ERC FUNDED PROJECTS

Most celestial bodies, from planets, to stars, to black holes; gain mass during their lives by means of an accretion disc. Understanding the physical processes that determine the rate at which matter accretes and energy is radiated in these discs is vital for unraveling the formation, evolution, and fate of almost every type of object in the Universe. Despite the fact that magnetic fields have been known to be crucial in accretion discs since the early 90’s, the majority of astrophysical questions that depend on the details of how disc accretion proceeds are still being addressed using the “standard” accretion disc model (developed in the early 70’s), where magnetic fields do not play an explicit role. This has prevented us from fully exploring the astrophysical consequences and observational signatures of realistic accretion disc models, leading to a profound disconnect between observations (usually interpreted with the standard paradigm) and modern accretion disc theory and numerical simulations (where magnetic turbulence is crucial). The goal of this proposal is to use several complementary approaches in order to finally move beyond the standard paradigm. This program has two main objectives: 1) Develop the theoretical framework to incorporate magnetic fields, and the ensuing turbulence, into self-consistent accretion disc models, and investigate their observational implications. 2) Investigate transport and radiative processes in collision-less disc regions, where non-thermal radiation originates, by employing a kinetic particle description of the plasma. In order to achieve these goals, we will use, and build upon, state-of-the-art magnetohydrodynamic and particle-in-cell codes in conjunction with theoretical modeling. This framework will make it possible to address fundamental questions on stellar and planet formation, binary systems with a compact object, and supermassive black hole feedback in a way that has no counterpart within the standard paradigm.

1 793 697 €

Start date: 2013-02-01, End date: 2018-01-31

The scientific goal of the proposal is to answer central questions related to diffeomorphism groups of manifolds of dimension 2 and 3, and to their deformation invariant analogs, the mapping class groups. While the classification of surfaces has been known for more than a century, their automorphism groups have yet to be fully understood. Even less is known about diffeomorphisms of 3-manifolds despite much interest, and the objects here have only been classified recently, by the breakthrough work of Perelman on the Poincar\'e and geometrization conjectures. In dimension 2, I will focus on the relationship between mapping class groups and topological conformal field theories, with applications to Hochschild homology. In dimension 3, I propose to compute the stable homology of classifying spaces of diffeomorphism groups and mapping class groups, as well as study the homotopy type of the space of diffeomorphisms. I propose moreover to establish homological stability theorems in the wider context of automorphism groups and more general families of groups. The project combines breakthrough methods from homotopy theory with methods from differential and geometric topology. The research team will consist of 3 PhD students, and 4 postdocs, which I will lead.

724 992 €

Start date: 2009-11-01, End date: 2014-10-31

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

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

Although we have extensive knowledge of many important processes in cell biology, including information on many of the molecules involved and the physical interactions among them, we still do not understand most of the dynamical features that are the essence of living systems. This is particularly true for the actin cytoskeleton, a major component of the internal architecture of eukaryotic cells. In living cells, actin networks constantly assemble and disassemble filaments while maintaining an apparent stable structure, suggesting a perfect balance between the two processes. Such behaviors are called “dynamic steady states”. They confer upon actin networks a high degree of plasticity allowing them to adapt in response to external changes and enable cells to adjust to their environments. Despite their fundamental importance in the regulation of cell physiology, the basic mechanisms that control the coordinated dynamics of co-existing actin networks are poorly understood. In the AAA project, first, we will characterize the parameters that allow the coupling among co-existing actin networks at steady state. In vitro reconstituted systems will be used to control the actin nucleation patterns, the closed volume of the reaction chamber and the physical interaction of the networks. We hope to unravel the mechanism allowing the global coherence of a dynamic actin cytoskeleton. Second, we will use our unique capacity to perform dynamic micropatterning, to add or remove actin nucleation sites in real time, in order to investigate the ability of dynamic networks to adapt to changes and the role of coupled network dynamics in this emergent property. In this part, in vitro experiments will be complemented by the analysis of actin network remodeling in living cells. In the end, our project will provide a comprehensive understanding of how the adaptive response of the cytoskeleton derives from the complex interplay between its biochemical, structural and mechanical properties.

2 349 898 €

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

"The 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

Pharaonic Egypt is commonly known for its pyramids and tomb treasures. The present knowledge of Egyptian everyday life and social structures derives mostly from mortuary records associated with the upper classes, whereas traces of ordinary life from domestic sites are generally disregarded. Settlement archaeology in Egypt and Nubia (Ancient North Sudan) is still in its infancy; it is timely to strenghten this field. Responsible for the pottery at three major settlement sites (Abydos and Elephantine in Egypt; Sai Island in Sudan), the PI is in a unique position to co-ordinate a research project on settlement patterns in Northeast Africa of the 2nd millennium BC based on the detailed analysis of material remains. The selected case studies situated across ancient and modern borders and of diverse environmental and cultural preconditions, show very similar archaeological remains. Up to now, no attempt has been made to explain this situation in detail. The focus of the project is the well-preserved, only partially explored site of Sai Island, seemingly an Egyptian microcosm in New Kingdom Upper Nubia. Little time is left to conduct the requisite large-scale archaeology as Sai is endangered by the planned high dam of Dal. With the application of microarchaeology we will introduce an approach that is new in Egyptian settlement archaeology. Our interdisciplinary research will result in novel insights into (a) multifaceted lives on Sai at a micro-spatial level and (b) domestic life in 2nd millennium BC Egypt and Nubia from a macroscopic view. The present understanding of the political situation in Upper Nubia during the New Kingdom as based on written records will be significantly enlarged by the envisaged approach. Furthermore, in reconstructing Sai Island as “home away from home”, the project presents a showcase study of what we can learn about acculturation and adaptation from ancient cultures, in this case from the coexistence of Egyptians and Nubians

1 497 460 €

Start date: 2012-12-01, End date: 2018-04-30

The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.

1 500 000 €

Start date: 2011-12-01, End date: 2017-08-31

The mechanism of cell division is conserved in many eukaryotes, from yeast to man. A contractile ring of filamentous actin and myosin II motors generates the force to bisect a mother cell into two daughters. The actomyosin ring is among the most complex cellular machines, comprising over 150 proteins. Understanding how these proteins organize themselves into a functional ring with appropriate contractile properties remains one of the great challenges in cell biology. Efforts to generate a comprehensive understanding of the mechanism of actomyosin ring assembly have been hampered by the lack of structural information on the arrangement of actin, myosin II, and actin modulators in the ring in its native state. Fundamental questions such as how actin filaments are assembled and organized into a ring remain actively debated. This project will investigate key issues pertaining to cytokinesis in the fission yeast Schizosaccharomyces pombe, which divides employing an actomyosin based contractile ring, using the methods of genetics, biochemistry, cellular imaging, DNA origami, genetic code expansion, and click chemistry. Specifically, we will (1) attempt to visualize actin filament assembly in live cells expressing fluorescent actin generated through synthetic biological approaches, including genetic code expansion and click chemistry (2) decipher actin filament polarity in the actomyosin ring using total internal reflection fluorescence microscopy of labelled dimeric and multimeric myosins V and VI generated through DNA origami approaches (3) address when, where, and how actin filaments for cytokinesis are assembled and organized into a ring and (4) reconstitute actin filament and functional actomyosin ring assembly in permeabilized spheroplasts and in supported bilayers. Success in the project will provide major insight into the mechanism of actomyosin ring assembly and illuminate principles behind cytoskeletal self-organization.

2 863 705 €

Start date: 2015-11-01, End date: 2020-10-31

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 and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and metabolites that influence WAT inflammation are entirely unknown. We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity. Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may generate a platform for microbiome-based personalized therapy against obesity and its complications.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29

The colonisation of Europe by anatomically modern humans (AMHs) ca. 45,000 years before present (BP) and the transition to farming ca. 8,000 BP are two major events in human prehistory. Both events involved certain cultural and biological adaptations, technological innovations, and behavioural plasticity which are unique to our species. The reconstruction of these processes and the causality between them has so far remained elusive due to technological, methodological and logistical complexities. Major developments in our understanding of the anthropology of the Upper Palaeolithic, Mesolithic and Neolithic, and advances in ancient DNA (aDNA) technology and chronometric methods now allow us to assess in sufficient resolution the interface between these evolutionary processes, and changes in human culture and behaviour. The proposed research will investigate the complex interface between the morphological, genetic, behavioural, and cultural factors that shaped the population history of European AMHs. The PI s interdisciplinary expertise in these areas, his access to and experience of relevant skeletal collections, and his ongoing European collaborations will allow significant progress in addressing these fundamental questions. The approach taken will include (a) the collection of bioarchaeological, aDNA, stable isotope (for the analysis of ancient diet) and radiometric data on 500 skeletons from key sites/phases in Europe and western Anatolia, and (b) the application of existing and novel aDNA, bioarchaeological and simulation methodologies. This research will yield results that transform our current understanding of major demographic and evolutionary processes and will place Europe at the forefront of anthropological biological and genetic research.

1 088 386 €

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

The discoveries that the expansion of the universe is accelerating due to an unknown “dark energy” and that most of the matter is invisible, highlight our lack of understanding of the major constituents of the universe. These surprising findings set the stage for research in cosmology at the start of the 21st century. The objective of this proposal is to advance observational constraints to a level where we can distinguish between physical mechanisms that aim to explain the properties of dark energy and the observed distribution of dark matter throughout the universe. We use a relatively new technique called weak gravitational lensing: the accurate measurement of correlations in the orientations of distant galaxies enables us to map the dark matter distribution directly and to extract the cosmological information that is encoded by the large-scale structure. To study the dark universe we will analyse data from a new state-of-the-art imaging survey: the Kilo- Degree Survey (KiDS) will cover 1500 square degrees in 9 filters. The combination of its large survey area and the availability of exquisite photometric redshifts for the sources makes KiDS the first project that can place interesting constraints on the dark energy equation-of-state using lensing data alone. Combined with complementary results from Planck, our measurements will provide one of the best views of the dark side of the universe before much larger space-based projects commence. To reach the desired accuracy we need to carefully measure the shapes of distant background galaxies. We also need to account for any intrinsic alignments that arise due to tidal interactions, rather than through lensing. Reducing these observational and physical biases to negligible levels is a necessarystep to ensure the success of KiDS and an important part of our preparation for more challenging projects such as the European-led space mission Euclid.

1 316 880 €

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

I propose to establish a research group to develop completely new tools in order to solve three important problems on the relationships between automorphic forms and Galois representations, which lie at the heart of the Langlands program. The first is to prove Serre’s conjecture for real quadratic fields. I will use automorphic induction to transfer the problem to U(4) over the rational numbers, where I will use automorphy lifting theorems and results on the weight part of Serre's conjecture that I established in my earlier work to reduce the problem to proving results in small weight and level. I will prove these base cases via integral p-adic Hodge theory and discriminant bounds. The second is to develop a geometric theory of moduli spaces of mod p and p-adic Galois representations, and to use it to establish the Breuil–Mézard conjecture in arbitrary dimension, by reinterpreting the conjecture in geometric terms. This will transform the subject by building the first connections between the p-adic Langlands program and the geometric Langlands program, providing an entirely new world of techniques for number theorists. As a consequence of the Breuil-Mézard conjecture, I will be able to deduce far stronger automorphy lifting theorems (in arbitrary dimension) than those currently available. The third is to completely determine the reduction mod p of certain two-dimensional crystalline representations, and as an application prove a strengthened version of the Gouvêa–Mazur conjecture. I will do this by means of explicit computations with the p-adic local Langlands correspondence for GL_2(Q_p), as well as by improving existing arguments which prove multiplicity one theorems via automorphy lifting theorems. This work will show that the existence of counterexamples to the Gouvêa-Mazur conjecture is due to a purely local phenomenon, and that when this local obstruction vanishes, far stronger conjectures of Buzzard on the slopes of the U_p operator hold.

1 131 339 €

Start date: 2012-10-01, End date: 2017-09-30

The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived. The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

750 000 €

Start date: 2009-03-01, End date: 2014-02-28

"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

Host cytokines, chemokines and type I IFNs are critical effectors of the innate immune response to viral and bacterial pathogens. Several classes of germ-line encoded pattern recognition receptors have been identified, which sense non-self nucleic acids and trigger these responses. Recently NLRP-3, a member of the NOD-like receptor (NLR) family, has been shown to sense endogenous danger signals, environmental insults and the DNA viruses adenovirus and HSV. Activation of NLRP-3 induces the formation of a large multiprotein complex in cells termed inflammasome , which controls the activity of pro-caspase-1 and the maturation of pro-IL-1² and pro-IL18 into their active forms. NLRP-3, however, does not regulate these responses to double stranded cytosolic DNA. We identified the cytosolic protein AIM2 as the missing receptor for cytosolic DNA. AIM2 contains a HIN200 domain, which binds to DNA and a pyrin domain, which associates with the adapter molecule ASC to activate both NF-ºB and caspase-1. Knock down of AIM2 down-regulates caspase-1-mediated IL-1² responses following DNA stimulation or vaccinia virus infection. Collectively, these observations demonstrate that AIM2 forms an inflammasome with the DNA ligand and ASC to activate caspase-1. Our underlying hypothesis for this proposal is that AIM2 plays a central role in host-defence to cytosolic microbial pathogens and also in DNA-triggered autoimmunity. The goals of this research proposal are to further characterize the DNA ligand for AIM2, to explore the molecular mechanisms of AIM2 activation, to define the contribution of AIM2 to host-defence against viral and bacterial pathogens and to assess its function in nucleic acid triggered autoimmune disease. The characterization of AIM2 and its role in innate immunity could open new avenues in the advancement of immunotherapy and treatment of autoimmune disease.

1 727 920 €

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

"In our largely unchanging radio Universe, a highly dynamic component was recently discovered: flashes of bright radio emission that last only milliseconds but appear all over the sky. Some of these radio bursts can be traced to intermittently pulsating neutron stars. Other bursts however, apparently originate far outside our Galaxy. Due to great observational challenges, the evolution of the neutron stars is not understood, while more importantly, the nature of the extragalactic bursts remains an outright mystery. My overall aim is to understand the physics that drives both kinds of brief and luminous bursts. My primary goal is to identify the highly compact astrophysical explosions powering the extragalactic bursts. My previous surveys are the state of the art in fast-transient detection; I will now increase by a factor of 10 this exploration volume. In real-time I will provide arcsec positions, 10,000-fold more accurate than currently possible, to localize such extragalactic bursts for the first time and understand their origin. My secondary goal is to unravel the unexplained evolution of intermittently pulsating neutron stars (building on e.g., my recent papers in Science, 2013), by doubling their number and modeling their population. To achieve these goals, I will carry out a highly innovative survey: the Apertif-LOFAR Exploration of the Radio Transient Sky. ALERT is over an order of magnitude more sensitive than all current state-of-the art fast-transient surveys. Through its novel, extremely wide field-of-view, Westerbork/Apertif will detect many tens of extragalactic bursts. Through real-time triggers to LOFAR I will next provide the precise localisation that is essential for radio, optical and high-energy follow-up to, for the first time, shed light on the physics and objects driving these bursts – evaporating primordial black holes; explosions in host galaxies; or, the unknown?"

1 999 823 €

Start date: 2014-12-01, End date: 2019-11-30

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

As diploid organisms inherit one gene copy from each parent, a gene can be expressed from both alleles (biallelic) or from only one allele (monoallelic). Although transcription from both alleles is detected for most genes in cell population experiments, little is known about allele-specific expression in single cells and its phenotypic consequences. To answer fundamental questions about allelic transcription heterogeneity in single cells, this research program will focus on single-cell transcriptome analyses with allelic-origin resolution. To this end, we will investigate both clonally stable and dynamic random monoallelic expression across a large number of cell types, including cells from embryonic and adult stages. This research program will be accomplished with the novel single-cell RNA-seq method developed within my lab to obtain quantitative, genome-wide gene expression measurement. To distinguish between mitotically stable and dynamic patterns of allelic expression, we will analyze large numbers a clonally related cells per cell type, from both primary cultures (in vitro) and using transgenic models to obtain clonally related cells in vivo. The biological significance of the research program is first an understanding of allelic transcription, including the nature and extent of random monoallelic expression across in vivo tissues and cell types. These novel insights into allelic transcription will be important for an improved understanding of how variable phenotypes (e.g. incomplete penetrance and variable expressivity) can arise in genetically identical individuals. Additionally, the single-cell transcriptome analyses of clonally related cells in vivo will provide unique insights into the clonality of gene expression per se.

1 923 060 €

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

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

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

The skeleton and the sinusoidal vasculature form a functional unit with great relevance in health, regeneration, and disease. Currently, fundamental aspects of sinusoidal vessel growth, specialization, arteriovenous organization and the consequences for tissue perfusion, or the changes occurring during ageing remain unknown. Our preliminary data indicate that key principles of bone vascularization and the role of molecular regulators are highly distinct from other organs. I therefore propose to use powerful combination of mouse genetics, fate mapping, transcriptional profiling, computational biology, confocal and two-photon microscopy, micro-CT and PET imaging, biochemistry and cell biology to characterize the growth, differentiation, dynamics, and ageing of the bone vasculature. In addition to established angiogenic pathways, the role of highly promising novel candidate regulators will be investigated in endothelial cells and perivascular osteoprogenitors with sophisticated inducible and cell type-specific genetic methods in the mouse. Complementing these powerful in vivo approaches, 3D co-cultures generated by cell printing technologies will provide insight into the communication between different cell types. The dynamics of sinusoidal vessel growth and regeneration will be monitored by two-photon imaging in the skull. Finally, I will explore the architectural, cellular and molecular changes and the role of capillary endothelial subpopulations in the sinusoidal vasculature of ageing and osteoporotic mice. Technological advancements, such as new transgenic strains, mutant models or cell printing approaches, are important aspects of this proposal. AngioBone will provide a first conceptual framework for normal and deregulated function of the bone sinusoidal vasculature. It will also break new ground by analyzing the role of blood vessels in ageing and identifying novel strategies for tissue engineering and, potentially, the prevention/treatment of osteoporosis.

2 478 750 €

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

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

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

Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease. Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection. This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and (ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the physiological function of APOLs by studying the phenotype of transgenic mice either expressing human APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new perspectives to treat kidney disease.

2 250 000 €

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

Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis. Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to: 1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry. 2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging. 3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies. This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.

2 000 000 €

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

This proposal aims to unravel mysteries at the frontier of number theory and other areas of mathematics and physics. The main focus will be to understand and exploit “modularity” of q-hypergeometric series. “Modular forms are functions on the complex plane that are inordinately symmetric.” (Mazur) The motivation comes from the wide-reaching applications of modularity in combinatorics, percolation, Lie theory, and physics (black holes). The interplay between automorphic forms, q-series, and other areas of mathematics and physics is often two-sided. On the one hand, the other areas provide interesting examples of automorphic objects and predict their behavior. Sometimes these even motivate new classes of automorphic objects which have not been previously studied. On the other hand, knowing that certain generating functions are modular gives one access to deep theoretical tools to prove results in other areas. “Mathematics is a language, and we need that language to understand the physics of our universe.”(Ooguri) Understanding this interplay has attracted attention of researchers from a variety of areas. However, proofs of modularity of q-hypergeometric series currently fall far short of a comprehensive theory to describe the interplay between them and automorphic forms. A recent conjecture of W. Nahm relates the modularity of such series to K-theory. In this proposal I aim to fill this gap and provide a better understanding of this interplay by building a general structural framework enveloping these q-series. For this I will employ new kinds of automorphic objects and embed the functions of interest into bigger families A successful outcome of the proposed research will open further horizons and also answer open questions, even those in other areas which were not addressed in this proposal; for example the new theory could be applied to better understand Donaldson invariants.

1 240 500 €

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

Most historians work in archives, but generally have not made archives into their primary object of research. While we tend to be preoccupied by documentary loss, what is striking is the sheer amount of paperwork preserved over the centuries. We need to study the reasons for this preservation. This project wishes to study the history of the archives and of the chanceries that oversaw their production storage and organization in late medieval and early modern Italy: essentially from the creation of the first chanceries in city-states in the late twelfth century to the opening of the Archivi di Stato that, after the ancient states’ dissolution, preserved documents as tools for scholarship rather than administration. Because of its fragmented political history, concentrating on Italy means having access to the archives of a wide variety of regimes; in turn, as institutions pursuing similar functions, archives lend themselves to comparison and therefore such research may help us overcome the traditional disconnectedness in the study of Italy’s past. The project proposes to break significantly new ground, first, by adopting a comparative approach through the in-depth analysis of seven case studies and, second, by contextualising the study of archives away from institutional history in a wider social and cultural context, by focusing on six themes researched in six successive phases: 1) the political role of archives, and the efforts devoted by governments to their development; 2) their organization, subdivisions, referencing systems; 3) the material culture of documents and physical repositories as well as spatial locations; 4) the social characteristiscs of the staff; 5) the archives’ place in society, including their access and misuse; 6) their use by historians. As implied in the choice of these themes, the project is deliberately interdisciplinary, and aims at the mutually beneficial exchange between archivists, social, political cultural and art historians.

1 107 070 €

Start date: 2012-02-01, End date: 2016-07-31

"Archaea constitute the third domain of life and are believed to be close to the origin of life. They comprise a diverse group of micro-organisms that combine bacterial and eukaryotic features, but also employ many novel mechanisms. They possess a unique cell envelope with a cytoplasmic membrane of ether lipids surrounded by a proteinaceous S-layer and various cell appendages such as flagella, pili and more unusual structures. Studies have shown that the archaeal flagellum is an unique structure as it functionally resembles the bacterial flagellum, but structurally it is a simple type IV pilus. Moreover, we have shown that this type IV pilus can rotate. Therefore I propose to name the archaeal flagellum, the archaellum, as it is fundamentally different from the bacterial flagellum. In this proposal I aim to understand the assembly and mechanism of rotation of the archaellum of the thermocacidophilic crenarchaen Sulfolobus acidocaldarius by using biochemical, genetic and biophysical methods. The main milestons are: - Biochemical and structural characterization of all archaellum subunits - To understand the assembly pathway of the archaellum and the interactions of its different subunits - To understand how rotation of the filament is achieved and which subunits are important for this movement This work will identify a new, relatively simple motor complex that has evolved from primordial type IV pili assembly machineries and therefore uncover general principles of macromolecular assemblies at cellular surfaces and a novel mechanism to generate mechanical force that can be translated into movement."

1 464 317 €

Start date: 2013-02-01, End date: 2018-01-31

Globular clusters (GCs) are enigmatic objects that hide a wealth of information. They are the living fossils of the history of their native galaxies and the record keepers of the violent events that made them change their domicile. This proposal aims to mine GCs as living fossils of galaxy evolution to address fundamental questions in astrophysics: (1) Do satellite galaxies merge as predicted by the hierarchical build-up of galaxies? (2) Which are the seeds of supermassive black holes in the centres of galaxies? (3) How did star formation originate in the earliest phases of galaxy formation? To answer these questions, novel population-dependent dynamical modelling techniques are required, whose development the PI has led over the past years. This uniquely positions him to take full advantage of the emerging wealth of chemical and kinematical data on GCs. Following the tidal disruption of satellite galaxies, their dense GCs, and maybe even their nuclei, are left as the most visible remnants in the main galaxy. The hierarchical build-up of their new host galaxy can thus be unearthed by recovering the GCs’ orbits. However, currently it is unclear which of the GCs are accretion survivors. Actually, the existence of a central intermediate mass black hole (IMBH) or of multiple stellar populations in GCs might tell which ones are accreted. At the same time, detection of IMBHs is important as they are predicted seeds for supermassive black holes in galaxies; while the multiple stellar populations in GCs are vital witnesses to the extreme modes of star formation in the early Universe. However, for every putative dynamical IMBH detection so far there is a corresponding non-detection; also the origin of multiple stellar populations in GCs still lacks any uncontrived explanation. The synergy of novel techniques and exquisite data proposed here promises a breakthrough in this emerging field of dynamical archeology with GCs as living fossils of the past of galaxies.

1 999 250 €

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

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

Quantum Chaos is an emerging discipline which is crossing over from Physics into Pure Mathematics. The recent crossover is driven in part by a connection with Number Theory. This project explores several aspects of this interrelationship and is composed of a number of sub-projects. The sub-projects deal with: statistics of energy levels and wave functions of pseudo-integrable systems, a hitherto unexplored subject in the mathematical community which is not well understood in the physics community; with statistics of zeros of zeta functions over function fields, a purely number theoretic topic which is linked to the subproject on Quantum Chaos through the mysterious connections to Random Matrix Theory and an analogy between energy levels and zeta zeros; and with spatial statistics in arithmetic.

1 714 000 €

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

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