ERC FUNDED PROJECTS

The idea that underpins this project is to use the material evidence from thousands of surviving 15th-c. books, as well as unique documentary evidence — the unpublished ledger of a Venetian bookseller in the 1480s which records the sale of 25,000 printed books with their prices — to address four fundamental questions relating to the introduction of printing in the West which have so far eluded scholarship, partly because of lack of evidence, partly because of the lack of effective tools to deal with existing evidence. The book trade differs from other trades operating in the medieval and early modern periods in that the goods traded survive in considerable numbers. Not only do they survive, but many of them bear stratified evidence of their history in the form of marks of ownership, prices, manuscript annotations, binding and decoration styles. A British Academy pilot project conceived by the PI produced a now internationally-used database which gathers together this kind of evidence for thousands of surviving 15th-c. printed books. For the first time, this makes it possible to track the circulation of books, their trade routes and later collecting, across Europe and the USA, and throughout the centuries. The objectives of this project are to examine (1) the distribution and trade-routes, national and international, of 15th-c. printed books, along with the identity of the buyers and users (private, institutional, religious, lay, female, male, and by profession) and their reading practices; (2) the books' contemporary market value; (3) the transmission and dissemination of the texts they contain, their survival and their loss (rebalancing potentially skewed scholarship); and (4) the circulation and re-use of the illustrations they contain. Finally, the project will experiment with the application of scientific visualization techniques to represent, geographically and chronologically, the movement of 15th-c. printed books and of the texts they contain.

1 999 172 €

Start date: 2014-04-01, End date: 2019-03-31

The traditional (Riemann) approach to analytic number theory uses the zeros of zeta functions. This requires the associated multiplicative function, say f(n), to have special enough properties that the associated Dirichlet series may be analytically continued. In this proposal we continue to develop an approach which requires less of the multiplicative function, linking the original question with the mean value of f. Such techniques have been around for a long time but have generally been regarded as “ad hoc”. In this project we aim to show that one can develop a coherent approach to the whole subject, not only reproving all of the old results, but also many new ones that appear inaccessible to traditional methods. Our first goal is to complete a monograph yielding a reworking of all the classical theory using these new methods and then to push forward in new directions. The most important is to extend these techniques to GL(n) L-functions, which we hope will now be feasible having found the correct framework in which to proceed. Since we rarely know how to analytically continue such L-functions this could be of great benefit to the subject. We are developing the large sieve so that it can be used for individual moduli, and will determine a strong form of that. Also a new method to give asymptotics for mean values, when they are not too small. We wish to incorporate techniques of analytic number theory into our theory, for example recent advances on mean values of Dirichlet polynomials. Also the recent breakthroughs on the sieve suggest strong links that need further exploration. Additive combinatorics yields important results in many areas. There are strong analogies between its results, and those for multiplicative functions, especially in large value spectrum theory, and its applications. We hope to develop these further. Much of this is joint work with K Soundararajan of Stanford University.

2 011 742 €

Start date: 2015-08-01, End date: 2020-07-31

Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

1 100 000 €

Start date: 2008-09-01, End date: 2014-04-30

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

1 999 750 €

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

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

2 500 000 €

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

The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.

1 203 627 €

Start date: 2016-03-01, End date: 2021-02-28

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

Extreme astrophysical events such as relativistic flows, cataclysmic explosions and black hole accretion are one of the key areas for astrophysics in the 21st century. The extremes of physics experienced in these environments are beyond anything achievable in any laboratory on Earth, and provide a unique glimpse at the laws of physics operating in extraordinary regimes. All of these events are associated with transient radio emission, a tracer both of the acceleration of particles to relativistic energies, and coherent emitting regions with huge effective temperatures. By studying radio bursts from these phenomena we can pinpoint the sources of explosive events, understand the budget of kinetic feedback by explosive events in the ambient medium, and probe the physical state of the universe back to the epoch of reionisation, less than a billion years after the big bang. In seeking to push back the frontiers of extreme astrophysics, I will use a trio of revolutionary new radio telescopes, LOFAR, ASKAP and MeerKAT, pathfinders for the Square Kilometre Array, and all facilities in which I have a major role in the search for transients. I will build an infrastructure which transforms their combined operations for the discovery, classification and reporting of transient astrophysical events, over the whole sky, making them much more than the sum of their parts. This will include development of environments for the coordinated handling of extreme astrophysical events, in real time, via automated systems, as well as novel techniques for the detection of these events in a sea of noise. I will furthermore augment this program by buying in as a major partner to a rapid-response robotic optical telescope, and by cementing my relationship with an orbiting X-ray facility. This multiwavelength dimension will secure the astrophysical interpretation of our observational results and help to revolutionise high-energy astrophysics via a strong scientific exploitation program.

2 999 847 €

Start date: 2011-07-01, End date: 2017-06-30

"High-energy observations of our Galaxy offer a good, albeit not complete, picture of the X-ray source populations, in particular the accreting binary sources. Recent ability to study accreting binaries in nearby galaxies has shown that we would be short-sighted if we restricted ourselves to our Galaxy or to a few nearby ones. I propose an ambitious project that involves a comprehensive study of all the galaxies within 10 Mpc for which we can study in detail their X-ray sources and stellar populations. The study will combine data from a unique suite of observatories (Chandra, XMM-Newton, HST, Spitzer) with state-of-the-art theoretical modelling of binary systems. I propose a novel approach that links the accreting binary populations to their parent stellar populations and surpasses any current studies of X-ray binary populations, both in scale and in scope, by: (a) combining methods and results from several different areas of astrophysics (compact objects, binary systems, stellar populations, galaxy evolution); (b) using data from almost the whole electromagnetic spectrum (infrared to X-ray bands); (c) identifying and studying the different sub-populations of accreting binaries; and (d) performing direct comparison between observations and theoretical predictions, over a broad parameter space. The project: (a) will answer the long-standing question of the formation efficiency of accreting binaries in different environments; and (b) will constrain their evolutionary paths. As by-products the project will provide eagerly awaited input to the fields of gravitational-wave sources, γ-ray bursts, and X-ray emitting galaxies at cosmological distances and it will produce a heritage multi-wavelength dataset and library of models for future studies of galaxies and accreting binaries."

1 242 000 €

Start date: 2014-04-01, End date: 2019-03-31

"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."

1 196 701 €

Start date: 2014-02-01, End date: 2018-01-31

This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics. We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.

1 000 000 €

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

The amazing rate of progress in the computer technologies and telecommunications presents many new challenges for Optimization Theory. New problems are usually very big in size, very special in structure and possibly have a distributed data support. This makes them unsolvable by the standard optimization methods. In these situations, old theoretical models, based on the hidden Black-Box information, cannot work. New theoretical and algorithmic solutions are urgently needed. In this project we will concentrate on development of fast optimization methods for problems of big and very big size. All the new methods will be endowed with provable efficiency guarantees for large classes of optimization problems, arising in practical applications. Our main tool is the acceleration technique developed for the standard Black-Box methods as applied to smooth convex functions. However, we will have to adapt it to deal with different situations. The first line of development will be based on the smoothing technique as applied to a non-smooth functions. We propose to substantially extend this approach to generate approximate solutions in relative scale. The second line of research will be related to applying acceleration techniques to the second-order methods minimizing functions with sparse Hessians. Finally, we aim to develop fast gradient methods for huge-scale problems. The size of these problems is so big that even the usual vector operations are extremely expensive. Thus, we propose to develop new methods with sublinear iteration costs. In our approach, the main source for achieving improvements will be the proper use of problem structure. Our overall aim is to be able to solve in a routine way many important problems, which currently look unsolvable. Moreover, the theoretical development of Convex Optimization will reach the state, when there is no gap between theory and practice: the theoretically most efficient methods will definitely outperform any homebred heuristics.

2 090 038 €

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

"Many of today's and tomorrow's computer systems are built on top of large-scale networks such as, e.g., the Internet, the world wide web, wireless ad hoc and sensor networks, or peer-to-peer networks. Driven by technological advances, new kinds of networks and applications have become possible and we can safely assume that this trend is going to continue. Often modern systems are envisioned to consist of a potentially large number of individual components that are organized in a completely decentralized way. There is no central authority that controls the topology of the network, how nodes join or leave the system, or in which way nodes communicate with each other. Also, many future distributed applications will be built using wireless devices that communicate via radio. The general objective of the proposed project is to improve our understanding of the algorithmic and theoretical foundations of decentralized distributed systems. From an algorithmic point of view, decentralized networks and computations pose a number of fascinating and unique challenges that are not present in sequential or more standard distributed systems. As communication is limited and mostly between nearby nodes, each node of a large network can only maintain a very restricted view of the global state of the system. This is particularly true if the network can change dynamically, either by nodes joining or leaving the system or if the topology changes over time, e.g., because of the mobility of the devices in case of a wireless network. Nevertheless, the nodes of a network need to coordinate in order to achieve some global goal. In particular, we plan to study algorithms and lower bounds for basic computation and information dissemination tasks in such systems. In addition, we are particularly interested in the complexity of distributed computations in dynamic and wireless networks."

1 148 000 €

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

One of the most exciting research questions within archaeology is that of the peopling of Australasia by at least c.50,000 years ago. This represents some of the earliest evidence of modern human colonization outside Africa, yet, even at the greatest sea-level lowstand, this migration would have involved seafaring. It is the maritime nature of this dispersal which makes it so important to questions of technological, cognitive and social human development. These issues have traditionally been the preserve of archaeologists, but with a multidisciplinary approach that embraces cutting-edge marine geophysical, hydrodynamic and archaeogenetic analyses, we now have the opportunity to examine the When, Where, Who and How of the earliest seafaring in world history. The voyage from Sunda (South East Asia) to Sahul (Australasia) provides evidence for the earliest ‘open water’ crossing in the world. A combination of the sparse number of early archaeological finds and the significant changes in the palaeolandscape and submergence of the broad north western Australian continental shelf, mean that little is known about the routes taken and what these crossings may have entailed. This project will combine research of the submerged palaeolandscape of the continental shelf to refine our knowledge of the onshore/offshore environment, identify potential submerged prehistoric sites and enhance our understanding of the palaeoshoreline and tidal regime. This will be combined with archaeogenetic research targeting mtDNA and Y-chromosome data to resolve questions of demography and dating. For the first time this project takes a truly multidisciplinary approach to address the colonization of Sahul, providing an unique opportunity to tackle some of the most important questions about human origins, the relationship between humans and the changing environment, population dynamics and migration, seafaring technology, social organisation and cognition.

1 134 928 €

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

In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.

1 500 000 €

Start date: 2011-04-01, End date: 2016-03-31

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

1 497 420 €

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

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

1 476 882 €

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

Relative to other species, humans are characterised by considerable biological diversity despite genetic homogeneity. This diversity is reflected in skeletal variation, but we lack sufficient understanding of the underlying mechanisms to adequately interpret the archaeological record. The proposed research will address problems in our current understanding of the origins of human variation in the past by: 1) documenting and interpreting the pattern of global hunter-gatherer variation relative to genetic phylogenies and climatic variation; 2) testing the relationship between environmental and skeletal variation among genetically related hunter-gatherers from different environments; 3) examining the adaptability of living humans to different environments, through the study of energetic expenditure and life history trade-offs associated with locomotion; and 4) investigating the relationship between muscle and skeletal variation associated with locomotion in diverse environments. This will be achieved by linking: a) detailed study of the global pattern of hunter-gatherer variation in the Late Pleistocene and Holocene with; b) ground-breaking experimental research which tests the relationship between energetic stress, muscle function, and bone variation in living humans. The first component tests the correspondence between skeletal variation and both genetic and climatic history, to infer mechanisms driving variation. The second component integrates this skeletal variation with experimental studies of living humans to, for the first time, directly test adaptive implications of skeletal variation observed in the past. ADaPt will provide the first links between prehistoric hunter-gatherer variation and the evolutionary parameters of life history and energetics that may have shaped our success as a species. It will lead to breakthroughs necessary to interpret variation in the archaeological record, relative to human dispersals and adaptation in the past.

1 911 485 €

Start date: 2014-07-01, End date: 2019-06-30

The numerical simulation of complex compressible flow problem is still a challenge nowaday even for simple models. In our opinion, the most important hard points that need currently to be tackled and solved is how to obtain stable, scalable, very accurate, easy to code and to maintain schemes on complex geometries. The method should easily handle mesh refinement, even near the boundary where the most interesting engineering quantities have to be evaluated. Unsteady uncertainties in the model, for example in the geometry or the boundary conditions should represented efficiently.This proposal goal is to design, develop and evaluate solutions to each of the above problems. Our work program will lead to significant breakthroughs for flow simulations. More specifically, we propose to work on 3 connected problems: 1-A class of very high order numerical schemes able to easily deal with the geometry of boundaries and still can solve steep problems. The geometry is generally defined by CAD tools. The output is used to generate a mesh which is then used by the scheme. Hence, any mesh refinement process is disconnected from the CAD, a situation that prevents the spread of mesh adaptation techniques in industry! 2-A class of very high order numerical schemes which can utilize possibly solution dependant basis functions in order to lower the number of degrees of freedom, for example to compute accurately boundary layers with low resolutions. 3-A general non intrusive technique for handling uncertainties in order to deal with irregular probability density functions (pdf) and also to handle pdf that may evolve in time, for example thanks to an optimisation loop. The curse of dimensionality will be dealt thanks Harten's multiresolution method combined with sparse grid methods. Currently, and up to our knowledge, no scheme has each of these properties. This research program will have an impact on numerical schemes and industrial applications.

1 432 769 €

Start date: 2008-12-01, End date: 2013-11-30

Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.

1 607 105 €

Start date: 2008-07-01, End date: 2013-06-30

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

2 192 500 €

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

The gas and dust in the interstellar medium (ISM) drive the chemical evolution of galaxies, the formation of stars and planets, and the synthesis of complex prebiotic molecules. The prime birth places for this interstellar material are the winds of evolved (super)giant stars. These winds are unique chemical laboratories, in which a large variety of gas and dust species radially expand away from the star. Recent progress on the observations of these winds has been impressive thanks to Herschel and ALMA. The next challenge is to unravel the wealth of chemical information contained in these data. This is an ambitious task since (1) a plethora of physical and chemical processes interact in a complex way, (2) laboratory data to interpret these interactions are lacking, and (3) theoretical tools to analyse the data do not meet current needs. To boost the knowledge of the physics and chemistry characterizing these winds, I propose a world-leading multi-disciplinary project combining (1) high-quality data, (2) novel theoretical wind models, and (3) targeted laboratory experiments. The aim is to pinpoint the dominant chemical pathways, unravel the transition from gas-phase to dust species, elucidate the role of clumps on the overall wind structure, and study the reciprocal effect between various dynamical and chemical phenomena. Now is the right time for this ambitious project thanks to the availability of (1) high-quality multi-wavelength data, including ALMA and Herschel data of the PI, (2) supercomputers enabling a homogeneous analysis of the data using sophisticated theoretical wind models, and (3) novel laboratory equipment to measure the gas-phase reaction rates of key species. This project will have far-reaching impact on (1) the field of evolved stars, (2) the understanding of the chemical lifecycle of the ISM, (3) chemical studies of dynamically more complex systems, such as exoplanets, protostars, supernovae etc., and (4) it will guide new instrument development.

2 605 897 €

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

"This proposal aims at strengthening the connections between more fundamentally oriented areas of mathematics like algebra, geometry, analysis, and topology, and the more applied oriented and more recently emerging disciplines of discrete mathematics, optimization, and algorithmics. The overall goal of the project is to obtain, with methods from fundamental mathematics, new effective tools to unravel the complexity of structures like graphs, networks, codes, knots, polynomials, and tensors, and to get a grip on such complex structures by new efficient characterizations, sharper bounds, and faster algorithms. In the last few years, there have been several new developments where methods from representation theory, invariant theory, algebraic geometry, measure theory, functional analysis, and topology found new applications in discrete mathematics and optimization, both theoretically and algorithmically. Among the typical application areas are networks, coding, routing, timetabling, statistical and quantum physics, and computer science. The project focuses in particular on: A. Understanding partition functions with invariant theory and algebraic geometry B. Graph limits, regularity, Hilbert spaces, and low rank approximation of polynomials C. Reducing complexity in optimization by exploiting symmetry with representation theory D. Reducing complexity in discrete optimization by homotopy and cohomology These research modules are interconnected by themes like symmetry, regularity, and complexity, and by common methods from algebra, analysis, geometry, and topology."

2 001 598 €

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

Aftermath seeks to understand the legacy of the East Asian War of 1592-1598. This conflict involved over 500,000 combatants from Japan, China, and Korea; up to 100,000 Korean civilians were abducted to Japan. The war caused momentous demographic upheaval and widespread destruction, but also had long-lasting cultural impact as a result of the removal to Japan of Korean technology and skilled labourers. The conflict and its aftermath bear striking parallels to events in East Asia during World War 2, and memories of the 16th century war remain deeply resonant in the region. However, the war and its immediate aftermath are also significant because they occurred at the juncture of periods often characterized as “medieval” and “early modern” in the East Asian case. What were the implications for the social, economic, and cultural contours of early modern East Asia? What can this conflict tell us about war “aftermath” across historical periods and about such periodization itself? There is little Western scholarship on the war and few studies in any language cross linguistic, disciplinary, and national boundaries to achieve a regional perspective that reflects the interconnected history of East Asia. Aftermath will radically alter our understanding of the region’s history by providing the first analysis of the state of East Asia as a result of the war. The focus will be on the period up to the middle of the 17th century, but not precluding ongoing effects. The team, with expertise covering Japan, Korea, and China, will investigate three themes: the movement of people and demographic change, the impact on the natural environment, and technological diffusion. The project will be the first large scale investigation to use Japanese, Korean, and Chinese sources to understand the war’s aftermath. It will broaden understandings of the early modern world, and push the boundaries of war legacy studies by exploring the meanings of “aftermath” in the early modern East Asian context.

1 444 980 €

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

"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."

1 499 768 €

Start date: 2013-01-01, End date: 2017-12-31

The establishment of farming is a pivotal moment in human history, setting the stage for the emergence of class-based society and urbanization. Monolithic views of the nature and development of early agriculture, however, have prevented clear understanding of how exactly farming fuelled, shaped and sustained the emergence of complex societies. A breakthrough in archaeological approach is needed to determine the actual roles of farming in the emergence of social complexity. The methodology required must push beyond conventional interpretation of the most direct farming evidence – archaeobotanical remains of crops and associated arable weeds – to reconstruct not only what crops were grown, but also how, where and why farming was practised. Addressing these related aspects, in contexts ranging from early agricultural villages to some of the world’s earliest cities, would provide the key to unraveling the contribution of farming to the development of lasting social inequalities. The research proposed here takes a new interdisciplinary approach combining archaeobotany, plant stable isotope chemistry and functional plant ecology, building on groundwork laid in previous research by the applicant. These approaches will be applied to two relatively well researched areas, western Asia and Europe, where a series of sites that chart multiple pathways to early complex societies offer rich plant and other bioarchaeological assemblages. The proposed project will set a wholly new standard of insight into early farming and its relationship with early civilization, facilitating similar approaches in other parts of the world and the construction of comparative perspectives on the global significance of early agriculture in social development.

1 199 647 €

Start date: 2013-02-01, End date: 2017-01-31

The Aryl hydrocarbon receptor is an evolutionary conserved widely expressed transcription factor that mediates the toxicity of a substantial variety of exogenous toxins, but is also stimulated by endogenous physiological ligands. While it is known that this receptor mediates the toxicity of dioxin, this is unlikely to be its physiological function. We have recently identified selective expression of AhR in the Th17 subset of effector CD4 T cells. Ligation of AhR by a candidate endogenous ligand (FICZ) which is a UV metabolite of tryptophan causes expansion of Th17 cells and the induction of IL-22 production. As a consequence, AhR ligation will exacerbate autoimmune diseases such as experimental autoimmune encephalomyelitis. Little is known so far about the impact of AhR ligands on IL-17/IL-22 mediated immune defense functions. IL-22 is considered a pro-inflammatory Th17 cytokine, which is involved in the etiology of psoriasis, but it has also been shown to be a survival factor for epithelial cells. AhR is polymorphic and defined as high or low affinity receptor for dioxin leading to the classification of high and low responder mouse strains based on defined mutations. In humans similar polymorphisms exist and although on the whole human AhR is thought to be of low affinity in humans, there are identified mutations that confer high responder status. No correlations have been made with Th17 mediated immune responses in mice and humans. This study aims to investigate the role of AhR ligands and polymorphisms in autoimmunity as well as protective immune responses using both mouse models and human samples from normal controls as well as psoriasis patients.

1 242 352 €

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

"Understanding the dawn of the first galaxies and how their light permeated the early Universe is at the very frontier of modern astrophysical cosmology. Generous resources, including ambitions observational programs, are being devoted to studying these epochs of Cosmic Dawn (CD) and Reionization (EoR). In order to interpret these observations, we propose to build on our widely-used, semi-numeric simulation tool, 21cmFAST, and apply it to observations. Using sub-grid, semi-analytic models, we will incorporate additional physical processes governing the evolution of sources and sinks of ionizing photons. The resulting state-of-the-art simulations will be well poised to interpret topical observations of quasar spectra and the cosmic 21cm signal. They would be both physically-motivated and fast, allowing us to rapidly explore astrophysical parameter space. We will statistically quantify the resulting degeneracies and constraints, providing a robust answer to the question, ""What can we learn from EoR/CD observations?"" As an end goal, these investigations will help us understand when the first generations of galaxies formed, how they drove the EoR, and what are the associated large-scale observational signatures."

1 468 750 €

Start date: 2015-05-01, End date: 2021-01-31

This project focuses on two questions about host/parasite interactions: how do biotrophic plant pathogens suppress host defence? and, what is the basis for pathogen specialization on specific host species? A broadly accepted model explains resistance and susceptibility to plant pathogens. First, pathogens make conserved molecules ( PAMPS ) such as flagellin, that plants detect via cell surface receptors, leading to PAMP-Triggered Immunity (PTI). Second, pathogens make effectors that suppress PTI. Third, plants carry 100s of Resistance (R) genes that detect an effector, and activate Effector-Triggered Immunity (ETI). One effector is sufficient to trigger resistance. Albugo candida (Ac) (white rust) strongly suppresses host defence; Ac-infected Arabidopsis are susceptible to pathogen races to which they are otherwise resistant. Ac is an oomycete, not a fungus. Arabidopsis is resistant to races of Ac that infect brassicas. The proposed project involves three programs. First ( genomics, transcriptomics and bioinformatics ), we will use next-generation sequencing (NGS) methods (Solexa and GS-Flex), and novel transcriptomics methods to define the genome sequence and effector set of three Ac strains, as well as carrying out >40- deep resequencing of 7 additional Ac strains. Second, ( effectoromics ), we will carry out functional assays using Effector Detector Vectors (Sohn Plant Cell 19:4077 [2007]), with the set of Ac effectors, screening for enhanced virulence, for suppression of defence, for effectors that are recognized by R genes in disease resistant Arabidopsis and for host effector targets. Third, ( resistance diversity ), we will characterize Arabidopsis germplasm for R genes to Ac, both for recognition of Arabidopsis strains of Ac, and for recognition in Arabidopsis of effectors from Ac strains that infect brassica. This proposal focuses on Ac, but will establish methods that could discover new R genes in non-hosts against many plant diseases.

2 498 923 €

Start date: 2009-01-01, End date: 2014-06-30

"Significant parts of our cultural heritage are produced on the Web, yet only insufficient opportunities exist for accessing and exploring the past of the Web. The ALEXANDRIA project aims to develop models, tools and techniques necessary to archive and index relevant parts of the Web, and to retrieve and explore this information in a meaningful way. While the easy accessibility to the current Web is a good baseline, optimal access to Web archives requires new models and algorithms for retrieval, exploration, and analytics which go far beyond what is needed to access the current state of the Web. This includes taking into account the unique temporal dimension of Web archives, structured semantic information already available on the Web, as well as social media and network information. Within ALEXANDRIA, we will significantly advance semantic and time-based indexing for Web archives using human-compiled knowledge available on the Web, to efficiently index, retrieve and explore information about entities and events from the past. In doing so, we will focus on the concurrent evolution of this knowledge and the Web content to be indexed, and take into account diversity and incompleteness of this knowledge. We will further investigate mixed crowd- and machine-based Web analytics to support long- running and collaborative retrieval and analysis processes on Web archives. Usage of implicit human feedback will be essential to provide better indexing through insights during the analysis process and to better focus harvesting of content. The ALEXANDRIA Testbed will provide an important context for research, exploration and evaluation of the concepts, methods and algorithms developed in this project, and will provide both relevant collections and algorithms that enable further research on and practical application of our research results to existing archives like the Internet Archive, the Internet Memory Foundation and Web archives maintained by European national libraries."

2 493 600 €

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

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

1 871 250 €

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

"Contemporary database query languages are ultimately founded on logic and feature an additive operation – usually a form of (multi)set union or disjunction – that is asymmetric in that additions or updates do not always have an inverse. This asymmetry puts a greater part of the machinery of abstract algebra for equation solving outside the reach of databases. However, such equation solving would be a key functionality that problems such as query equivalence testing and data integration could be reduced to: In the current scenario of the presence of an asymmetric additive operation they are undecidable. Moreover, query languages with a symmetric additive operation (i.e., which has an inverse and is thus based on ring theory) would open up databases for a large range of new scientific and mathematical applications. The goal of the proposed project is to reinvent database management systems with a foundation in abstract algebra and specifically in ring theory. The presence of an additive inverse allows to cleanly define differences between queries. This gives rise to a database analog of differential calculus that leads to radically new incremental and adaptive query evaluation algorithms that substantially outperform the state of the art techniques. These algorithms enable a new class of systems which I call Dynamic Data Management Systems. Such systems can maintain continuously fresh query views at extremely high update rates and have important applications in interactive Large-scale Data Analysis. There is a natural connection between differences and updates, motivating the group theoretic study of updates that will lead to better ways of creating out-of-core data processing algorithms for new storage devices. Basing queries on ring theory leads to a new class of systems, Algebraic Data Management Systems, which herald a convergence of database systems and computer algebra systems."

1 480 548 €

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

Recurrent neural networks (RNNs) are general parallel-sequential computers. Some learn their programs or weights. Our supervised Long Short-Term Memory (LSTM) RNNs were the first to win pattern recognition contests, and recently enabled best known results in speech and handwriting recognition, machine translation, etc. They are now available to billions of users through the world's most valuable public companies including Google and Apple. Nevertheless, in lots of real-world tasks RNNs do not yet live up to their full potential. Although universal in theory, in practice they fail to learn important types of algorithms. This ERC project will go far beyond today's best RNNs through novel RNN-like systems that address some of the biggest open RNN problems and hottest RNN research topics: (1) How can RNNs learn to control (through internal spotlights of attention) separate large short-memory structures such as sub-networks with fast weights, to improve performance on many natural short-term memory-intensive tasks which are currently hard to learn by RNNs, such as answering detailed questions on recently observed videos? (2) How can such RNN-like systems metalearn entire learning algorithms that outperform the original learning algorithms? (3) How to achieve efficient transfer learning from one RNN-learned set of problem-solving programs to new RNN programs solving new tasks? In other words, how can one RNN-like system actively learn to exploit algorithmic information contained in the programs running on another? We will test our systems existing benchmarks, and create new, more challenging multi-task benchmarks. This will be supported by a rather cheap, GPU-based mini-brain for implementing large RNNs.

2 500 000 €

Start date: 2017-10-01, End date: 2022-09-30

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

1 222 329 €

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

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

2 493 322 €

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

Currently, more than 30% of all Europeans suffer from one or more allergic disorder but treatment is still mostly symptomatic due to a lack of understanding the underlying causality. Allergies are caused by type 2 immune responses triggered by recognition of harmless antigens. Both genetic and environmental factors have been proposed to favour allergic predisposition and both factors have a huge impact on the symbiotic microbiota and the intestinal immune system. Recently we and others showed that the transcription factor ROR(γt) seems to play a key role in mucosal tolerance in the gut and also regulates intestinal type 2 immune responses. Based on these results I postulate two major events in the gut for the development of an allergy in the lifetime of an individual: First, a failure to establish mucosal tolerance or anergy constitutes a necessity for the outbreak of allergic symptoms and allergic disease. Second, a certain ‘core’ microbiome or pathway of the intestinal microbiota predispose certain individuals for the later development of allergic disorders. Therefore, I will address the following aims: 1) Influence of ROR(γt) on mucosal tolerance induction and allergic disorders 2) Elucidate the T cell receptor repertoire of intestinal Th2 and ROR(γt)+ Tregs and assess the role of alternative NFκB pathway for induction of mucosal tolerance 3) Identification of ‘core’ microbiome signatures or metabolic pathways that favour allergic predisposition ALLERGUT will provide ground-breaking knowledge on molecular mechanisms of the failure of mucosal tolerance in the gut and will prove if the resident ROR(γt)+ T(reg) cells can function as a mechanistic starting point for molecular intervention strategies on the background of the hygiene hypothesis. The vision of ALLERGUT is to diagnose mucosal disbalance, prevent and treat allergic disorders even before outbreak and thereby promote Public Health initiative for better living.

1 498 175 €

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

Alpha shapes were invented in the early 80s of last century, and their implementation in three dimensions in the early 90s was at the forefront of the exact arithmetic paradigm that enabled fast and correct geometric software. In the late 90s, alpha shapes motivated the development of the wrap algorithm for surface reconstruction, and of persistent homology, which was the starting point of rapidly expanding interest in topological algorithms aimed at data analysis questions. We now see alpha shapes, wrap complexes, and persistent homology as three aspects of a larger theory, which we propose to fully develop. This viewpoint was a long time coming and finds its clear expression within a generalized version of discrete Morse theory. This unified framework offers new opportunities, including (I) the adaptive reconstruction of shapes driven by the cavity structure; (II) the stochastic analysis of all aspects of the theory; (III) the computation of persistence of dense data, both in scale and in depth; (IV) the study of long-range order in periodic and near-periodic point configurations. These capabilities will significantly deepen as well as widen the theory and enable new applications in the sciences. To gain focus, we concentrate on low-dimensional applications in structural molecular biology and particle systems.

1 678 432 €

Start date: 2018-07-01, End date: 2023-06-30

Algebras of operators on Hilbert spaces were originally introduced as the right framework for the mathematical description of quantum mechanics. In modern mathematics the scope has much broadened due to the highly versatile nature of operator algebras. They are particularly useful in the analysis of groups and their actions. Amenability is a finiteness property which occurs in many different contexts and which can be characterised in many different ways. We will analyse amenability in terms of approximation properties, in the frameworks of abstract C*-algebras, of topological dynamical systems, and of discrete groups. Such approximation properties will serve as bridging devices between these setups, and they will be used to systematically recover geometric information about the underlying structures. When passing from groups, and more generally from dynamical systems, to operator algebras, one loses information, but one gains new tools to isolate and analyse pertinent properties of the underlying structure. We will mostly be interested in the topological setting, and in the associated C*-algebras. Amenability of groups or of dynamical systems then translates into the completely positive approximation property. Systems of completely positive approximations store all the essential data about a C*-algebra, and sometimes one can arrange the systems so that one can directly read of such information. For transformation group C*-algebras, one can achieve this by using approximation properties of the underlying dynamics. To some extent one can even go back, and extract dynamical approximation properties from completely positive approximations of the C*-algebra. This interplay between approximation properties in topological dynamics and in noncommutative topology carries a surprisingly rich structure. It connects directly to the heart of the classification problem for nuclear C*-algebras on the one hand, and to central open questions on amenable dynamics on the other.

1 596 017 €

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

Online markets currently form an important share of the global economy. The Internet hosts classical markets (real-estate, stocks, e-commerce) as well allowing new markets with previously unknown features (web-based advertisement, viral marketing, digital goods, crowdsourcing, sharing economy). Algorithms play a central role in many decision processes involved in online markets. For example, algorithms run electronic auctions, trade stocks, adjusts prices dynamically, and harvest big data to provide economic information. Thus, it is of paramount importance to understand the algorithmic and mechanism design foundations of online markets. The algorithmic research issues that we consider involve algorithmic mechanism design, online and approximation algorithms, modelling uncertainty in online market design, and large-scale data analysisonline and approximation algorithms, large-scale optimization and data mining. The aim of this research project is to combine these fields to consider research questions that are central for today's Internet economy. We plan to apply these techniques so as to solve fundamental algorithmic problems motivated by web-basedInternet advertisement, Internet market designsharing economy, and crowdsourcingonline labour marketplaces. While my planned research is focussedcentered on foundational work with rigorous design and analysis of in algorithms and mechanismsic design and analysis, it will also include as an important component empirical validation on large-scale real-life datasets.

1 780 150 €

Start date: 2018-07-01, End date: 2023-06-30

Current technical sensor systems offer capabilities that are superior to human perception. Cameras can capture a spectrum that is wider than visible light, high-speed cameras can show movements that are invisible to the human eye, and directional microphones can pick up sounds at long distances. The vision of this project is to lay a foundation for the creation of digital technologies that provide novel sensory experiences and new perceptual capabilities for humans that are natural and intuitive to use. In a first step, the project will assess the feasibility of creating artificial human senses that provide new perceptual channels to the human mind, without increasing the experienced cognitive load. A particular focus is on creating intuitive and natural control mechanisms for amplified senses using eye gaze, muscle activity, and brain signals. Through the creation of a prototype that provides mildly unpleasant stimulations in response to perceived information, the feasibility of implementing an artificial reflex will be experimentally explored. The project will quantify the effectiveness of new senses and artificial perceptual aids compared to the baseline of unaugmented perception. The overall objective is to systematically research, explore, and model new means for increasing the human intake of information in order to lay the foundation for new and improved human senses enabled through digital technologies and to enable artificial reflexes. The ground-breaking contributions of this project are (1) to demonstrate the feasibility of reliably implementing amplified senses and new perceptual capabilities, (2) to prove the possibility of creating an artificial reflex, (3) to provide an example implementation of amplified cognition that is empirically validated, and (4) to develop models, concepts, components, and platforms that will enable and ease the creation of interactive systems that measurably increase human perceptual capabilities.

1 925 250 €

Start date: 2016-07-01, End date: 2021-06-30

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

The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967. My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic? My motivation is two-fold: - Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious. - In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood. The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.

1 065 500 €

Start date: 2011-04-01, End date: 2016-03-31

AncientAdhesives addresses the most crucial problem in Palaeolithic archaeology: How to reliably infer cognitively complex behaviour in the deep past. To study the evolution of Neandertal and modern human cognitive capacities, certain find categories are taken to reflect behavioural and thus cognitive complexitye.g. Among these are art objects, personal ornaments and complex technology. Of these technology is best-suited to trace changing behavioural complexity, because 1) it is the least vulnerable to differential preservation, and 2) technological behaviours are present throughout the history of our genus. Adhesives are the oldest examples of highly complex technology. They are also known earlier from Neandertal than from modern human contexts. Understanding their technological complexity is thus essential to resolve debates on differences in cognitive complexity of both species. However, currently, there is no agreed-upon method to measure technological complexity. The aim of AncientAdhesives is to create the first reliable method to compare the complexity of Neandertal and modern human technologies. This is achieved through three main objectives: 1. Collate the first comprehensive body of knowledge on adhesives, including ethnography, archaeology and (experimental) material properties (e.g. preservation, production). 2. Develop a new archaeological methodology by modifying industrial process modelling for archaeological applications. 3. Evaluate the development of adhesive technological complexity through time and across species using a range of explicit complexity measures. By analysing adhesives, it is possible to measure technological complexity, to identify idiosyncratic behaviours and to track adoption and loss of complex technological know-how. This represents a step-change in debates about the development of behavioural complexity and differences/similarities between Neanderthals and modern humans.

1 499 926 €

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

Computer animation has traditionally been associated with applications in virtual-reality-based training, video games or feature films. However, interactive animation is gaining relevance in a more general scope, as a tool for early-stage analysis, design and planning in many applications in science and engineering. The user can get quick and visual feedback of the results, and then proceed by refining the experiments or designs. Potential applications include nanodesign, e-commerce or tactile telecommunication, but they also reach as far as, e.g., the analysis of ecological, climate, biological or physiological processes. The application of computer animation is extremely limited in comparison to its potential outreach due to a trade-off between accuracy and computational efficiency. Such trade-off is induced by inherent complexity sources such as nonlinear or anisotropic behaviors, heterogeneous properties, or high dynamic ranges of effects. The Animetrics project proposes a modeling and animation methodology, which consists of a multi-scale decomposition of complex processes, the description of the process at each scale through combination of simple local models, and fitting the parameters of those local models using large amounts of data from example effects. The modeling and animation methodology will be explored on specific problems arising in complex mechanical phenomena, including viscoelasticity of solids and thin shells, multi-body contact, granular and liquid flow, and fracture of solids.

1 277 969 €

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

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

2 307 800 €

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

Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for human health. Novel methods for controlling the natural vector populations are urgently needed, given the evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for the control of natural populations. We will focus our analysis on three major players of mosquito reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings. We will then translate this information into the identification of inhibitors of mosquito fertility. The experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead focus on the identification of the male and female factors responsible for sperm viability and function. Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the fight against malaria.

1 500 000 €

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

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

This is a proposal for research at the interface of analytic number theory, automorphic forms and algebraic geometry. Motivated by fundamental conjectures in number theory, classical problems will be investigated in higher order situations: general number fields, automorphic forms on higher rank groups, the arithmetic of algebraic varieties of higher degree. In particular, I want to focus on - computation of moments of L-function of degree 3 and higher with applications to subconvexity and/or non-vanishing, as well as subconvexity for multiple L-functions; - bounds for sup-norms of cusp forms on various spaces and equidistribution of Hecke correspondences; - automorphic forms on higher rank groups and general number fields, in particular new bounds towards the Ramanujan conjecture; - a proof of Manin's conjecture for a certain class of singular algebraic varieties. The underlying methods are closely related; for example, rational points on algebraic varieties will be counted by a multiple L-series technique.

1 004 000 €

Start date: 2010-10-01, End date: 2015-09-30

"Humans are equipped with a variety of intrinsic immunity or host restriction factors. These evolved under positive selection pressure for diversification and represent a first line of defence against invading viruses. Unfortunately, however, many pathogens have evolved effective antagonists against our defences. For example, the capability of HIV-1 to counteract human restriction factors that interfere with reverse transcription, uncoating and virion release has been a prerequisite for the global spread of AIDS. We are just beginning to understand the diversity and induction of antiretroviral factors and how pandemic HIV-1 group M (major) strains evolved to counteract all of them. Here, I propose to use a genetics, proteomics and evolutionary approach to discover and define as-yet-unknown antiviral effectors and their inducers. To identify novel antiviral factors, we will examine the capability of all primate genes that are under strong positive selection pressure to inhibit HIV and its simian (SIV) precursors. This examination from the evolutionary perspective of the invading pathogen will also reveal which adaptations allowed HIV-1 to cause the AIDS pandemic. Furthermore, complex peptide-protein libraries representing essentially the entire human peptidome, will be utilized to identify novel specific inducers of antiviral restriction factors. My ultimate aim is to unravel the network of inducers and effectors of antiviral immunity - the ""Anti-Virome"" - and to use this knowledge to develop novel effective preventive and therapeutic approaches based on the induction of combinations of antiviral factors targeting different steps of the viral life cycle. The results of this innovative and interdisciplinary program will provide fundamental new insights into intrinsic immunity and may offer alternatives to conventional vaccine and therapeutic approaches because most restriction factors have broad antiviral activity and are thus effective against various pathogens."

1 915 200 €

Start date: 2013-04-01, End date: 2018-03-31