ERC FUNDED PROJECTS

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

1 999 750 €

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

This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology. In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome. Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes. Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.

1 499 750 €

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

This long-term research project is based on the data-mining of the Llibres d'Esposalles conserved at the Archives of the Barcelona Cathedral, an extraordinary data source comprising 244 books of marriage licenses records. It covers about 550.000 unions from over 250 parishes of the Diocese between 1451 and 1905. Its impeccable conservation is a miracle in a region where parish archives have undergone massive destruction. The books include data on the tax posed on each couple depending on their social class, on an eight-tiered scale. These data allow for research on multiple aspects of demographic research, especially on the very long run, such as: population estimates, marriage dynamics, cycles, and indirect estimations for fertility, migration and survival, as well as socio-economic studies related to social homogamy, social mobility, and transmission of social and occupational position. Being continuous over five centuries, the source constitutes a unique instrument to study the dynamics of population distribution, the expansion of the city of Barcelona and the constitution of its metropolitan area, as well as the chronology and the geography in the constitution of new social classes. To this end, a digital library and a database, the Barcelona Historical Marriages Database (BHiMaD), are to be created and completed. An ERC-AG will help doing so while undertaking the research analysis of the database in parallel. The research team, at the U. Autònoma de Barcelona, involves researchers from the Center for Demo-graphic Studies and the Computer Vision Center experts in historical databases and computer-aided recognition of ancient manuscripts. 5CofM will serve the preservation of the original “Llibres d’Esposalles” and unlock the full potential embedded in the collection.

1 847 400 €

Start date: 2011-05-01, End date: 2016-04-30

The primary purpose of this project is to build on recent spectacular progress in the Langlands program to study the arithmetic properties of automorphic motives constructed in the cohomology of Shimura varieties. Because automorphic methods are available to study the L-functions of these motives, which include elliptic curves and certain families of Calabi-Yau varieties over totally real fields (possibly after base change), they represent the most accessible class of varieties for which one can hope to verify fundamental conjectures on special values of L-functions, including Deligne's conjecture and the Main Conjecture of Iwasawa theory. Immediate goals include the proof of irreducibility of automorphic Galois representations; the establishment of period relations for automorphic and potentially automorphic realizations of motives in the cohomology of distinct Shimura varieties; the construction of p-adic L-functions for these and related motives, notably adjoint and tensor product L-functions in p-adic families; and the geometrization of the p-adic and mod p Langlands program. All four goals, as well as the others mentioned in the body of the proposal, are interconnected; the final goal provides a bridge to related work in geometric representation theory, algebraic geometry, and mathematical physics.

1 491 348 €

Start date: 2012-06-01, End date: 2018-05-31

The main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.

1 000 000 €

Start date: 2008-11-01, End date: 2014-10-31

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

3 199 078 €

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

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

1 989 518 €

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

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

2 491 157 €

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

This project focuses on one of the most fascinating events of the long history of the human species: the origins and spread of agriculture. Research over the past 40 years has provided an invaluable dataset on crop domestication and the spread of agriculture into Europe. However, despite the enormous advances in research there are important areas that remain almost unexplored, some of immense interest. This is the case of the western Mediterranean region from where our knowledge is still limited (Iberian Peninsula) or almost inexistent (northern Morocco). The last few years have witnessed a considerable increase in archaeobotany and the effort of a group of Spanish researchers working together in different aspects of agriculture has started to produce the first results. My proposal will approach the study of the arrival of agriculture to the western Mediterranean by exploring different interrelated research areas. The project involves the application of different techniques (analysis of charred plant remains, pollen and non-pollen microfossils, phytoliths, micro-wear analyses, isotopes, soil micromorphology, genetics, and ethnoarchaeology) which will help to define the emergence and spread of agriculture in the area, its likely place of origin, its main technological attributes as well as the range crop husbandry practices carried out. The interaction between the different approaches and the methodologies involved will allow achieving a greater understanding of the type of agriculture that characterized the first farming communities in the most south-western part of Europe.

1 545 169 €

Start date: 2009-04-01, End date: 2013-03-31

Air pollution is the main urban-related environmental hazard. It appears to affect brain development, although current evidence is inadequate given the lack of studies during the most vulnerable stages of brain development and the lack of brain anatomical structure and regional connectivity data underlying these effects. Of particular interest is the prenatal period, when brain structures are forming and growing, and when the effect of in utero exposure to environmental factors may cause permanent brain injury. I and others have conducted studies focused on effects during school age which could be less profound. I postulate that: pre-natal exposure to urban air pollution during pregnancy impairs foetal and postnatal brain development, mainly by affecting myelination; these effects are at least partially mediated by translocation of airborne particulate matter to the placenta and by placental dysfunction; and prenatal exposure to air pollution impairs post-natal brain development independently of urban context and post-natal exposure to air pollution. I aim to evaluate the effect of pre-natal exposure to urban air pollution on pre- and post-natal brain structure and function by following 900 pregnant women and their neonates with contrasting levels of pre-natal exposure to air pollutants by: i) establishing a new pregnancy cohort and evaluating brain imaging (pre-natal and neo-natal brain structure, connectivity and function), and post-natal motor and cognitive development; ii) measuring total personal exposure and inhaled dose of air pollutants during specific time-windows of gestation, noise, paternal stress and other stressors, using personal samplers and sensors; iii) detecting nanoparticles in placenta and its vascular function; iv) modelling mathematical causality and mediation, including a replication study in an external cohort. The expected results will create an impulse to implement policy interventions that genuinely protect the health of urban citizens.

2 499 992 €

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

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

1 222 329 €

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

Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders

2 000 000 €

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

DNA repair pathways evolved as an intricate network that senses DNA damage and resolves it in order to minimise genetic lesions and thus preventing tumour formation. Gaining in recognition the last few years, the alternative end-joining (alt-EJ) DNA repair pathway was recently shown to be up-regulated and required for cancer cell viability in the absence of homologous recombination-mediated repair (HR). Despite this integral role, the alt-EJ repair pathway remains poorly characterised in humans. As such, its molecular composition, regulation and crosstalk with HR and other repair pathways remain elusive. Additionally, the contribution of the alt-EJ pathway to tumour progression as well as the identification of a mutational signature associated with the use of alt-EJ has not yet been investigated. Moreover, the clinical relevance of developing small-molecule inhibitors targeting players in the alt-EJ pathway, such as the polymerase Pol Theta (Polθ), is of importance as current anticancer drug treatments have shown limited effectiveness in achieving cancer remission in patients with HR-deficient (HRD) tumours. Here, we propose a novel, multidisciplinary approach that aims to characterise the players and mechanisms of action involved in the utilisation of alt-EJ in cancer. This understanding will better elucidate the changing interplay between different DNA repair pathways, thus shedding light on whether and how the use of alt-EJ contributes to the pathogenic history and survival of HRD tumours, eventually paving the way for the development of novel anticancer therapeutics. For all the abovementioned reasons, we are convinced this project will have important implications in: 1) elucidating critical interconnections between DNA repair pathways, 2) improving the basic understanding of the composition, regulation and function of the alt-EJ pathway, and 3) facilitating the development of new synthetic lethality-based chemotherapeutics for the treatment of HRD tumours.

1 498 750 €

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

We are concerned with localization properties of solutions to hyperbolic PDEs, especially problems with a geometric component: how do boundaries and heterogeneous media influence spreading and concentration of solutions. While our first focus is on wave and Schrödinger equations on manifolds with boundary, strong connections exist with phase space localization for (clusters of) eigenfunctions, which are of independent interest. Motivations come from nonlinear dispersive models (in physically relevant settings), properties of eigenfunctions in quantum chaos (related to both physics of optic fiber design as well as number theoretic questions), or harmonic analysis on manifolds. Waves propagation in real life physics occur in media which are neither homogeneous or spatially infinity. The birth of radar/sonar technologies (and the raise of computed tomography) greatly motivated numerous developments in microlocal analysis and the linear theory. Only recently toy nonlinear models have been studied on a curved background, sometimes compact or rough. Understanding how to extend such tools, dealing with wave dispersion or focusing, will allow us to significantly progress in our mathematical understanding of physically relevant models. There, boundaries appear naturally and most earlier developments related to propagation of singularities in this context have limited scope with respect to crucial dispersive effects. Despite great progress over the last decade, driven by the study of quasilinear equations, our knowledge is still very limited. Going beyond this recent activity requires new tools whose development is at the heart of this proposal, including good approximate solutions (parametrices) going over arbitrarily large numbers of caustics, sharp pointwise bounds on Green functions, development of efficient wave packets methods, quantitative refinements of propagation of singularities (with direct applications in control theory), only to name a few important ones.

1 293 763 €

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

"We propose to study different questions in the area of the so called geometric analysis. Most of the topics we are interested in deal with the connection between the behavior of singular integrals and the geometry of sets and measures. The study of this connection has been shown to be extremely helpful in the solution of certain long standing problems in the last years, such as the solution of the Painlev\'e problem or the obtaining of the optimal distortion bounds for quasiconformal mappings by Astala. More specifically, we would like to study the relationship between the L^2 boundedness of singular integrals associated with Riesz and other related kernels, and rectifiability and other geometric notions. The so called David-Semmes problem is probably the main open problem in this area. Up to now, the techniques used to deal with this problem come from multiscale analysis and involve ideas from Littlewood-Paley theory and quantitative techniques of rectifiability. We propose to apply new ideas that combine variational arguments with other techniques which have connections with mass transportation. Further, we think that it is worth to explore in more detail the connection among mass transportation, singular integrals, and uniform rectifiability. We are also interested in the field of quasiconformal mappings. We plan to study a problem regarding the quasiconformal distortion of quasicircles. This problem consists in proving that the bounds obtained recently by S. Smirnov on the dimension of K-quasicircles are optimal. We want to apply techniques from quantitative geometric measure theory to deal with this question. Another question that we intend to explore lies in the interplay of harmonic analysis, geometric measure theory and partial differential equations. This concerns an old problem on the unique continuation of harmonic functions at the boundary open C^1 or Lipschitz domain. All the results known by now deal with smoother Dini domains."

1 105 930 €

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

Blood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance.

1 481 375 €

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

Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics. A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.

1 438 745 €

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

RNA interference (RNAi) is a conserved sequence-specific, gene-silencing mechanism that is induced by double-stranded RNA (dsRNA). One of the functions of this pathway is the defense against parasitic nucleic acids: transposons and viruses. Previous results demonstrated that viral infections in Drosophila melanogaster are fought by an antiviral RNAi response and that components of the endocytic pathway are required for dsRNA entry to initiate the RNAi response. Recently we have shown that infected insect cells spread a systemic silencing signal that elicits a protective RNAi-dependent immunity throughout the organism. This suggests that the cell-autonomous RNAi response is insufficient to control a viral infection and that flies also rely on systemic immune response to fight against such infections. As a junior group leader, I will study the mechanisms that mediate the RNAi-based antiviral response in insects. By combining biochemical, cellular, molecular and genomic approaches, both in vivo and in cell culture, I will analyze the mechanisms underlying viral tropism, systemic propagation of the antiviral signal and the basis of the persistence of the antiviral state. Furthermore, I will examine whether the dsRNA-uptake pathway is conserved in mosquitoes and its relationship with viral immunity in that host. This comprehensive approach will tackle how this nucleic acid-based immunity works in insects to generate an anti-viral stage. A better understanding of the role of RNA silencing in insects during virus infection will allow the exploitation of this pathway for improvement of public health related problems such as arbovirus infection and disease.

1 900 000 €

Start date: 2009-10-01, End date: 2014-12-31

"A conventional assumption in dynamic models is that agents form their expectations in a very sophisticated manner. In particular, that they have Rational Expectations (RE). We develop some tools to relax this assumption while retaining fully optimal behaviour by agents. We study implications for asset pricing and macro policy. We assume that agents have a consistent set of beliefs that is close, but not equal, to RE. Agents are ""Internally Rational"", that is, they behave rationally given their system of beliefs. Thus, it is conceptually a small deviation from RE. It provides microfoundations for models of adaptive learning, since the learning algorithm is determined by agents’ optimal behaviour. In previous work we have shown that this framework can match stock price and housing price fluctuations, and that policy implications are quite different. In this project we intend to: i) develop further the foundations of internally rational (IR) learning, ii) apply this to explain observed asset price price behavior, such as stock prices, bond prices, inflation, commodity derivatives, and exchange rates, iii) extend the IR framework to the case when agents entertain various models, iv) optimal policy under IR learning and under private information when some hidden shocks are not revealed ex-post. Along the way we will address policy issues such as: effects of creating derivative markets, sovereign spread as a signal of sovereign default risk, tests of fiscal sustainability, fiscal policy when agents learn, monetary policy (more specifically, QE measures and interest rate policy), and the role of credibility in macro policy."

1 970 260 €

Start date: 2013-06-01, End date: 2018-08-31

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

1 797 840 €

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

Cellular organelles are continuously remodelled by numerous cytosolic proteins that associate transiently with their lipid membrane. Some distort the bilayer, others change its composition, extract lipids or bridge membranes at distance. Previous works from my laboratory have underlined the importance of membrane sensors, i.e. elements within proteins that help to organize membrane-remodelling events by sensing the physical and chemical state of the underlying membrane. A membrane sensor is not necessarily of well-folded domain that interacts with a specific lipid polar head: some intrinsically unfolded motifs harboring deceptively simple sequences can display remarkable membrane adhesive properties. Among these are some amphipathic helices: the ALPS motif with a polar face made mostly by small uncharged polar residues, the Spo20 helix with several histidines in its polar face and, like a mirror image of the ALPS motif, the alpha-synuclein helix with very small hydrophobic residues. Using biochemistry and molecular dynamics, we will compare the membrane binding properties of these sequences (effect of curvature, charge, lipid unsaturation); using bioinformatics we will look for new motifs, using cell biology we will assess the adaptation of these motifs to the physical and chemical features of organelle membranes. Concurrently, we will use reconstitution approaches on artificial membranes to dissect how membrane sensors contribute to the organization of vesicle tethering by golgins and sterol transport by ORP proteins. We surmise that the combination of a molecular ¿switch¿, a small G protein of the Arf family, and of membrane sensors permit to organize these complex reactions in time and in space.

1 997 321 €

Start date: 2011-05-01, End date: 2015-04-30

European incursions onto the narrow isthmian pass that divided and connected the Atlantic and Pacific oceans made it a strategic node of the Spanish Empire and a crucial site for early modern globalization. On the front lines of the convergence of four continents, Old Panama offers an unusual opportunity for examining the diverse, often asymmetrical impacts of cultural and commercial contacts. The role of Italian, Portuguese, British, Dutch, and French interests in the area, as well as an influx of African slaves and Asian merchandise, have left a unique material legacy that requires an integrated, interdisciplinary approach to its varied sources. Bones, teeth and artifacts on this artery of Empire offer the possibility of new insights into the cultural and biological impact of early globalization. They also invite an interdisciplinary approach to different groups’ tactics for survival, including possible dietary changes, and the pursuit of profit. Such strategies may have led the diverse peoples inhabiting this junction, from indigenous allies to African and Asian bandits to European corsairs, to develop and to favor local production and Pacific trade networks at the expense of commerce with the metropolis. This project applies historical, archaeological and archaeometric methodologies to evidence of encounters between peoples and goods from Europe, America, Africa and Asia that took place on the Isthmus of Panama during the sixteenth and seventeenth centuries. Forging an interdisciplinary approach to early globalization, it challenges both Euro-centric and Hispano-phobic interpretations of the impact of the conquest of America, traditionally seen as a demographic catastrophe that reached its nadir in the so-called seventeenth-century crisis. Rather than applying quantitative methods to incomplete source material, researchers will adopt a contextualized, inter-disciplinary, qualitative approach to diverse agents involved in cultural and commercial exchange.

1 998 875 €

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

Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.

1 223 639 €

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

Autophagy is a catabolic pathway that delivers cytoplasmic material to lysosomes for degradation. Under vegetative conditions, the pathway serves as quality control system, specifically targeting damaged or superfluous organelles and protein-aggregates. Cytotoxic stresses and starvation, however, induces the formation of larger autophagosomes that capture cargo unselectively. Autophagosomes are being generated from a cup-shaped precursor membrane, the isolation membrane, which expands to engulf cytoplasmic components. Sealing of this structure gives rise to the double-membrane surrounded autophagosomes. Two interconnected ubiquitin (Ub)-like conjugation systems coordinate the expansion of autophagosomes by conjugating the autophagy related (Atg)-protein Atg8 to the isolation membrane. In an effort to unravel the function of Atg8, we reconstituted the system on model membranes in vitro and found that Atg8 forms together with the Atg12–Atg5-Atg16 complex a membrane scaffold which is required for productive autophagy in yeast. Humans possess seven Atg8-homologs and two mutually exclusive Atg16-variants. Here, we propose to investigate the function of the human Ub-like conjugation system using a fully reconstituted in vitro system. The spatiotemporal organization of recombinant fluorescent-labeled proteins with synthetic model membranes will be investigated using confocal and TIRF-microscopy. Structural information will be obtained by atomic force and electron microscopy. Mechanistic insights, obtained from the in vitro work, will be tested in vivo in cultured human cells. We belief that revealing 1) the function of the human Ub-like conjugation system in autophagy, 2) the functional differences of Atg8-homologs and the two Atg16-variants Atg16L1 and TECPR1 and 3) how Atg16L1 coordinates non-canonical autophagy will provide essential insights into the pathophysiology of cancer, neurodegenerative, and autoimmune diseases.

1 499 726 €

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

The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies.

2 214 035 €

Start date: 2012-04-01, End date: 2017-09-30

Infant is the most powerful learner: He learns in a few months to master language, complex social interactions, etc. Powerful statistical algorithms, simultaneously acting at the different levels of functional hierarchies have been proposed to explain learning. I propose here that two other elements are crucial. The first is the particular human cerebral architecture that constrains statistical computations. The second is the human’s ability to access a rich symbolic system. I have planned 6 work packages using the complementary information offered by non-invasive brain-imaging techniques (EEG, MRI and optical topography) to understand the neural bases of infant statistical computations and symbolic competence from 6 months of gestation up until the end of the first year of life. WP1 studies from which preterm age, statistical inferences can be demonstrated using hierarchical auditory oddball paradigms. WP2 investigates the consequences of a different pre-term environment (in-utero versus ex-utero) on the early statistical computations in the visual and auditory domains and their consequences on the ongoing brain activity along the first year of life. WP3 explores the neural bases of how infants infer word meaning and word category, and in particular the role of the left perisylvian areas and of their particular connectivity. WP4 questions infant symbolic competency. I propose several criteria (generalization, bidirectionality, use of algebraic rules and of logical operations) tested in successive experiments to clarify infant symbolic abilities during the first semester of life. WP5-6 are transversal to WP1-4: WP5 uses MRI to obtain accurate functional localization and maturational markers correlated with functional results. In WP6, we develop new tools to combine and analyse multimodal brain images. With this proposal, I hope to clarify the specificities of a neural functional architecture that are critical for human learning from the onset of cortical circuits.

2 554 924 €

Start date: 2016-09-01, End date: 2021-08-31

Sustainable agriculture is an ambitious concept conceived to improve productivity but minimizing side effects. Why the efficiency of a biocontrol agent is so variable? How can different therapies be efficiently exploited in a combined way to combat microbial diseases? These are questions that need investigation to convey with criteria of sustainability. What I present is an integral proposal aim to study the microbial ecology and specifically bacterial biofilms as a central axis of two differential but likely interconnected scenarios in plant health: i) the beneficial interaction of the biocontrol agent (BCA) Bacillus subtilis, and ii) the non-conventional interaction of the food-borne pathogen Bacillus cereus. I will start working with B. subtilis, and reasons are: 1) Different isolates are promising BCAs and are commercialized for such purpose, 2) There exist vast information of the genetics circuitries that govern important aspects of B. subtilis physiology as antibiotic production, cell differentiation, and biofilm formation. In parallel I propose to study the way B. cereus, a food-borne pathogenic bacterium interacts with vegetables. I am planning to set up a multidisciplinary approach that will combine genetics, biochemistry, proteomics, cell biology and molecular biology to visualize how these bacterial population interacts, communicates with plants and other microorganisms, or how all these factors trigger or inhibit the developmental program ending in biofilm formation. I am also interested on knowing if structural components of the bacterial extracellular matrix (exopolysaccharides or amyloid proteins) are important for bacterial fitness. If this were the case, I will also investigate which external factors affect their expression and assembly in functional biofilms. The insights get on these studies are committed to impulse our knowledge on microbial ecology and their biotechnological applicability to sustainable agriculture and food safety.

1 453 563 €

Start date: 2015-03-01, End date: 2021-02-28

In bacteria, the though external cell wall and the intracellular actin-like (MreB) cytoskeleton are major determinants of cell shape. The biosynthetic pathways and chemical composition of the cell wall, a three dimensional polymer network that is one of the most prominent targets for antibiotics, are well understood. However, despite decades of study, little is known about the complex cell wall ultrastructure and the molecular mechanisms that control cell wall morphogenesis in time and space. In rod-shaped bacteria, MreB homologues assemble into dynamic structures thought to control shape by serving as organizers for the movement and assembly of macromolecular machineries that effect sidewall elongation. However, the mechanistic details used by the MreB cytoskeleton to fulfil this role remain to be elucidated. Furthermore, development of high-resolution microscopy techniques has led to new breakthroughs this year, published by our lab and others, which are shaking the model developed over the last decade and re-questioning the MreB “actin cytoskeleton” designation. The aim of this project is to combine powerful genetic, biochemical, genomic and systems biology approaches available in the model bacterium Bacillus subtilis with modern high-resolution light microscopic techniques to study the dynamics and mechanistic details of the MreB cytoskeleton and of CW assembly. Parameters measured by the different approaches will be combined to quantitatively describe the features of bacterial cell morphogenesis.

1 650 050 €

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

One of the ultimate goals in cell biology is to understand how cells determine their shape. In bacteria, the cell wall and the actin-like (MreB) cytoskeleton are major determinants of cell shape. As a hallmark of microbial life, the external cell wall is the most conspicuous macromolecule expanding in concert with cell growth and one of the most prominent targets for antibiotics. Despite decades of study, the mechanism of cell wall morphogenesis remains poorly understood. In rod-shaped bacteria, actin-like MreB proteins assemble into disconnected membrane-associated structures (patches) that move processively around the cell periphery and are thought to control shape by spatiotemporally organizing macromolecular machineries that effect sidewall elongation. However, the ultrastructure of MreB assemblies and the mechanistic details underlying their morphogenetic function remain to be elucidated. The aim of this project is to combine ground-breaking light microscopy and spectroscopy techniques with cutting-edge genetic, biochemical and systems biology approaches available in the model rod-shaped bacterium Bacillus subtilis to elucidate how MreB and cell wall biosynthetic enzymes collectively act to build a cell. Within this context, new features of MreB assemblies will be determined in vivo and in vitro, and a “toolbox” of approaches to determine the modes of action of antibiotics targeting cell wall processes will be developed. Parameters measured by the different approaches will be used to refine a mathematical model aiming to quantitatively describe the features of bacterial cell wall growth. The long-term goals of BActin are to understand general principles of bacterial cell morphogenesis and to provide mechanistic templates and new reporters for the screening of novel antibiotics.

1 902 195 €

Start date: 2019-02-01, End date: 2024-01-31

In many European countries with ostensibly liberal abortion laws, women face legal restrictions to abortion beyond the first trimester of pregnancy, as well as other barriers to legal abortion, in particular shortages of providers willing and able to offer abortion due to poor training and to conscientious objection among physicians. The Council of Europe has recognized that conscientious objection can make access to safe abortion more difficult or impossible, particularly in rural areas and for low income women, who are forced to travel far to seek abortion care, including abroad. The WHO also highlights that delaying abortion care increases risks for women’s reproductive health. Despite the relevance of this topic from a public health and human rights perspective, the impact of procedural and social barriers to legal abortion on women in countries with ostensibly liberal abortion laws has not been studied by social scientists in Europe. This five-year research project is envisaged as a ground-breaking multi-disciplinary, mixed-methods investigation that will fill this gap, by capitalizing on previous, pioneer anthropological research of the PI on abortion and conscientious objection. It will contribute to the anthropology of reproduction in Europe, and particularly to the existing literature on abortion, conscientious objection and the medicalization of reproduction, and to the international debate on gender inequalities and citizenship, by exploring how barriers to legal abortion are constructed and how women embody and challenge them in different countries, by travelling or seeking illegal abortion, as well as their conceptualizations of abortion and their self perception as moral/political subjects. The project will be carried out in France, Italy and Spain, where the few existing studies show that women face several barriers to legal abortion as well as in the UK, the Netherlands and Spain, where Italian and French women travel to seek abortion care.

1 495 753 €

Start date: 2016-10-01, End date: 2021-09-30

The functioning of a single cell or organism is governed by the laws of chemistry and physics. The bridge from biology to chemistry and physics is provided by structural biology: to understand the functioning of a cell, it is necessary to know the atomic structure of macromolecular assemblies, which may contain hundreds of components. To characterise the structures of the increasingly large and often flexible complexes, high resolution structure determination (as was possible for example for the ribosome) will likely stay the exception, and multiple sources of structural data at multiple resolutions are employed. Integrating these data into one consistent picture poses particular difficulties, since data are much more sparse than in high resolution methods, and the data sets from heterogeneous sources are of highly different and unknown quality and may be mutually inconsistent, and that data are in general averaged over large ensembles and long times. Molecular modelling, a crucial element of any structure determination, plays an even more important role in these multi-scale and multi-technique approaches, not only to obtain structures from the data, but also to evaluate their reliability. This proposal is to develop a consistent framework for this highly complex data integration problem, principally based on Bayesian probability theory. Appropriate models for the major types data types used in hybrid approaches will be developed, as well as representations to include structural knowledge for the components of the complexes, at multiple scales. The new methods will be applied to a series of problems with increasing complexity, going from the determination of protein complexes with high resolution information, over low resolution structures based on protein-protein interaction data such as the nuclear pore, to the genome organisation in the nucleus.

2 130 212 €

Start date: 2012-05-01, End date: 2017-04-30

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

1 500 000 €

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

The goal of this proposal is to deliver a new theoretical framework to understand how transcription factors (TFs) sustain cell identity during developmental processes. Recognised as key drivers of cell fate acquisition, TFs are currently not considered to directly contribute to the mitotic inheritance of chromatin states. Instead, these are passively propagated through cell division by a variety of epigenetic marks. Recent discoveries, including by our lab, challenge this view: developmental TFs may impact the propagation of regulatory information from mother to daughter cells through a process known as mitotic bookmarking. This hypothesis, largely overlooked by mainstream epigenetic research during the last two decades, will be investigated in embryo-derived stem cells and during early mouse development. Indeed, these immature cell identities are largely independent from canonical epigenetic repression; hence, current models cannot account for their properties. We will comprehensively identify mitotic bookmarking factors in stem cells and early embryos, establish their function in stem cell self-renewal, cell fate acquisition and dissect how they contribute to chromatin regulation in mitosis. This will allow us to study the relationships between bookmarking factors and other mechanisms of epigenetic inheritance. To achieve this, unique techniques to modulate protein activity and histone modifications specifically in mitotic cells will be established. Thus, a mechanistic understanding of how mitosis influences gene regulation and of how mitotic bookmarking contributes to the propagation of immature cell identities will be delivered. Based on robust preliminary data, we anticipate the discovery of new functions for TFs in several genetic and epigenetic processes. This knowledge should have a wide impact on chromatin biology and cell fate studies as well as in other fields studying processes dominated by TFs and cell proliferation.

1 900 844 €

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

The linguistic capacity to express and comprehend an unlimited number of ideas when combining a limited number of elements has only been observed in humans. Nevertheless, research has not fully identified the components of language that make it uniquely human and that allow infants to grasp the complexity of linguistic structure in an apparently effortless manner. Research on comparative cognition suggests humans and other species share powerful learning mechanisms and basic perceptual abilities we use for language processing. But humans display remarkable linguistic abilities that other animals do not possess. Understanding the interplay between general mechanisms shared across species and more specialized ones dedicated to the speech signal is at the heart of current debates in human language acquisition. This is a highly relevant issue for researchers in the fields of Psychology, Linguistics, Biology, Philosophy and Cognitive Neuroscience. By conducting experiments across several populations (human adults and infants) and species (human and nonhuman animals), and using a wide array of experimental techniques, the present proposal hopes to shed some light on the origins of shared biological constraints that guide more specialized mechanisms in the search for linguistic structure. More specifically, we hope to understand how general perceptual and cognitive mechanisms likely present in other animals constrain the way humans tackle the task of language acquisition. Our hypothesis is that differences between humans and other species are not the result of humans being able to process increasingly complex structures that are the hallmark of language. Rather, differences might be due to humans and other animals focusing on different cues present in the signal to extract relevant information. This research will hint at what is uniquely human and what is shared across different animals species.

1 305 973 €

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

BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways

2 290 046 €

Start date: 2009-04-01, End date: 2014-03-31

Tissue morphogenesis is a complex process that emerges from spatially controlled patterns of cell shape changes. Dedicated genetic programmes regulate cell behaviours, exemplified in animals by the specification of apical constriction in invaginating epithelial tissues, or the orientation of cell intercalation during tissue extension. This genetic control is constrained by physical properties of cells that dictate how they can modify their shape. A major challenge is to understand how biochemical pathways control subcellular mechanics in epithelia, such as how forces are produced by interactions between actin filaments and myosin motors, and how these forces are transmitted at cell junctions. The major objective of our project is to investigate the fundamental principles of epithelial mechanics and to understand how intercellular signals and mechanical coupling between cells coordinate individual behaviours at the tissue level. We will study early Drosophila embryogenesis and combine quantitative cell biological studies of cell dynamics, biophysical characterization of cell mechanics and genetic control of cell signalling to answer the following questions: i) how are forces generated, in particular what underlies deformation and stabilization of cell shape by actomyosin networks, and pulsatile contractility; ii) how are forces transmitted at junctions, what are the feedback interactions between tension generation and transmission; iii) how are individual cell mechanics orchestrated at the tissue level to yield collective tissue morphogenesis? We expect to encapsulate the information-based, cell biological and physical descriptions of morphogenesis in a single, coherent framework. The project should impact more broadly on morphogenesis in other organisms and shed light on the mechanisms underlying robustness and plasticity in epithelia.

2 473 313 €

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

Biodiversity loss is one of the greatest environmental challenges of our time. There is mounting evidence that biodiversity increases the stability of ecosystem functions and services, suggesting that it may be critical to the sustainability of ecosystems and human societies in the face of environmental changes. Classical ecological theory, however, has focused on measures of stability that cannot explain and predict these stabilizing effects, especially in spatial systems. The goal of BIOSTASES is to develop a coherent body of new theory on the stability of ecosystems and coupled social–ecological systems and its relationships with biodiversity at multiple spatial scales that can better inform empirical research. BIOSTASES will reach this goal through four complementary objectives. First, it will propose a mathematical framework focused on temporal variability as an empirically relevant measure of stability, and use this framework to build robust early warning signals for critical transitions. Second, it will use dynamical metacommunity models to explore a wide range of novel questions related to ecosystem stability and diversity–stability relationships across scales. Third, it will study the stability of complex meta-ecosystems to provide new perspectives on the stability of food webs and on synergies and trade-offs between multiple ecosystem services across space. Fourth, it will develop novel theory to study the long-term dynamics and sustainability of coupled social–ecological systems. BIOSTASES proposes an ambitious innovative research programme that will provide new perspectives on the stability and sustainability of ecological and coupled social–ecological systems in the face of environmental changes. It will contribute to bridging the gaps between theoretical and empirical ecology and between ecology and social sciences, and to developing new approaches in biodiversity conservation, landscape management, and sustainable development.

2 092 644 €

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

Boundary layer theory is a large component of fluid dynamics. It is ubiquitous in Oceanography, where boundary layer currents, such as the Gulf Stream, play an important role in the global circulation. Comprehending the underlying mechanisms in the formation of boundary layers is therefore crucial for applications. However, the treatment of boundary layers in ocean dynamics remains poorly understood at a theoretical level, due to the variety and complexity of the forces at stake. The goal of this project is to develop several tools to bridge the gap between the mathematical state of the art and the physical reality of oceanic motion. There are four points on which we will mainly focus: degeneracy issues, including the treatment Stewartson boundary layers near the equator; rough boundaries (meaning boundaries with small amplitude and high frequency variations); the inclusion of the advection term in the construction of stationary boundary layers; and the linear and nonlinear stability of the boundary layers. We will address separately Ekman layers and western boundary layers, since they are ruled by equations whose mathematical behaviour is very different. This project will allow us to have a better understanding of small scale phenomena in fluid mechanics, and in particular of the inviscid limit of incompressible fluids. The team will be composed of the PI, two PhD students and three two-year postdocs over the whole period. We will also rely on the historical expertise of the host institution on fluid mechanics and asymptotic methods.

1 267 500 €

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

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

2 079 798 €

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

From testicular grafting (1920s) to step counting watches (2014), the perceptions and practices of health seeking individuals have been marked by continuities and profound changes during a twentieth century largely shaped by the advent of a communication society. Visuals can be a source to understand transformations by postulating an interactive, performative power of mass media in societies. Which roles did visuals play in changes from public health and human capital collective understandings of the healthy self to new (sometimes debated) perceptions and practices of our bodies as forms of individual capital in an increasing market-economized world? Pursuing these questions, the project focuses on four fields of investigation -food/nutrition; movement/exercise/sports; sexuality/reproduction/infants and dependency/addiction/overconsumption- in Germany, France and Great Britain studied with an entangled history framework. Within this scope the project aims at understanding (1)how visuals shape our health related self-understandings and practices in a continuity/discontinuity from the bio-political to the bio-economic logic. (2) The project will explore and explain how and why understandings of body capital differ or overlap in European countries. (3) The project will analyse if and how visual media serve as a promotion-communication hyphen for twentieth century preventive-self understanding. With a visual perspective on a long twentieth century, the project seeks to better understand changes and continuities in the history of health intertwined with the history of media. This will provide new insights into how the internalization of bodycapital has evolved throughout the past century, how transformations in the media world (from film to TV to internet) play out at the individual level and how health challenges and cultural differences in body perceptions and practices persist in producing social distinction in an age of global information and advanced health systems.

2 492 124 €

Start date: 2016-09-01, End date: 2021-08-31

The present project focuses on a barely scratched aspect of invasive cognitive brain-computer interfaces (cBCIs), i.e. closed-loop invasive cBCIs to augment and restore attentional functions. Its aim is to achieve an efficient enhanced cognition protocol both in the healthy brain and in the damaged brain and to study the local and global plasticity mechanisms underlying these effects. The project relies on the unique methodological combination of multi-electrode multisite intracortical recordings and functional magnetic resonance imaging, in association with reversible cortical lesions and intracortical microstimulations, in an experimental model allowing to approach the attentional human function and its dysfunctions to the best. Our goal is to achieve: 1. A closed-loop invasive cBCI for augmented attention, by providing the subjects with a feedback on their cortical spatial and feature attention information content as estimated from real-time population decoding procedures, using reinforcement learning, to have them improve this cognitive content, and as a result, improve their overt attentional behavioural performance. 2. A closed-loop invasive cBCI for restored attention, by inducing a controlled attentional loss thanks to reversible cortical lesions targeted to key functionally-identified cortical regions and using the closed-loop cBCI to restore attentional performance. 3. An invasive cBCI for stimulated attentional functions. We will identify the neuronal population changes leading to a voluntary enhancement of attentional functions as quantified in aim 1 and inject these changes, using complex patterns of microstimulations, mimicking spikes, to enhance or restore attention, in the absence of any active control by the subjects. This project will contribute to the development of novel therapeutical applications to restore acute or chronic severe attentional deficits and to provide an in depth understanding of the neural bases underlying closed-loop cBCIs.

1 997 748 €

Start date: 2016-10-01, End date: 2021-09-30

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

1 333 718 €

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

Subjectivity defines the subject who is perceiving, feeling, thinking, acting, and is essential to understand the conscious mind from the inside. However, subjectivity, or non-reflective first-person perspective, is not identified as a core concept in cognitive neuroscience and its neural basis remain largely unknown. BRAVIUS offers a unified framework to appraise both the concept and the neural mechanisms generating subjectivity. The hypothesis relies on two vital organs that generate their own rhythmic electrical activity, the stomach and the heart, and therefore constantly send information up to the neocortex, even in the absence of bodily change. Cortical responses to those visceral organs would define the organism as an entity at the neural level, and create a subject-centered referential from which first-person perspective can develop. In other words, the cardiac and gastric pacemakers could feed the brain with self-specifying inputs. BRAVIUS builds on previous theories and studies on visceral states but focuses on ascending information, from viscera to brain, and does not require visceral states to change nor to be consciously perceived. Experimentally, BRAVIUS measures the understudied neural response evoked by heartbeats and introduces a new measure, the electrogastrogram, to quantify the slow gastric pacemaker. BRAVIUS will test with magneto-encephalography (MEG) the role of neural responses to ascending visceral signals in generating subjectivity by cutting across domains of cognitive sciences and exploring diverse paradigms where subjectivity is engaged: perceptual consciousness, self-consciousness, emotions and decision making. BRAVIUS will further explore how cardiac and gastric ascending signals shape the temporal (MEG) and spatial (fMRI) organization of spontaneous brain activity. The project outcome is a detailed mechanistic neural account of the most private part of the human mind, and a unified concept of subjectivity across cognitive domains.

2 080 000 €

Start date: 2015-12-01, End date: 2020-11-30

Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.

2 499 969 €

Start date: 2019-07-01, End date: 2024-06-30

Intercellular communication is critical for multicellularity. It coordinates the activities within individual cells to support the function of an organism as a whole. Plants have developed remarkable cellular machines -the Plasmodesmata (PD) pores- which interconnect every single cell within the plant body, establishing direct membrane and cytoplasmic continuity, a situation unique to plants. PD are indispensable for plant life. They control the flux of molecules between cells and are decisive for development, environmental adaptation and defence signalling. However, how PD integrate signalling to coordinate responses at a multicellular level remains unclear. A striking feature of PD organisation, setting them apart from animal cell junctions, is a strand of endoplasmic reticulum (ER) running through the pore, tethered extremely tight (~10nm) to the plasma membrane (PM) by unidentified “spokes”. To date, the function of ER-PM contacts at PD remains a complete enigma. We don’t know how and why the two organelles come together at PD cellular junctions. I recently proposed that ER-PM tethering is in fact central to PD function. In this project I will investigate the question of how integrated cellular responses benefit from organelle cross-talk at PD. The project integrates proteomic/bioinformatic approaches, biophysical/modelling methods and ultra-high resolution 3D imaging into molecular cell biology of plant cell-to-cell communication and will, for the first time, directly address the mechanism and function of ER-PM contacts at PD. We will pursue three complementary objectives to attain our goal: 1) Identify the mechanisms of PD membrane-tethering at the molecular level 2) Elucidate the dynamics and 3D architecture of ER-PM contact sites at PD 3) Uncover the function of ER-PM apposition for plant intercellular communication. Overall, the project will pioneer a radically new perspective on PD-mediated cell-to-cell communication, a fundamental aspect of plant biology

1 999 840 €

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

"The proposed research project seeks to further our understanding on two important questions for the design of monetary policy: (a) What are the effects of monetary policy interventions on asset price bubbles? (b) How should monetary policy be conducted in the presence of asset price bubbles? The first part of the project will focus on the development of a theoretical framework that can be used to analyze rigorously the implications of alternative monetary policy rules in the presence of asset price bubbles, and to characterize the optimal monetary policy. In particular, I plan to use such a framework to assess the merits of a “leaning against the wind” strategy, which calls for a systematic rise in interest rates in response to the development of a bubble. The second part of the project will seek to produce evidence, both empirical and experimental, regarding the effects of monetary policy on asset price bubbles. The empirical evidence will seek to identify and estimate the sign and response of asset price bubbles to interest rate changes, exploiting the potential differences in the joint behavior of interest rates and asset prices during “bubbly” episodes, in comparison to “normal” times. In addition, I plan to conduct some lab experiments in order to shed some light on the link between monetary policy and bubbles. Participants will trade two assets, a one-period riskless asset and a long-lived stock, in an environment consistent with the existence of asset price bubbles in equilibrium. Monetary policy interventions will take the form of changes in the short-term interest rate, engineered by the experimenter. The experiments will allow us to evaluate some of the predictions of the theoretical models regarding the impact of monetary policy on the dynamics of bubbles, as well as the effectiveness of “leaning against the wind” policies."

799 200 €

Start date: 2014-01-01, End date: 2017-12-31

Synaptic scaffolding molecules control the localization and the abundance of neurotransmitter receptors at the synapse, a key parameter to shape synaptic transfer function. Most characterized synaptic scaffolds are intracellular, yet a growing number of secreted proteins appear to organize the synapse from the outside of the cell. We recently demonstrated in C. elegans that an evolutionarily conserved protein secreted by motoneurons specifies the excitatory versus inhibitory identity of the postsynaptic domains at neuromuscular synapses. We propose to use this system as a genetically tractable paradigm to perform a comprehensive characterization of this unforeseen synaptic organization. Specifically, this project will pursue 4 complementary aims: 1) Identify and characterize a comprehensive set of genes that organize and control the formation and maintenance of these scaffolds through a series of genetic screens based on the direct visualization of fluorescent acetylcholine and GABA receptors in living animals. 2) Solve the spatial synaptic organization of these scaffolds at a nanoscale resolution using super-resolutive and correlative light and electron microscopy, and analyze their dynamic behavior in vivo by implementing Single Particle Tracking imaging in living worms. 3) Decipher the role of the synaptomatrix in the organization of synaptic extracellular scaffolds and evaluate its functional contribution at the physiological and molecular levels using a candidate gene strategy and innovative imaging. 4) Analyze the formation and decline of these scaffolds at the lifetime scale and evaluate the role of synaptic activity and aging in these processes by taking advantage of the possibility to follow identified synapses over the entire life of C. elegans. Using powerful genetics in combination with cutting-edge in vivo imaging and electrophysiology, we anticipate to identify new genes and new mechanisms at work to regulate normal and pathological synaptic function.

2 492 750 €

Start date: 2016-10-01, End date: 2021-09-30

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

1 972 797 €

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

The composition and molecular features of tumours vary during the course of the disease, and the selection pressure imposed by the environment is a central component in this process. Evolutionary principles have been exploited to explain the genomic aberrations in cancer. However, the phenotypic changes underlying disease progression remain poorly understood. In the past years, I have contributed to identify and characterise the therapeutic implications underlying metabolic alterations that are intrinsic to primary tumours or metastasis. In CancerADAPT I postulate that cancer cells rely on adaptive transcriptional & metabolic mechanisms [converging on a Metabolic Phenotype] in order to rapidly succeed in their establishment in new microenvironments along disease progression. I aim to predict the molecular cues that govern the adaptive properties in prostate cancer (PCa), one of the most commonly diagnosed cancers in men and an important source of cancer-related deaths. I will exploit single cell RNASeq, spatial transcriptomics and multiregional OMICs in order to identify the transcriptional and metabolic diversity within tumours and along disease progression. I will complement experimental strategies with computational analyses that identify and classify the predicted adaptation strategies of PCa cells in response to variations in the tumour microenvironment. Metabolic phenotypes postulated to sustain PCa adaptability will be functionally and mechanistically deconstructed. We will identify therapeutic strategies emanating from these results through in silico methodologies and small molecule high-throughput screening, and evaluate their potential to hamper the adaptability of tumour cells in vitro and in vivo, in two specific aspects: metastasis and therapy response. CancerADAPT will generate fundamental understanding on how cancer cells adapt in our organism, in turn leading to therapeutic strategies that increase the efficacy of current treatments.

1 999 882 €

Start date: 2019-11-01, End date: 2024-10-31