ERC FUNDED PROJECTS

The paradigm of the structure-function relationship in proteins is outdated. Biological macromolecules and supramolecular assemblies are highly dynamic objects. Evidence that their motions are of utmost importance to their functions is regularly identified. The understanding of the physical chemistry of biological processes at an atomic level has to rely not only on the description of structure but also on the characterization of molecular motions. The investigation of protein motions will be undertaken with a very innovative methodological approach in nuclear magnetic resonance relaxation. In order to widen the ranges of frequencies at which local motions in proteins are probed, we will first use and develop new techniques for a prototype shuttle system for the measurement of relaxation at low fields on a high-field NMR spectrometer. Second, we will develop a novel system: a set of low-field NMR spectrometers designed as accessories for high-field spectrometers. Used in conjunction with the shuttle, this system will offer (i) the sensitivity and resolution (i.e. atomic level information) of a high-field spectrometer (ii) the access to low fields of a relaxometer and (iii) the ability to measure a wide variety of relaxation rates with high accuracy. This system will benefit from the latest technology in homogeneous permanent magnet development to allow a control of spin systems identical to that of a high-resolution probe. This new apparatus will open the way to the use of NMR relaxation at low fields for the refinement of protein motions at an atomic scale. Applications of this novel approach will focus on the bright side of protein dynamics: (i) the largely unexplored dynamics of intrinsically disordered proteins, and (ii) domain motions in large proteins. In both cases, we will investigate a series of diverse protein systems with implications in development, cancer and immunity.

1 462 080 €

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

At the end of their life, stars spread their inner material into the diffuse interstellar medium. This diffuse medium gets locally denser and form dark clouds (also called dense or molecular clouds) whose innermost part is shielded from the external UV field by the dust, allowing for molecules to grow and get more complex. Gravitational collapse occurs inside these dense clouds, forming protostars and their surrounding disks, and eventually planetary systems like (or unlike) our solar system. The formation and evolution of molecules, minerals, ices and organics from the diffuse medium to planetary bodies, their alteration or preservation throughout this cosmic chemical history set the initial conditions for building planets, atmospheres and possibly the first bricks of life. The current view of interstellar chemistry is based on fragmental works on key steps of the sequence that are observed. The objective of this proposal is to follow the fractionation of the elements between the gas-phase and the interstellar grains, from the most diffuse medium to protoplanetary disks, in order to constrain the chemical composition of the material in which planets are formed. The potential outcome of this project is to get a consistent and more accurate description of the chemical evolution of interstellar matter. To achieve this objective, I will improve our chemical model by adding new processes on grain surfaces relevant under the diffuse medium conditions. This upgraded gas-grain model will be coupled to 3D dynamical models of the formation of dense clouds from diffuse medium and of protoplanetary disks from dense clouds. The computed chemical composition will also be used with 3D radiative transfer codes to study the chemical tracers of the physics of protoplanetary disk formation. The robustness of the model predictions will be studied with sensitivity analyses. Finally, model results will be confronted to observations to address some of the current challenges.

1 166 231 €

Start date: 2013-09-01, End date: 2018-08-31

What is responsible for the emergence of homochirality, the almost exclusive use of one enantiomer over its mirror image? And what led to the evolution of life’s homochiral biopolymers, DNA/RNA, proteins and lipids, where all the constituent monomers exhibit the same handedness? Based on in-situ observations and laboratory studies, we propose that this handedness occurs when chiral biomolecules are synthesized asymmetrically through interaction with circularly polarized photons in interstellar space. The ultimate goal of this project will be to demonstrate how the diverse set of heterogeneous enantioenriched molecules, available from meteoritic impact, assembles into homochiral pre-biopolymers, by simulating the evolutionary stages on early Earth. My recent research has shown that the central chiral unit of RNA, ribose, forms readily under simulated comet conditions and this has provided valuable new insights into the accessibility of precursors of genetic material in interstellar environments. The significance of this project arises due to the current lack of experimental demonstration that amino acids, sugars and lipids can simultaneously and asymmetrically be synthesized by a universal physical selection process. A synergistic methodology will be developed to build a unified theory for the origin of all chiral biological building blocks and their assembly into homochiral supramolecular entities. For the first time, advanced analyses of astrophysical-relevant samples, asymmetric photochemistry triggered by circularly polarized synchrotron and laser sources, and chiral amplification due to polymerization processes will be combined. Intermediates and autocatalytic reaction kinetics will be monitored and supported by quantum calculations to understand the underlying processes. A unified theory on the asymmetric formation and self-assembly of life’s biopolymers is groundbreaking and will impact the whole conceptual foundation of the origin of life.

1 500 000 €

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

The Acts of the Ecumenical Councils of Late Antiquity include (purportedly) verbatim minutes of the proceedings, a formal framework and copies of relevant documents which were either (allegedly) read out during the proceedings or which were later attached to the Acts proper. Despite this unusual wealth of documentary evidence, the daunting nature of the Acts demanding multidisciplinary competency, their complex structure with a matryoshka-like nesting of proceedings from different dates, and the stereotype that their contents bear only on Christological niceties have deterred generations of historians from studying them. Only in recent years have their fortunes begun to improve, but this recent research has not always been based on sound principles: the recorded proceedings of the sessions are still often accepted as verbatim minutes. Yet even a superficial reading quickly reveals widespread editorial interference. We must accept that in many cases the Acts will teach us less about the actual debates than about the editors who shaped their presentation. This does not depreciate the Acts’ evidence: on the contrary, they are first-rate material for the rhetoric of persuasion and self-representation. It is possible, in fact, to take the investigation to a deeper level and examine in what manner the oral proceedings were put into writing: several passages in the Acts comment upon the process of note-taking and the work of the shorthand writers. Thus, the main objective of the proposed research project could be described as an attempt to trace the destinies of the Acts’ texts, from the oral utterance to the manuscript texts we have today. This will include the fullest study on ancient transcript techniques to date; a structural analysis of the Acts’ texts with the aim of highlighting edited passages; and a careful comparison of the various editions of the Acts, which survive in Greek, Latin, Syriac and Coptic, in order to detect traces of editorial interference.

1 497 250 €

Start date: 2016-05-01, End date: 2021-04-30

"I propose a systematic study of the type of genetic variation enabling adaptation and factors that limit rates of adaptation in natural populations. New methods will be developed for analysing data from experimental evolution and population genomics. The methods will be applied to state of the art data from both fields. Adaptation is generated by natural selection sieving through heritable variation. Examples of adaptation are available from the fossil record and from extant populations. Genomic studies have supplied many instances of genomic regions exhibiting footprint of natural selection favouring new variants. Despite ample proof that adaptation happens, we know little about beneficial mutations– the raw stuff enabling adaptation. Is adaptation mediated by genetic variation pre-existing in the population, or by variation supplied de novo through mutations? We know even less about what factors limit rates of adaptation. Answers to these questions are crucial for Evolutionary Biology, but also for believable quantifications of the evolutionary potential of populations. Population genetic theory makes predictions and allows inference from the patterns of polymorphism within species and divergence between species. Yet models specifying the fitness effects of mutations are often missing. Fitness landscape models will be mobilized to fill this gap and develop methods for inferring the distribution of fitness effects and factors governing rates of adaptation. Insights into the processes underlying adaptation will thus be gained from experimental evolution and population genomics data. The applicability of insights gained from experimental evolution to comprehend adaptation in nature will be scrutinized. We will unite two very different approaches for studying adaptation. The project will boost our understanding of how selection shapes genomes and open the way for further quantitative tests of theories of adaptation."

1 159 857 €

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

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

Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not only in how long they live and when they start to senesce, but also in how they react to environmental interventions aimed at prolonging their life span or decelerating the onset of aging. Therefore, sex differences in life span and aging have important implications beyond the questions posed by fundamental science. Both evolutionary reasons and medical implications of sex differences in demographic, reproductive and physiological senescence are and will be crucial targets of present and future research in the biology of aging. Here I propose a two-step approach that can provide a significant breakthrough in our understanding of the biological basis of sex differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific mortality rate in sex differences in aging by developing a series of targeted experimental evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I address the role of intra-locus sexual conflict in the evolution of aging by combining novel methodology from nutritional ecology – the Geometric Framework – with artificial selection approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the adaptive evolution of diet choice. By combining techniques from evolutionary biology and nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to the training of young scientists in this rapidly developing field.

1 391 904 €

Start date: 2010-12-01, End date: 2016-05-31

Understanding how and why individuals develop strikingly different life histories is a major goal in evolutionary biology. It is also a prerequisite for conserving important biodiversity within species and predicting the impacts of environmental change on populations. The aim of my study is to examine a key threshold phenotypic trait (alternative migratory tactics) in a series of large scale laboratory and field experiments, integrating several previously independent perspectives from evolutionary ecology, ecophysiology and genomics, to produce a downstream predictive model. My chosen study species, the brown trout Salmo trutta, has an extensive history of genetic and experimental work and exhibits ‘partial migration’: individuals either migrate to sea (‘sea trout’) or remain in freshwater their whole lives. Recent advances in molecular parentage assignment, quantitative genetics and genomics (next generation sequencing and bioinformatics) will allow unprecedented insight into how alternative life history phenotypes are moulded by the interaction between genes and environment. To provide additional mechanistic understanding of these processes, the balance between metabolic requirements during growth and available extrinsic resources will be investigated as the major physiological driver of migratory behaviour. Together these results will be used to develop a predictive model to explore the consequences of rapid environmental change, accounting for the effects of genetics and environment on phenotype and on population demographics. In addition to their value for conservation and management of an iconic and key species in European freshwaters and coastal seas, these results will generate novel insight into the evolution of migratory behaviour generally, providing a text book example of how alternative life histories are shaped and maintained in wild populations.

1 499 202 €

Start date: 2015-05-01, End date: 2020-04-30

New neurons are continuously generated in certain regions of adult mammalian brain. One of those regions is the dentate gyrus, a subregion of hippocampus, which is essential for memory formation. Although these new neurons in the adult dentate gyrus are thought to have an important role in learning and memory, it is largely unclear how new neurons are involved in information processing and storage underlying memory. Because new neurons constitute a minor portion of intermingled local neuronal population, simple application of conventional techniques such as multi-unit extracellular recording and pharmacological lesion are not suitable for the functional analysis of new neurons. In this proposed research program, I will combine multi-unit recording and behavioral analysis with virus mediated, cell-type-specific genetic manipulation of neuronal activity, to investigate computational roles of new neurons in learning and memory. Specifically, I will determine: 1) specific memory processes that require new neurons, 2) dynamic patterns of activity that new neurons express during memory-related behavior, 3) influence of new neurons on their downstream structure. Further, based on the information obtained by these three lines of studies, we will establish causal relationship between specific memory-related behavior and specific pattern of activity in new neurons. Solving these issues will cooperatively provide important insight into the understanding of computational roles performed by adult neurogenesis. The information on the function of new neurons in normal brain could contribute to future development of efficient therapeutic strategy for a variety of brain disorders.

1 991 743 €

Start date: 2009-01-01, End date: 2013-12-31

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

1 481 375 €

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

The goal of crystal engineering is the design of functional crystalline materials in which the arrangement of basic structural building blocks imparts desired properties. The engineering of organic molecular crystals has, to date, relied largely on empirical rules governing the intermolecular association of functional groups in the solid state. However, many materials properties depend intricately on the complete crystal structure, i.e. the unit cell, space group and atomic positions, which cannot be predicted solely using such rules. Therefore, the development of computational methods for crystal structure prediction (CSP) from first principles has been a goal of computational chemistry that could significantly accelerate the design of new materials. It is only recently that the necessary advances in the modelling of intermolecular interactions and developments in algorithms for identifying all relevant crystal structures have come together to provide predictive methods that are becoming reliable and affordable on a timescale that could usefully complement an experimental research programme. The principle aim of the proposed work is to establish the use of state-of-the-art crystal structure prediction methods as a means of guiding the discovery and design of novel molecular materials. This research proposal both continues the development of the computational methods for CSP and, by developing a computational framework for screening of potential molecules, develops the application of these methods for materials design. The areas on which we will focus are organic molecular semiconductors with high charge carrier mobilities and, building on our recently published results in Nature [1], the development of porous organic molecular materials. The project will both deliver novel materials, as well as improvements in the reliability of computational methods that will find widespread applications in materials chemistry. [1] Nature 2011, 474, 367-371.

1 499 906 €

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

"During the last decade, a strikingly successful cosmological concordance model has been established. With only six free parameters, nearly all observables, comprising millions of data points, may be fitted with outstanding precision. However, in this beautiful picture a few ""blemishes"" have turned up, apparently not consistent with the standard model: While the model predicts that the universe is isotropic (i.e., looks the same in all directions) and homogeneous (i.e., the statistical properties are the same everywhere), subtle hints of the contrary are now seen. For instance, peculiar preferred directions and correlations are observed in the cosmic microwave background; some studies considering nearby galaxies suggest the existence of anomalous large-scale cosmic flows; a study of distant quasars hints towards unexpected large-scale correlations. All of these reports are individually highly intriguing, and together they hint toward a more complicated and interesting universe than previously imagined -- but none of the reports can be considered decisive. One major obstacle in many cases has been the relatively poor data quality. This is currently about to change, as the next generation of new and far more powerful experiments are coming online. Of special interest to me are Planck, an ESA-funded CMB satellite currently taking data; QUIET, a ground-based CMB polarization experiment located in Chile; and various large-scale structure (LSS) data sets, such as the SDSS and 2dF surveys, and in the future Euclid, a proposed galaxy survey satellite also funded by ESA. By combining the world s best data from both CMB and LSS measurements, I will in the proposed project attempt to settle this question: Is our universe really anisotropic? Or are these recent claims only the results of systematic errors or statistical flukes? If the claims turn out to hold against this tide of new and high-quality data, then cosmology as a whole may need to be re-written."

1 500 000 €

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

Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.

1 474 560 €

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

Tip-enhanced Raman spectroscopy (TERS) is often described as the most powerful tool for optical characterization of surfaces and their proximities. It combines the intrinsic spatial resolution of scanning probe techniques (AFM or STM) with the chemical information content of vibrational Raman spectroscopy. Capable to reveal surface heterogeneity at the nanoscale, TERS is currently playing a fundamental role in the understanding of interfacial physicochemical processes in key areas of science and technology such as chemistry, biology and material science. Unfortunately, the undeniable potential of TERS as a label-free tool for nanoscale chemical and structural characterization is, nowadays, limited to air and vacuum environments, with it failing to operate in a reliable and systematic manner in liquid. The reasons are more technical than fundamental, as what is hindering the application of TERS in water is, among other issues, the low stability of the probes and their consistency. Fields of science and technology where the presence of water/electrolyte is unavoidable, such as biology and electrochemistry, remain unexplored with this powerful technique. We propose a revolutionary approach for TERS in liquids founded on the employment of pipet-based scanning probe microscopy techniques (pb-SPM) as an alternative to AFM and STM. The use of recent but well established pb-SPM brings the opportunity to develop unprecedented pipet-based TERS probes (beyond the classic and limited metallized solid probes from AFM and STM), together with the implementation of ingenious and innovative measures to enhance tip stability, sensitivity and reliability, unattainable with the current techniques. We will be in possession of a unique nano-spectroscopy platform capable of experiments in liquids, to follow dynamic processes in-situ, addressing fundamental questions and bringing insight into interfacial phenomena spanning from materials science, physics, chemistry and biology.

1 528 442 €

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

With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance. With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation. Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.

1 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.

1 483 180 €

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

Modern telescopes like Herschel and ALMA open up a new window into molecular astrophysics to investigate a surprisingly rich chemistry that operates even at low densities and low temperatures. Observations with these instruments have the potential of unraveling key questions of astrobiology, like the accumulation of water and pre-biotic organic molecules on (exo)planets from asteroids and comets. Hand-in-hand with the heightened observational activities comes a strong demand for a thorough understanding of the molecular formation mechanisms. The vast majority of interstellar molecules are formed in ion-neutral reactions that remain efficient even at low temperatures. Unfortunately, the unusual nature of these processes under terrestrial conditions makes their laboratory study extremely difficult. To address these issues, I propose to build a versatile merged beams setup for laboratory studies of ion-neutral collisions at the Cryogenic Storage Ring (CSR), the most ambitious of the next-generation storage devices under development worldwide. With this experimental setup, I will make use of a low-temperature and low-density environment that is ideal to simulate the conditions prevailing in interstellar space. The cryogenic surrounding, in combination with laser-generated ground state atom beams, will allow me to perform precise energy-resolved rate coefficient measurements for reactions between cold molecular ions (like, e.g., H2+, H3+, HCO+, CH2+, CH3+, etc.) and neutral atoms (H, D, C or O) in order to shed light on long-standing problems of astrochemistry and the formation of organic molecules in space. With the large variability of the collision energy (corresponding to 40-40000 K), I will be able to provide data that are crucial for the interpretation of molecular observations in a variety of objects, ranging from cold molecular clouds to warm layers in protoplanetary disks.

1 486 800 €

Start date: 2012-09-01, End date: 2017-11-30

Which molecules are present in the atmosphere of exoplanets? What are their mass, radius and age? Do they have clouds, convection (atmospheric turbulence), fingering convection, or a circulation induced by irradiation? These questions are fundamental in exoplanetology in order to study issues such as planet formation and exoplanet habitability. Yet, the impact of fingering convection and circulation induced by irradiation remain poorly understood: - Fingering convection (triggered by gradients of mean-molecular-weight) has already been suggested to happen in stars (accumulation of heavy elements) and in brown dwarfs and exoplanets (chemical transition e.g. CO/CH4). A large-scale efficient turbulent transport of energy through the fingering instability can reduce the temperature gradient in the atmosphere and explain many observed spectral properties of brown dwarfs and exoplanets. Nonetheless, this large-scale efficiency is not yet characterized and standard approximations (Boussinesq) cannot be used to achieve this goal. - The interaction between atmospheric circulation and the fingering instability is an open question in the case of irradiated exoplanets. Fingering convection can change the location and magnitude of the hot spot induced by irradiation, whereas the hot deep atmosphere induced by irradiation can change the location of the chemical transitions that trigger the fingering instability. This project will characterize the impact of fingering convection in the atmosphere of stars, brown dwarfs, and exoplanets and its interaction with the circulation in the case of irradiated planets. By developing innovative numerical models, we will characterize the reduction of the temperature gradient of the atmosphere induced by the instability and study the impact of the circulation. We will then predict and interpret the mass, radius, and chemical composition of exoplanets that will be observed with future missions such as the James Webb Space Telescope (JWST).

1 500 000 €

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

"The goal of the present proposal is to realize measurements of electronic dynamics in polyatomic molecules with attosecond temporal resolution (1 as = 10^-18s). We propose to study electronic rearrangements following photoexcitation, charge migration in a molecular chain induced by ionization and non-adiabatic multi-electron dynamics in an intense laser field. The grand question addressed by this research is the characterization of electron correlations which control the shape, properties and function of molecules. In all three proposed projects, a time-domain approach appears to be the most suitable since it reduces complex molecular dynamics to the purely electronic dynamics by exploiting the hierarchy of motional time scales. Experimentally, we propose to realize an innovative experimental setup. A few-cycle infrared (IR) pulse will be used to generate attosecond pulses in the extreme-ultraviolet (XUV) by high-harmonic generation. The IR pulse will be separated from the XUV by means of an innovative interferometer. Additionally, it will permit the introduction of a controlled attosecond delay between the two pulses. We propose to use the attosecond pulses as a tool to look inside individual IR- or UV-field cycles to better understand light-matter interactions. Time-resolved pump-probe experiments will be carried out on polyatomic molecules by detecting the energy and angular distribution of photoelectrons in a velocity-map imaging spectrometer. These experiments are expected to provide new insights into the dynamics of multi-electron systems along with new results for the validation and improvement of theoretical models. Multi-electron dynamics is indeed a very complex subject on its own and even more so in the presence of strong laser fields. The proposed experiments directly address theses challenges and are expected to provide new insights that will be beneficial to a wide range of scientific research areas."

1 999 992 €

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

The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.

1 618 750 €

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

The role of intestinal bacteria in human health and disease has been intensively studied; however the viral composition of the microbiome, the virome, remains largely unknown. As many of the viruses are bacteriophages, they are expected to be a major factor shaping the human microbiome. The dynamics of the virome during early life, its interaction with host and environmental factors, is likely to have profound effects on human physiology. Therefore it is extremely timely to study the virome in depth and on a wide scale. This ERC project aims at understanding how the gut virome develops during the first year of life and how that relates to the composition of the bacterial microbiome. In particular, we will determine which intrinsic and environmental factors, including genetics and the mother’s microbiome and diet, interact with the virome in shaping the early gut microbiome ecosystem. In a longitudinal study of 1,000 newborns followed at 7 time points from birth till age 12 months, I will investigate: (1) the composition and evolution of the virome and bacterial microbiome in the first year of life; (2) the role of factors coming from the mother and from the host genome on virome and bacterial microbiome development and their co-evolution; and (3) the role of environmental factors, like infectious diseases, vaccinations and diet habits, on establishing the virome and overall microbiome composition during the first year of life. This project will provide crucial knowledge about composition and maturation of the virome during the first year of life, and its symbiotic relation with the bacterial microbiome. This longitudinal dataset will be instrumental for identification of microbiome markers of diseases and for the follow up analysis of the long-term effect of microbiota maturation later in life. Knowledge of the role of viruses in shaping the microbiota may promote future directions for manipulating the human gut microbiota in health and disease.

1 499 881 €

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

Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.

1 499 869 €

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

Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes. The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD. In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery. I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.

1 499 354 €

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

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

Start date: 2013-10-01, End date: 2018-09-30

Learning from others is fundamental to ecological success across the animal kingdom, but a key theme to emerge from recent research is that individuals respond differently to social information. Understanding this diversity is an imposing challenge, because it is hard to replicate the overwhelming complexity of free-living groups within controlled laboratory conditions. Yet here I propose that one of the most complex social models that we know of— the sophisticated eusocial societies of honeybees— offer unrivaled and yet unrecognized potential to study social information flow through a natural group. The honeybee “dance language” is one of the most celebrated communication systems in the animal world, and central to a powerful information network that drives our most high-profile pollinator to food, but bee colonies are uniquely tractable for two reasons. Firstly, next-generation transcriptomics could allow us to delve deep into this complexity at the molecular level, on a scale that is simply not available in vertebrate social systems. I propose to track information flow through a natural group using brain gene expression profiles, to understand how dances elicit learning in the bee brain. Secondly, although bee foraging ranges are vast and diverse, social learning takes place in one centralized location (the hive). The social sciences now offer powerful new tools to analyze social networks, and I will use a cutting-edge network-based modelling approach to understand how the importance of social learning mechanisms shifts with ecology. In the face of global pollinator decline, understanding the contribution of foraging drivers to colony success has never been more pressing, but the importance of the dance language reaches far beyond food security concerns. This research integrates proximate and ultimate perspectives to produce a comprehensive, multi-disciplinary program; a high-risk, high-gain journey into new territory for understanding animal communication.

1 422 010 €

Start date: 2016-02-01, End date: 2021-01-31

A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.

1 445 000 €

Start date: 2010-09-01, End date: 2015-08-31

This project investigates the cross-fertilisation of Anglo/American and German literature and film during the Allied Occupation of Germany. It will be the first study to survey the cultural landscape of the British and American zones of Occupied Germany in any detail. By doing so it will offer a new interpretative framework for postwar culture, in particular in three areas: the history of the Allied Occupation of Germany; the history of postwar Anglophone and Germanophone literature (arguing the two were more intertwined than has previously been suggested); and the history of the relationship between postwar and Cold War. Combining Anglo-American and German literature and film history with critical analysis, cultural history and life-writing, this is a necessarily ambitious, multidisciplinary study which will open up a major new field of research.

1 414 601 €

Start date: 2013-09-01, End date: 2019-02-28

Epidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. The recent swine-derived influenza A/H1N1 pandemic may represent a tipping point in this trend, as it is arguably the first time when multiple strains of a human pathogen have been sequenced essentially in real time from the very beginning of its spread. However, the full potential of genetic information cannot be fully exploited to infer the spread of epidemics due to the lack of statistical methodologies capable of reconstructing transmission routes from genetic data structured both in time and space. To address this urgent need, we propose to develop a methodological framework for the reconstruction of the spatiotemporal dynamics of disease outbreaks and epidemics based on genetic sequence data. Rather than reconstructing most recent common ancestors as in phylogenetics, we will directly infer the most likely ancestries among the sampled isolates. This represents an entirely novel paradigm and allows for the development of statistically coherent and powerful inference software within a Bayesian framework. The methodological framework will be developed in parallel with the analysis of real genetic/genomic data from important human pathogens. We will in particular focus on the 2009 A/H1N1 pandemic influenza, methicilin-resistant Staphylococcus aureus clones (MRSAs), Batrachochytrium dendrobatidis, a fungus currently devastating amphibian populations worldwide. The tools we are proposing to develop are likely to impact radically on the field of infectious disease epidemiology and affect the way infectious emerging pathogens are monitored by biologists and public health professionals.

1 483 080 €

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

Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012). I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work. This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.

1 926 634 €

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

Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology’s regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.

1 887 180 €

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

Biofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance.

1 494 963 €

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

Graphene – a one atom thin material – has the potential to act as a sensor, primarily the surface and the edges of graphene. This proposal aims at exploring new biosensing routes by exploiting the unique surface and edge chemistry of graphene.

1 499 996 €

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

This project will focus on the use of nanoporous metal organic frameworks (Fe, Zn, Ti) for bioapplications. These systems are exciting porous solids, built up from inorganic clusters and polycarboxylates. This results in open-framework solids with different pore shapes and dimensions, and applications such as catalysis, separation and storage of gases. I have recently initiated the synthesis of new trivalent transition metal carboxylates. Among them, the metal carboxylates MIL-100 and MIL-101 (MIL: Materials of Institut Lavoisier) are spectacular solids with giant pores (25-34 Å), accessible metal sites and huge surface areas (3100-5900 m2.g-1). Recently, it was shown that these solids could be used for drug delivery with a loading of 1.4 g of Ibuprofen per gram of MIL-101 solid and a total release in six days. This project will concentrate on the implication of MOFs for drug release and other bioapplications. Whereas research on drug delivery is currently focused either on the use of bio-compatible polymers or mesoporous materials, our method will combine advantages of both routes including a high loading and a slow release of therapeutic molecules. A second application will use solids with accessible metal sites to coordinate NO for its controlled delivery. This would provide exogenous NO for prophylactic and therapeutic processes, anti-thrombogenic medical devices, improved dressings for wounds and ulcers, and the treatment of fungal and bacterial infections. Finally, other applications will be envisaged such as the purification of physiological fluids. The project, which will consist of a systematic study of the relation between these properties and both the composition and structure of the hybrid solids, will be assisted by a strong modelling effort including top of the art computational methods (QSAR and QSPKR). This highly impact project will be realised by assembling experienced researchers in multidisplinary areas including materials science, biology and modelling. It will involve P. Horcajada (Institut Lavoisier), whose background in pharmaceutical science will fit with my experience in inorganic chemistry and G. Maurin (Institut Gerhardt, Montpellier) expert in computational chemistry.

1 250 000 €

Start date: 2008-06-01, End date: 2013-05-31

Primary energy conversion in nature is powered by highly efficient enzymes that capture chemical or light energy and transduce it into other energy forms. These processes are catalyzed by coupled transfers of protons and electrons (PCET), but their fundamental mechanistic principles are not well understood. In order to obtain a molecular-level understanding of the functional elements powering biological energy conversion processes, we will study the catalytic machinery of one of the largest and most intricate enzymes in mitochondria and bacteria, the respiratory complex I. This gigantic redox-driven proton-pump functions as the entry point for electrons into aerobic respiratory chains, and it employs the energy released from a chemical reduction process to transport protons up to 200 Å away from its active site. Its molecular structure from bacteria and eukaryotes was recently resolved, but the origin of this remarkable action-at-a-distance effect still remains unclear. We employ and develop multi-scale quantum and classical molecular simulation techniques in combination with de novo-protein design methodology to identify and isolate the functional elements that catalyze the long-range PCET reactions in complex I. To fully understand the natural PCET-elements, we will further engineer central parts of this machinery into artificial protein frameworks, with the goal of designing modules for redox-driven proton pumps from first principles. The project aims to establish a fundamental understanding of nature's toolbox of catalytic elements, to elucidate how the complex biochemical environment contributes to the catalytic effects, and to provide blueprints that can guide the design of man-made enzymes for sustainable energy technology.

1 494 368 €

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

The standard variational principles (VPs) are cornerstones of quantum mechanics, and one can hardly overestimate their usefulness as tools for generating approximations to the time-independent and time-dependent Schröodinger equations. The aim of the proposal is to study and apply a generalization of these, the bivariational principles (BIVPs), which arise naturally when one does not assume a priori that the system Hamiltonian is Hermitian. This unconventional approach may have transformative impact on development of ab initio methodology, both for electronic structure and dynamics. The first objective is to establish the mathematical foundation for the BIVPs. This opens up a whole new axis of method development for ab initio approaches. For instance, it is a largely ignored fact that the popular traditional coupled cluster (TCC) method can be neatly formulated with the BIVPs, and TCC is both polynomially scaling with the number of electrons and size-consistent. No “variational” method enjoys these properties simultaneously, indeed this seems to be incompatible with the standard VPs. Armed with the BIVPs, the project aims to develop new and understand existing ab initio methods. The second objective is thus a systematic multireference coupled cluster theory (MRCC) based on the BIVPs. This is in itself a novel approach that carries large potential benefits and impact. The third and last objective is an implementation of a new coupled-cluster type method where the orbitals are bivariational parameters. This gives a size-consistent hierarchy of approximations to multiconfiguration Hartree--Fock. The PI's broad contact with and background in scientific disciplines such as applied mathematics and nuclear physics in addition to quantum chemistry increases the feasibility of the project.

1 499 572 €

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

Spectroscopic binary stars (SB2s) and in particular spectroscopic eclipsing binaries are one of the most useful objects in astrophysics. Their photometric and spectroscopic observations allow one to determine basic parameters of stars and carry out a wide range of tests of stellar structure, evolution and dynamics. Perhaps somewhat surprisingly, they can also contribute to our understanding of the formation and evolution of (extrasolar) planets. We will study eclipsing binary stars by combining the classic - stellar astronomy - and the modern - extrasolar planets - subjects into a cutting edge project. We propose to search for and subsequently characterize circumbinary planets around ~350 eclipsing SB2s using our own novel cutting edge radial velocity technique for binary stars and a modern version of the photometry based eclipse timing of eclipsing binary stars employing 0.5-m robotic telescopes. We will also derive basic parameters of up to ~700 stars (~350 binaries) with an unprecedented precision. In particular for about 50% of our sample we expect to deliver masses of the components with an accuracy ~10-100 times better than the current state of the art. Our project will provide unique constraints for the theories of planet formation and evolution and an unprecedented in quality set of the basic parameters of stars to test the theories of the stellar structure and evolution.

1 500 000 €

Start date: 2010-12-01, End date: 2016-11-30

How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

909 850 €

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

More than 30 million people are living with diabetes in the EU, with a prevalence expected to grow to over 10% of the adult population by the year 2030. Type 2 diabetes is a major cause of cardiovascular disease related death and disability, substantially increasing the risk of myocardial infarction, stroke and peripheral arterial disease. Recent landmark trials, showing that intensive glucose control does not improve cardiovascular outcomes and may increase mortality in some circumstances, provide a compelling rationale for intense research aimed at developing novel therapeutic strategies. Type 2 diabetes is underpinned by resistance to the effects of insulin, which I have shown in endothelial cells causes reduced bioavailability of the anti-atherosclerotic molecule nitric oxide and leads to accelerated atherosclerosis. The cellular effects of insulin are mirrored by insulin-like growth factor factor-1, the bioavailability of which at its receptor is in turn is regulated by a family of high affinity binding proteins (IGFBP). Epidemiological studies demonstrate and inverse association between one of these binding proteins, IGFBP1, and diabetes-related cardiovascular risk. I have recently demonstrated that IGFBP1 when expressed in mice can ameliorate insulin resistance, obesity and atherosclerosis. In endothelial cells, I showed that IGFBP1 upregulates the production of nitric oxide indepenedently of IGF. These findings suggest that IGFBP1 may be a ‘protective’ endogenous protein and that increasing circulating levels may be a therapeutic strategy to prevent development of diabetes and cardiovascular disease. In this proposal I will address this hypothesis by employing state of the art studies in cells and novel gene modified mice to unravel the molecular basis of the protective effects of IGFBP1 and to investigate the possibility of exploiting the IGF-IGFBP axis to prevent cardiovascular disease in the setting of diabetes and obesity.

1 493 543 €

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

"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."

1 750 000 €

Start date: 2008-08-01, End date: 2013-07-31

Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.

1 552 620 €

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

Combinatorial Computational Chemistry is developed as a standard tool to tackle complex problems in chemistry and materials science. The method employs a series of state-of-the-art methods, ranging from empirical molecular mechanics to first principles calculations, as well as of mathematical (graph theoretical and combinatorial) methods. The process is similar as in experimental combinatorial chemistry: First, a large set of candidate structures is generated which is complete in the sense that the best possible structure for a particular purpose must be found among the set. This structure is then identified using computational chemistry. We will apply methodologies at different stages in hierarchical order and successively screen the set of candidate structures. Screening criteria are based on the computer simulations and include geometry, stability and properties of the candidate structures. Detailed characteristics of the final materials will be simulated, including the X-ray diffraction pattern, the electronic structure, and the target properties. We will apply C3 to two important problems of environmental science. (i) We will optimise nanoporous materials to act as molecular sieves to separate water from ethanol, an important task for the production of biofuels. Here, materials are optimised to transport ethanol, but not water (or vice versa). The tuning parameters are the channel size of the material and its polarity. (ii) We will optimise nanoporous materials to transport protons, an important task for the design of energy-efficient fuel cells, by distributing flexible functional groups, acting as hopping sites for the protons, in the framework.

1 500 000 €

Start date: 2011-02-01, End date: 2016-04-30

Constructing Age for Young Readers (CAFYR) CAFYR starts from the observations that Europe has recently witnessed a few pertinent crises in intergenerational tension, that age norms and ageism frequently go unchecked and that they are part of children’s socialization. It aims at developing pioneering research for understanding how age is constructed in cultural products. CAFYR focuses on fiction for young readers as a discourse that often naturalizes age norms as part of an engaging story and that is endorsed in educational contexts for contributing to children’s literacy, social and cultural development. The effect of three factors on the construction of age in children’s books is studied: the age of the author, the age of the intended reader, and the age of the real reader. CAFYR aims to lay bare whether and how the age and aging process of children’s authors affect their construction of the life stages in their works. It will show how various crosswriters shape the stages in life differently for young and adult readers. It considers the age of young readers as varied in its own right, and investigates how age is constructed differently for children of different ages, from preschoolers to adolescents. Finally, it brings together readers of various stages in the life course in a reception study that will help understand how real readers construct age, during the reading process and in dialogue with each other. CAFYR also aims to break new theoretical and methodological ground. It offers an interdisciplinary approach that enriches children’s literature research with concepts and theories from age studies. It combines close reading strategies with distant reading and tools developed for digital text analysis. It provides a platform to people of different stages in life, contributing to their awareness about age, and facilitating and investigating dialogues about age, with the aim of ultimately fostering them more.

1 400 885 €

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

What did politicians sound like before they were on the radio and television? The fascination with politicians’ vocal characteristics and quirks is often connected to the rise of audio-visual media. But in the age of the printed press, political representatives also had to ‘speak well’ – without recourse to amplification. Historians and linguists have provided sophisticated understandings of the discursive and aesthetic aspects of politicians’ language, but have largely ignored the importance of the acoustic character of their speech. CALLIOPE studies how vocal performances in parliament have influenced the course of political careers and political decision making in the 19th century. It shows how politicians’ voices helped to define the diverse identities they articulated. In viewing parliament through the lens of audibility, the project offers a new perspective on political representation by reframing how authority was embodied (through performances that were heard, rather than seen). It does so for the Second Chamber in Britain and France, and in dialogue with ‘colonial’ modes of speech in Kolkata and Algiers, which, we argue, exerted considerable influence on European vocal culture. The project devises an innovative methodological approach to include the sound of the human voice in studies of the past that precede acoustic recording. Adapting methods developed in sound studies and combining them with the tools of political history, the project proposes a new way to analyse parliamentary reporting, while also drawing on a variety of sources that are rarely connected to the history of politics. The main source material for the study comprise transcripts of parliamentary speech (official reports and renditions by journalists). However, the project also mobilizes educational, satirical and fictional sources to elucidate the convoluted processes that led to the cultivation, exertion, reception and evaluation of a voice ‘fit’ for nineteenth-century politics.

1 499 905 €

Start date: 2018-03-01, End date: 2023-02-28

This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.

1 497 000 €

Start date: 2011-03-01, End date: 2017-02-28

Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited. The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands. The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.

1 500 000 €

Start date: 2016-04-01, End date: 2021-03-31

The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.

1 498 686 €

Start date: 2013-11-01, End date: 2019-10-31

This project proposes an analysis of the reconfigurations established in the socio-political vocabulary of the western Saharan region – southern Morocco, Western Sahara and Mauritania – from the “post-empire” to the contemporary period. The project should produce an analysis of 1) the social and political structures shared in the region, 2) the local variations of those structures, based on case studies, 3) their specific configurations, based on social markers such as gender, age, and class, 4) the use of those structures in different historical periods. All these will be under theoretical and ethnographic scrutiny in order to achieve its main goal: 5) to understand the recent articulation of the social and political structures of the Western Saharan region, with broader and often exogenous political vocabularies. The methodology used in this project is based on readings associated with different social sciences, with a particular focus on anthropology, history, and political science. The members of the research team, with experience and linguistic competence in the different geographies involved in this project, are expected to conduct original field enquiries, enabling a significant enhancement of the theoretical and ethnographic knowledge associated with this region. The project’s main goal is to analyse the types of interplay established between pre-modern socio-political traditions and contemporary political expression and activism, in a particularly sensitive – and academically disregarded – region. Its effort to integrate a context that is usually compartmentalized, as well as to put together a group of researchers generally “isolated” in their particular areas of expertise, geographies, or nations, should also be valued. The project’s results should enable the different contexts under study to be integrated into the wider maps of current scientific research, providing, at the same time a dissemination of its outputs to an extended audience.

1 192 144 €

Start date: 2017-04-01, End date: 2021-03-31

The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes. These include mutations leading to: (1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes; (2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and (3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties. These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies. Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside

1 500 000 €

Start date: 2011-03-01, End date: 2016-02-29

In the epoch of Gaia, fundamental stellar properties will be made widely available for large numbers of stars. These properties are expected to unleash a new wave of discovery in the field of astrophysics. But while many properties of stars are measurable, meaningful Helium abundances (Y) remain elusive and as a result fundamental properties are not accurate. Helium enrichment laws, which underpin most stellar properties, link initial Y to initial metallicity, but these relations are very uncertain with gradients (dY/dZ) spanning the range 1 to 3. This uncertainty is the initial Y problem and this is a bottleneck that must be overcome to unleash the true potential of Gaia. Without measurements of initial Y for all stars we need to find alternative observables that trace out the evolution of initial Y. We will search for better tracers using the power of asteroseismology as a calibrator. Asteroseismic measures of Helium will be used to construct a map from observable properties (fundamental, chemical or even dynamical) back to initial Helium. This is a challenge that can only be solved through the use of the latest asteroseismic techniques coupled to a rigorous yet flexible statistical scheme. I am uniquely qualified in the cutting edge methods of asteroseismology and the application of advanced multi-level statistical models. The intersection of these two skill sets will allow me to solve the initial Helium problem. The motivation for a timely solution to this problem could not be stronger. We have just entered an age of large asteroseismic datasets, vast spectroscopic surveys, and the billion star program of Gaia. The next wave of scientific breakthroughs in stellar physics, exoplanetary science, and Galactic archeology will be held back unless accurate fundamental stellar properties are available. We can only produce these accurate properties with a reliable map of stellar Helium.

1 496 203 €

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