturation and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as gasdermin-D-dependent cell necrosis, namely pyroptosis. While both pyroptosis and IL-1β/IL-18 release play key parts in controlling microbial infections, the host-regulated pathways that promote detection of microbial ligands by cytosolic inflammasome-forming sensors and the non-canonical functions of inflammasome-derived components, remain to be fully characterized. Building on my expertise in the field of inflammasome regulators during microbial infections, I propose to study several key, yet unexplored aspects of the functions of inflammasomes in immunity from different angles. In particular, I propose to 1/ identify and characterize new host interferon-inducible factors that mediate microbial sensing by the inflammasomes, and 2/ unravel new non-canonical functions of inflammasome-derived proteases and gasdermins. To address these issues, I will use a combination of state-of-the-art and innovative technologies in biochemistry, molecular and cell biology, and immunology in various in vitro and in vivo models. For example, I propose to develop an unbiased genome-wide search for novel effectors involved in inflammasome activation based on the unprecedented coupling of the CRISPR-Cas9 technology to automated visual high-throughput screening. This multidisciplinary proposal will provide breakthroughs in the field of microbial pathogens detection by the host immune system, and will nucleate entirely novel immune paradigms on microbial sensing by new unsuspected host cytosolic proteins, namely the gasdermins. The results of this project will also provide strong bases for building innovative host-directed therapies for auto-inflammatory disorders and infectious diseases.

1 498 799 €

Start date: 2018-12-01, End date: 2023-11-30

This proposal seeks to analyze the effects of incomplete dispersed information for macroeconomic dynamics, broadly defined. First, the proposal seeks to develop methods for the analysis of dynamic equilibrium models, in which different participants hold different views of the aggregate conditions. Theoretical and quantitative solution methods will be proposed that can be applied to almost arbitrary equilibrium models of financial markets or the macro-economy, integrating information with other sources of micro-level heterogeneity (such as income risk), and other sources of micro-level adjustment frictions. Second, the proposal will apply these methods to gain a better understanding of the channels through which information heterogeneity affects aggregate dynamics. The project will develop macroeconomic models with heterogeneity in beliefs, and different important macroeconomic adjustment channels (including pricing and investment decisions by firms, consumption-savings decisions of households, port-folio choice, idiosyncratic risk) to assess the effect of information heterogeneity from a theoretical as well as a quantitative angle. Third, our methods of analysis will be extended to study asset pricing dynamics with heterogeneous expectations. This part also aims to integrate asset pricing dynamics with corporate decision making, in order to gain a better understanding of the intraction between asset valuations (or mis-valuation) and real economic variables. Fourth, this project will use these methods and models to gain insight into normative questions such as the welfare implications of information disclosures, optimal design of managerial incentive structures, regulation of firm behavior and firm dynamics, or macroeconomic policy.

1 500 000 €

Start date: 2010-11-01, End date: 2015-10-31

Tuberculosis, caused by Mycobacterium tuberculosis is still a major threat to global health. Because the treatment of an infected individual requires more than six months of chemotherapy, compliance is low, which can result in the development of multidrug resistant (MDR-TB) strains. New drugs and new targets are needed to combat MDR-TB. A critical feature of the Mycobacterium tuberculosis bacillus is its ability to survive and even replicate within macrophages, making these host cells an ideal niche for persisting microbes. The goal of our project is to understand the biological mechanisms underlying the persistence of intracellular mycobacteria and to develop novel approaches to eradicate the bacillus from its hiding spot. To this end, we have been undertaking global approaches using visual phenotypic assays (relying on monitoring by automated confocal fluorescence microscopy) of the trafficking and replication of M. tuberculosis inside macrophages. Screening of a small interfering RNA library, a M. tuberculosis transposon mutant library and hundreds of thousands of small chemical molecules has led to the identification of key host and mycobacterial genes involved in the intracellular fate of M. tuberculosis, as well as chemicals able to prevent intracellular bacterial growth. Building on the considerable data generated and on the powerful high throughput / high content (HT/HC) confocal microscopy, our project is to further explore the signalling pathways used specifically by M. tuberculosis. We will focus on the in depth study of bacterial protein effectors belonging to the ESX and PPE families and of the SOCS family member CISH, which promotes intracellular mycobacterial survival. Finally, chemicals that target cellular partners of M. tuberculosis will constitute a new starting point for the development of drugs able to counteract this host response manipulation without directly targeting the pathogen, thereby overcoming the issue of the emergence of MDR-TB.

1 982 371 €

Start date: 2010-12-01, End date: 2015-11-30

Electrochemical Double-Layer Capacitors Electrochemical Capacitors (EDLC) are promising devices for clean energy storage applications. In EDLCs, the charges are stored electrostatically at the electrolyte / electrode interface, which confers them high power and cycling capabilities. Until recently, it was believed that charge storage in porous carbon EDLC electrodes could be achieved only if the pore size of the carbon was larger than the electrolyte ions with their solvation shells. Using Carbides Derived Carbons (CDCs) which have controlled pore sizes between 0.6 nm and 1.1 nm, we recently demonstrated that high capacitive performances could be obtained when the pore size is smaller than the solvated ion size. The origin of this capacitance increase is still unclear despite important modelling efforts achieved by many research groups. Using our fine-tuned, controlled pore size CDCs carbons with narrow pore size distribution, we propose here an integrated approach combining the use of experimental electrochemical methods (EQCM, EIS, CV…) and in-situ analytical techniques (NMR, XRD), to computational modelling (Molecular Dynamics, Monte Carlo and Reverse Monte Carlo methods) to elucidate the ion transport and adsorption mechanisms inside nanopores. A direct application of this fundamental approach concerns the energy storage with supercapacitors. Thanks to the unique features offered by the CDCs, we propose to develop the next generation of high-energy density micro-supercapacitors from bulk CDC films. The evidence of the increase of the capacitive ion adsorption associated with ion partial desolvation in micropores is also of great interest in different areas such as water desalination. CDCs, which have demonstrated volumetric capacitance improvement of 100% compared to activated carbon for supercapacitor application, are appealing materials for water desalination applications, which will be the last part of the project.

1 494 050 €

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

The immune system is composed of different cell types that work in a coordinated manner to maintain the integrity of the organism in situations of threats or danger. Dendritic cells (DC) act as sentinels in peripheral tissue and mucosal interfaces where they integrate a diversity of danger- and inflammation-associated stimuli, then migrate to secondary lymphoid organs, and instruct naïve CD4 T cells to differentiate into the appropriate effector T cells. Hence, they play a critical role in linking innate to adaptive immunity. Three important levels of complexity characterize the DC system: 1) DC integrate multiple stimuli within complex inflammatory microenvironments, 2) these signals induce a complex output response and modify the global state of DC (environmental plasticity), 3) DC exist in different subsets generated by distinct differentiation pathways (evolutionary selection). In this proposal, we use cellular and molecular immunology combined to computational biology and modeling to study these properties at the large-scale level, and understand their interdependence in controlling DC biology. We ask the following specific questions: WP1: How DC subsets integrate combinations of stimuli at the large-scale level; WP2: How single and multiple stimuli modify DC state over time (dynamic modeling); WP3: How the DC global state influences response to a given stimulus. These questions will be addressed using a data-driven strategy combining global unsupervised exploratory analysis, gene-by-gene analysis and modeling, experimental validation of testable hypothesis. Through this systems level integrative approach, we will dissect the complexity of DC reciprocal interactions with their complex microenvironment, and hope to unravel novel mechanisms and concepts determining DC function.

1 498 997 €

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

Complexes containing redox non-innocent ligands have been well developed in the last decade with transition metal ions and have led to very important chemical transformations at lowest environmental and economic costs. Nonetheless examples with f-element are very rare and the field is almost empty with lanthanides. This is unfortunate since divalent lanthanides are excellent sources of single electron and would provide a good control of the ligand reduction because of strong electron correlation in these systems. Thus, this proposal aims at developing this field with organolanthanides. The synthesis of original complexes containing lanthanides, redox non-innocent ligands and transitions metals is herein proposed: the first providing reversible electron(s) source(s) (remote control), the second acting as electron(s) reservoir and controlling the electron correlation strength (“dimmer switch”), and the last being the site of the selective catalytic reaction. Because of this regulated electron transfer, the oxidation state of the transition metal will be modified only at specific steps, allowing the establishment of a new paradigm is organometallic catalysis with group 9 and 10 transition metals. These original complexes will be synthetized and deeply characterized by specific spectroscopic and theoretical analyses. The principal goal is to synthetize active catalysts toward C-H bonds activation, and methane activation is regarded as an ultimate achievement as is hydroalkylation of olefins. To increase the chances of success, the proposal is based on preliminary results obtained recently in the group. Several examples of original heterobimetallic and heterotrimetallic complexes containing lanthanides and transition metals of group 10 will be discussed as a good starting point for the feasibility of this challenging project that aims at answering a large societal concern: the reduction of atmospheric pollutants, such as methane, and transformation in valuable products.

1 499 929 €

Start date: 2017-04-01, End date: 2022-03-31

A lattice is defined as the set of all integer combinations of $n$ linearly independent vectors in $\R^n$. These geometrical objects possess a rich combinatorial structure that has attracted the attention of great mathematicians over the last two centuries. Lattices have an impressive number of applications in mathematics and computer science, from number theory and Diophantine approximation to complexity theory and cryptography. Over the last two decades, the computational study of lattices has witnessed several remarkable discoveries. Most notable are the development of the LLL algorithm by Lenstra, Lenstra and Lovasz and Ajtai's discovery of lattice-based cryptographic constructions. I propose to pursue these research directions and attempt to discover new connections between lattices and computer science. A particular focus will be put on applications in cryptography, as these can lead to many advances in the field and are also of great practical importance. I believe that the extraordinary properties of lattices have the potential to revolutionize many other areas of computer science such as complexity, cryptography, machine learning theory, quantum computation, and more. My scientific goals include obtaining stronger and more practical lattice-based cryptographic constructions, resolving important questions regarding the complexity of lattice problems, finding sub-exponential time algorithms for lattice problems and exploring some novel applications of lattices to areas such as Markov chains and machine learning theory.

822 000 €

Start date: 2008-07-01, End date: 2012-08-31

This “Life-Cycle” ERC proposal aims to develop a new class of artificial supramolecular materials that are kept in sustained non-equilibrium states by continuous dissipation of chemical fuels. Supramolecular polymers in current artificial materials stick together through weak reversible bonds that can be exchange by thermal energy. In contrast, natural supramolecular polymers such as those in the cytoskeletal network use chemical fuels such as adenosine triphosphate (ATP) to achieve an incredible adaptivity, motility, growth, and response to external inputs. Development of chemically fueled artificial supramolecular polymers should therefore lead to more life-like materials that could perform functions so far reserved only for living beings. The proposed materials are based on supramolecular reaction cycles that have both positive and negative feedback in order to achieve emergent properties, such as oscillations and waves. Two different approaches are used: i) supramolecular polymers that are fueled by redox reactions, and ii) enzyme-switchable supramolecular polymers that consume one of the natural fuels, namely ATP. The proposed polymers self-assemble cooperatively, which is used as a positive feedback mechanism. Using other co-assembling species we can engineer negative feedback in our reaction cycles to obtain unique supramolecular dynamics. Since the building blocks react, but also self-assemble they have built-in chemomechanical properties, much like in living materials such as the cytoskeleton. First we study the temporal behavior (part A) of our reaction cycles in well-stirred environments. Next, we move to non-stirred conditions (part B), where spatiotemporal behavior can be studied. And lastly, we develop free-standing non-equilibrium interactive materials based on our reaction cycles (part C). Overall, our approach opens a new way to obtain more life-like artificial materials that can eventually perform complex (biological) functions.

1 762 488 €

Start date: 2018-01-01, End date: 2022-12-31

The analogy-based expectation equilibrium (Jehiel, 2005) has been introduced to cope with strategic environments in which agents form their expectations by bundling data that come from different sources (see also the valuation equilibrium defined in Jehiel and Samet, 2007). An essential next step is to make progress on when and how subjects bundle data to facilitate learning. Various principles are proposed to discipline the choices of analogy partitions in ABEE and of similarity classes in VE: the observation-based principle views the bundling as a consequence of a lack of accessibility to missing information in past interactions, the psychologically-based principle views categorizations as the consequence of observed similarity in early interactions, the culturally-based principle views the bundling of actions into similarity classes either as a consequence of a common labelling of actions or as a consequence of ethical considerations that lead us to think of different actions as having similar consequences. The impact of such principles will be studied both theoretically and experimentally with the goals of explaining a number of new phenomena and shifting the conventional wisdom in behavioural economics that has pointed out a number of anomalies in behaviors without systematically relating them to imperfections in the learning process. In addition, I will be concerned with the aggregation of different types of feedback such as data on one own performance or data on others’ attitudes in multi-context environments, as well as putting the proposed approach of learning through categories in the broader perspective of the literature on bounded rationality

1 523 217 €

Start date: 2018-01-01, End date: 2022-12-31

MaGIC intends to explore the use of nano/micro objects, in particular zeolite L, as materials for imaging, and, when the zeolites are used as substrates, for analyzing and manipulating cells. In particular in vivo and in vitro imaging, cell growth on nano/micro patterned zeolite monolayers, and understanding some of the processes of cell-to-cell communication are the ambitious goals of this proposal. We intend to achieve these goals through 5 objectives: 1. Synthesis and characterization of zeolites and loading and trapping of dye molecules. 2. Patterned zeolite monolayers and microcontact printing for asymmetric functionalization and cells transfer. 3. Molecular imaging using nanoporous materials as multiresponsive probes. 4. Cell growth, proliferation and stimulation of processes in spatially confined areas. 5. Communication between cells and cell differentiation. The project is extremely challenging and if successful will open new horizons in the use of nanomaterials in combination with living systems and will develop new technologies for handling delicate substrates and assemblies. The numerous ideas and problems that MaGIC addresses are of fundamental importance and collectively represent an interesting approach to simply mimicking nature, connecting biological components to abiotic materials in order to understand the mechanisms of the biological systems or to take advantage of the unique properties of the ‘non-biological’ components in a natural setting (in vivo and in vitro). The stepwise approach, starting from the use of the nanomaterials for observing the surrounding environment (cell imaging), and proceeding to their assembly in functional architectures, culminates in the realization of special interfaces with the ambition to realize and study cell-to-cell communication.

1 800 270 €

Start date: 2010-07-01, End date: 2015-06-30

The MECHANO-FLUO project aims at preparing mechanofluorochromic molecules and materials, understand and tune their photophysical and mechanofluorochromic properties, and implement these new materials as quantitative mechanical force sensors. Mechanofluorochromism relates to fluorescent compounds in the solid state for which emission spectrum changes upon application of a mechanical stimulus. The interest for this phenomenon has enormously increased for the last 4 years but studies aiming at understanding the structure-mechanofluorochromic properties relationships are still in their infancy and many examples remain purely qualitative. In the MECHANO-FLUO project, I will synthesize a library of mechanofluorochromic molecules responsive to different mechanical stimuli (pressure, shearing), with various sensitivities. I aim at relating the molecular structure to the sensitivity to different mechanical stimuli. Two aspects seldom explored in the literature so far will be particularly studied. The first one is the study at the micro- to nanoscale, so as to obtain an amplification of the mechanofluorochromic response and develop ultra-sensitive mechanofluorochromic probes. The second one is the quantification of the mechanofluorochromic response, from the nano- to the macroscopic scales. Two applications will be investigated. The first one is stress metrology: fluorescent materials with a quantitative mechanofluorochromic response could give access to the stress level in various materials and thus constitute an entirely new method for in situ control of the damaging of materials classically used in the nuclear industry or the aeronautics. The second one is mechanobiology: I hope to provide a tool for direct force measurement at the cellular scale, which would have tremendous implications for the comprehension of biological phenomena where mechanotransduction is implied, especially embryogenesis and tumor proliferation.

1 499 172 €

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

A fundamental difference between man-made and living matter is metabolism: the ability to dissipate chemical energy to drive many different chemical processes out of equilibrium. Metabolism endows chemical systems within living organisms with properties that are standard in biology but odd in chemistry: the capability to process information, to move and to react to the external world. My goal is to endow soft materials with dynamic life-like properties. I have chosen four: molecular computation, movement, self-construction and the capacity to entertain complex chemical conversations with living cells. To do so I will embed stimuli-responsive materials with a biocompatible synthetic metabolism capable of sustaining autonomous chemical feedback loops that process information and perform autonomous macroscopic actions. My approach combines concepts from systems chemistry, synthetic biology and DNA molecular programming with soft materials and uses a biochemical system that I have contributed to pioneer: DNA/enzyme active solutions that remain out of equilibrium by consuming a chemical fuel with non-trivial reaction kinetics. This system has three unique properties: programmability, biocompatibility and a long-term metabolic autonomy. Metabolic matter will be assembled in two stages: i) enabling metabolic materials with dynamic chemical, biological and mechanical responses, and ii) creating metabolic materials with unprecedented properties, in particular, the capacity of self-construction, which I will seek by emulating embryogenesis, and the ability to autonomously pattern a community of living cells. By doing this I will create for the first time chemical matter that is both dynamically and structurally complex, thus bringing into the realm of synthetic chemistry behaviors that so far only existed in biological systems. In the long term, metabolic matter could provide revolutionary solutions for soft robotics and tissue engineering.

1 899 333 €

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

Age-related macular degeneration (AMD) is the leading cause of vision loss in the Europe. New anti-angiogenic therapies of AMD do not treat the neurodegenerative aspect of AMD. Recent evidence suggests an implication of inflammatory mediators in AMD. We have focused our interest on the potential role of chemokines (Ch) and microglial cells (MC) in this condition. Our data concerning the chemokine receptor (CR) CX3CR1, indicates that (i) CR are expressed on MCs in human and mice; (ii) CR-positive MC accumulate in affected areas of the macula in human AMD, (iii) CX3CR1 deficient mice develop age dependent subretinal MC accumulation, Drusen formation, retinal degeneration and exacerbated neovascularization, similarly to AMD. Our data suggests an important role of subretinal MC accumulation in the development of AMD. We hypothesize that (1) function altering polymorphisms in genes of Ch pathways are associated with AMD, that (2) this pathway dysfunction leads to MC accumulate in the subretinal space with age and (3) the consequential prolonged MC presence in the subretinal space leads to cardinal features of AMD (Drusen, retinal degeneration, neovascularization). Therefore we believe that decreasing subretinal MCs or interfering with their neurotoxic and angiogenic factors will inhibit AMD development. Our specific aim is to study (1) polymorphisms of Ch pathways in AMD and controls, (2) determine the Ch pathways involved in the recruitment and accumulation of MCs to the subretinal space, (3) determine the implication of MC in Drusen formation, retinal degeneration and neovascularization and characterize the implicated molecular mediators and (4) test the identified mediators of microglial cell neurotoxicity and angiogenicity as drug targets in AMD models. The aim of this work, from clinical polymorphism studies to transgenic mouse models, is to propose new mechanisms in the pathogenesis of AMD and to develop novel therapeutic strategies for the treatment of AMD.

1 560 000 €

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

Host-pathogen interactions have recently received much attention. Yet, a more comprehensive understanding of these interplays should provide fundamental advances in biology and help generating new therapeutics. The intracellular bacterium Listeria monocytogenes has emerged as an exceptional model organism to address key questions in biology such as actin-based motility, phagocytosis and post-transcriptional regulation. We will exploit our deep knowledge of Listeria and use this bacterium as a model to explore new landmarks in biology. In that aim, we will analyze several aspects of the infectious process, in a spatio-temporal fashion, at the bacteria, cell, tissue and host levels. Specifically, we will 1) search and analyze the function of new non-coding RNAs involved in virulence, and of new RNA-mediated regulations; 2) investigate new facets of bacterial entry and cell-to-cell spread in particular the role of uncharacterized cytoskeletal components, septins; 3) address the role of mitochondria and their dynamics in infection; 4) systematically analyze post-translational modifications during infection, starting with SUMOylation, a reversible modification and proteolysis, an irreversible one; 5) investigate chromatin remodeling upon infection; 6) characterize new virulence factors identified by their interaction with known signaling components or cellular sensors, by post genomics or by their effect on cellular responses analyzed herein ; 7) investigate further the intestinal phase of Listeria infection by analyzing in the germ-free transgenic mouse that we generated, the impact of commensals on Listeria (growth and transcription including non-coding RNAs) and on the intestinal tissue (histology and transcription of genes and microRNAs). Our main goal is to improve significantly our understanding of bacterial infections, by discovering important new concepts in microbiology, cell biology and infection biology thereby opening new avenues for further research.

1 800 000 €

Start date: 2009-06-01, End date: 2015-05-31

MONACAT proposes a novel approach to address the challenge of intermittent energy storage. Specifically, the purpose is to conceive and synthesize novel complex nano-objects displaying both physical and chemical properties that enable catalytic transformations with a fast and optimum energy conversion. It follows over 20 years of research on “organometallic nanoparticles”, an approach of nanoparticles (NPs) synthesis where the first goal is to control the surface of the particles as in molecular organometallic species. Two families of NPs will be studied: 1) magnetic NPs that can be heated by excitation with an alternating magnetic field and 2) plasmonic NPs that absorb visible light and transform it into heat. In all cases, deposition of additional materials as islands or thin layers will improve the NPs catalytic activity. Iron carbides NPs have recently been shown to heat efficiently upon magnetic excitation and to catalyse CO hydrogenation into hydrocarbons. In order to transform this observation into a viable process, MONACAT will address the following challenges: determination and control of surface temperature using fluorophores or quantum dots, optimization of heating capacity (size, anisotropy of the material, crystallinity, phases: FeCo, FeNi, chemical order), optimization of catalytic properties (islands vs core-shell structures; Ru, Ni for methane, Cu/Zn for methanol), stability and optimization of energy efficiency. A similar approach will be used for direct light conversion using as first proofs of concept Au or Ag NPs coated with Ru. Catalytic tests will be performed on two heterogeneous reactions after deposition of the NPs onto a support: CO2 hydrogenation into methane and methanol synthesis. In addition, the potential of catalysis making use of self-heated and magnetically recoverable NPs will be studied in solution (reduction of arenes or oxygenated functions, hydrogenation and hydrogenolysis of biomass platform molecules, Fischer-Tropsch).

2 472 223 €

Start date: 2016-06-01, End date: 2021-05-31

The goal of the MULTIPROSMM project is to design systems able to present magnetic bistabilities under different stimuli (temperature, magnetic field or light) on an unprecedented large temperature range, i.e. very low temperature with Single Molecule Magnet (SMM) behaviour, intermediate temperature with Light Induced Excited State Trapping (LIESST) and high temperature with SpinCrossOver (SCO). On one hand, as a photography of the energy-splitting of the spectroscopic states, the lanthanide luminescence will be used as a key tool for the understanding of the magnetic properties of lanthanide ions. On the other hand, Circularly Polarized Luminescence (CPL) combines the sensitivity of the luminescence with crucial information on the chiral environment. A step by step synthetic strategy will be used to elaborate molecular systems in which the coexistence of i) SMM and SCO; ii) SMM and CPL and iii) SMM, SCO and CPL are operating. The enhancement of the magnetic properties is needed to step forward towards applications. To reach such optimizations, the quantum regime of the SMM and the internal magnetic field must be vanished playing with the hyperfine coupling and magnetic dilutions. Both isotopic enrichment and shaping (i.e. decoration of both mesoporous silica and nanoparticle surfaces) of the designed systems could allow high magnetic performance in multiple properties SMM. The final result could be a system suitable for very high density data storage on a wide temperature range (from cryogenic to room temperature).

1 505 000 €

Start date: 2017-08-01, End date: 2022-07-31

Anaphylaxis is a hyperacute allergic reaction of increasing incidence that can be of fatal consequence and that has no specific treatment. Anaphylaxis is thought to rely on mechanisms involving mast cells that bear allergen-specific IgE and that release histamine when encountering allergen. Clinical cases, however, report anaphylaxis in the absence of specific IgE or medical history of allergy. We reported that murine models of anaphylaxis rely on IgG, rather than on IgE, that enable neutrophils, monocytes and basophils, rather than mast cells, to release Platelet Activating Factor following engagement of their IgG receptors. Supporting these findings, allergen-specific IgG are found in anaphylactic patients, and we reported that anaphylaxis in mice expressing a human IgG receptor relies also on circulating myeloid cells. We aim at unravelling the parameters that control anaphylaxis in a novel clinically-relevant model of drug-induced anaphylaxis, strengthened by human-based studies involved patients undergoing drug-induced anaphylaxis in collaboration with clinicians and, altogether, rethink the principles of anaphylaxis. Do allergen-specific IgG concur to anaphylaxis in humans? Do these IgG antibodies regulate IgE-induced reactions? Which IgG receptors are involved? In which tissue does the anaphylactic reaction start? Which cell type(s) are responsible? Among the mediators that are released, which ones are responsible for the shock? Can an anaphylactic reaction be stopped specifically for an allergen? We propose to address these questions by exploiting humanized mice we obtained and by establishing novel models, by visualizing anaphylactic reactions in real time in vivo, by dissecting the cascade of events leading to the shock. Finally, we aim at establishing the proof of concept of allergen capture/encapsulation and propose the first allergen-specific strategy for treating the life-threatening clinical situation that represents drug-induced anaphylaxis.

1 999 704 €

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

Associating bulky and strong Lewis acid and base creates a Frustrated Lewis Pair (FLP). Traditionally, both FLP partners are molecules. Molecular FLPs have shown excellent abilities to catch and dissociate small molecules such as H2 in a heterolytic way, under mild conditions. The driving force is the destabilization of the initial acid-base adduct, sterically frustrated: it liberates a reactive pocket that catches the small molecule guest, and strongly lowers the activation energy for bond dissociation. The pristine and challenging concept of NanoFLP consists in replacing one of the molecular FLP partner, either the acid or the base, by an inorganic nanoparticle: the other molecular partner will adsorb on the surface and boosts the reactivity of the nanoparticle by creating a frustrated active site. I will demonstrate the versatility of NanoFLPs with three families of inorganic nanoparticles (metals, acidic oxides, basic oxides), illustrating the two schemes: nanoparticle is either the Lewis acid or the Lewis base. I will use probe molecules (CO2, H2, SO2 and N2O) to investigate the nature and reactivity of the active sites. All reactions should be achieved under much milder conditions (rt.-150 °C, 1-3 bars) than those required using similar nanoparticles in the absence of the molecular partner. I will fully describe the nanoparticle surface and the dynamics of the molecular partner using benchtop and synchrotron spectroscopies with in situ cells: infrared, nuclear magnetic resonance in solution, X-ray absorption and near-ambient-pressure X-ray photoelectron spectroscopy. In the last stage of the project, I will take advantage of the several active sites that one nanoparticle can bear to achieve combined reactions of two small molecules (reactants) on a single NanoFLP. NanoFLP proposes a new type of active site for utilizing small molecules as sources of C, N, S and O. It will open an avenue in the design of reactive interfaces, eg. for catalysis and sensors.

1 499 875 €

Start date: 2018-01-01, End date: 2022-12-31

Economists are becoming increasingly aware of the importance and ubiquity of social networks. The economics of social networks constitutes one of the most active areas of research in economics. Despite much progress, however, our understanding of the relationships between markets and networks is still poor and fragmentary. This project will advance the state of the art by analyzing the relations between markets and networks in two domains. I will first study theoretically the interaction between formal insurance and networks of informal insurance. I will analyze how the position in a risk-sharing network affects the incentives to adopt formal insurance, how network structure affects overall adoption, how formal insurance could benefit from network monitoring on efforts and whether the adoption of formal insurance strengthen or weaken the risk-sharing network. Second, I will study theoretically the impact of networks on markets with search frictions. I will derive the full-fledged equilibrium implications of network-based search in matching models of the labor market. I will also introduce recall in a finite-horizon matching model and study the impact of the emerging network of trading partners.

481 087 €

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

"This project principally concerns the use of silicon (the second most abundant element in the Earth’s crust) as catalyst instead of transition metals. Although the importance of its abundance is well recognized in material chemistry, as it can be seen by the vast world production of silicon based materials (polymers, rubber, semiconductors), real success in chemistry with such a vision has never been achieved. This is probably due to the lack of appropriate stable silicon species with particular and highly modulable electronic properties which can be applied for various catalytic systems. We propose, in this project, the development of new silicon species with a transition metal like behavior. The success of this project should open a new wide research domain in chemistry and could change the vision of catalysis."

1 433 725 €

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

A debate in the development of legal institutions is whether individuals obey the law because the law incentivizes or because the law has legitimacy. Much of the PI’s research in law and in development seeks to understand how people form normative commitments, i.e., what people view as the moral and right thing to do, and how they respond to these normative commitments. His work traces the incentives that lead to human rights violations. The PI has examined how interpretations of religious and legal texts, particularly those associated with fundamentalism, interact with market forces. In two multi-part studies, the PI investigated the economic forces underlying the religious provision of social insurance, social sanctions, social conservatism, and the economic incentives that give rise to gender violence, sexual harassment, and regulation of the private domain. Through these investigations, the PI formulated a theory for why church-state separation arose in some countries but not in others, developed a methodology for empirically evaluating the effects of normative commitments, and used a particular instance of interpretive injustice where capital cases in the British Army during World War I were randomly executed or commuted, in order to estimate the deterrent and delegitimizing effects of the death penalty. The proposed project builds on this previous work. The proposal rests on 2 pillars: Normative Commitments in Health Care and Normative Commitments in Courts. Within these 2 pillars, the PI studies the effects of market forces on normative commitments and examines how normative commitments come into existence in the first place. (1) Normative Commitments in Health Care: The PI will measure the influence of pharmaceutical company payments to physicians on their normative commitments. This pillar will evaluate the effects of payments on physician prescriptions and patient outcomes. The pillar will examine whether disclosure laws affect the relationship between payments, prescriptions, and patient outcomes. The pillar will employ a unique U.S. dataset on over 2 billion prescription claims per year on up to 177 million individuals and a Danish database of all prescription drugs sold linked to prescribers with pharmaceutical associations. (2) Normative Commitments in Courts: This pillar will use the random assignment of judges in common law courts to measure the impact of exogenous changes in legal precedent. The pillar will apply a method co-developed by the PI for two-stage least squares estimation (Econometrica (80(6), 2369-2429, 2012) that exploits judicial characteristics as instrumental variables. The pillar will study the effects of 24 legal areas, including capital punishment, free speech, gay rights, gender discrimination, sexual harassment, and rights of the disabled. The pillar will use this data to study the origin of rights.

1 591 939 €

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

Nuclear weapons choices commit populations and societies for decades and can wipe them out in matters of minutes. How is the scope of available nuclear weapons choices decided? Direct experience cannot be the answer as no one can rely on personal experience of nuclear war. Most decision-makers no longer even have the experience of the effects of such weapons either given that North Korea has been the only country testing nuclear weapons since 1998. The populations’ wishes do not qualify either, since they are very rarely consulted and only few studies on those attitudes exist. Therefore this project offers the first in depth global investigation of the grounds on which the scope of publicly acceptable nuclear weapons choices have been based since the end of nuclear testing. To do so, this project constructs an interdisciplinary research program about responsibility in an age of nuclear vulnerabilities. It investigates four ways in which nuclear weapons choices are bounded: 1) the intellectual categories we depend on to think about those issues; 2) the governance of nuclear knowledge by nuclear-weapons related institutions; 3) specific readings of the past identifying events or trends from which lessons are expected to be learned about the scope of the possible, and 4) the imaginary of possible futures as opposed to the ones deemed utopian. Combining archival research and interviews worldwide, with large-scale polling and discourse analysis of policy officials and strategists over several decades, it assesses the blinding power of categories created several decades ago and sometimes still deemed as irreplaceable lexicon of the nuclear age as well as the way in which nuclear weapons programs modify the governance of knowledge. Based on those findings, it offers a renewed notion of responsibility in the nuclear age built on full awareness of nuclear vulnerabilities in their epistemic and political dimensions, and not only the material ones.

1 480 145 €

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