ERC FUNDED PROJECTS

"Electrical motors consume about 40 % of the electrical energy produced in the European Union. About 90 % of this energy is converted to mechanical work. However, 0.5-2.5 % of it goes to so called additional load losses whose exact origins are unknown. Our ambitious aim is to reveal the origins of these losses, build up numerical tools for modeling them and optimize electrical motors to minimize the losses. As the hypothesis of the research, we assume that the additional losses mainly result from the deterioration of the core materials during the manufacturing process of the machine. By calorimetric measurements, we have found that the core losses of electrical machines may be twice as large as comprehensive loss models predict. The electrical steel sheets are punched, welded together and shrink fit to the frame. This causes residual strains in the core sheets deteriorating their magnetic characteristics. The cutting burrs make galvanic contacts between the sheets and form paths for inter-lamination currents. Another potential source of additional losses are the circulating currents between the parallel strands of random-wound armature windings. The stochastic nature of these potential sources of additional losses puts more challenge on the research. We shall develop a physical loss model that couples the mechanical strains and electromagnetic losses in electrical steel sheets and apply the new model for comprehensive loss analysis of electrical machines. The stochastic variables related to the core losses and circulating-current losses will be discretized together with the temporal and spatial discretization of the electromechanical field variables. The numerical stochastic loss model will be used to search for such machine constructions that are insensitive to the manufacturing defects. We shall validate the new numerical loss models by electromechanical and calorimetric measurements."

2 489 949 €

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

The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity. To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles. This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.

2 462 154 €

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

Most of the technological materials have been developed by very expensive and cumbersome trial and error methods. On the other hand, computer based theoretical design of advanced materials is an area where rapid and extensive developments are taking place. Within my group new theoretical tools have now been established which are extremely well suited to the study of complex materials. In this approach basic quantum mechanical theories are used to describe fundamental properties of alloys and compounds. The utilization of such calculations to investigate possible optimizations of certain key properties represents a major departure from the traditional design philosophy. The purpose of my project is to build up a new competence in the field of computer-aided simulations of advanced materials. The main goal will be to achieve a deep understanding of the behaviour of complex metallic systems under equilibrium and non-equilibrium conditions at the atomic level by studying their electronic, magnetic and atomic structure using the most modern and advanced computational methods. This will enable us to establish a set of materials parameters and composition-structure-property relations that are needed for materials optimization. The research will be focused on fundamental technological properties related to defects in advanced metallic alloys (high-performance steels, superalloys, and refractory, energy related and geochemical materials) and alloy phases (solid solutions, intermetallic compounds), which will be studied by means of parameter free atomistic simulations combined with continuum modelling. As a first example, we will study the Fe-Cr system, which is of great interest to industry as well as in connection to nuclear waste. The Fe-Cr-Ni system will form another large group of materials under the aegis of this project. Special emphasis will also be placed on those Fe-alloys which exist under extreme conditions and are possible candidates for the Earth core.

2 000 000 €

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

This proposal targets the emerging frontier research field of multiple-input multiple-output (MIMO) systems along with several innovative and somewhat unconventional applications of such systems. The use of arrays of transmitters and receivers will have a profound impact on future medical imaging/therapy systems, radar systems, and radio communication networks. Multiple transmitters provide a tremendous versatility and allow waveforms to be adapted temporally and spatially to environmental conditions. This is useful for individually tailored illumination of human tissue in biomedical imaging or ultrasound therapy. In radar systems, multiple transmit beams can be formed simultaneously via separate waveform designs allowing accurate target classification. In a wireless communication system, multiple communication signals can be directed to one or more users at the same time on the same frequency carrier. In addition, multiple receivers can be used in the above applications to provide increased detection performance, interference rejection, and improved estimation accuracy. The joint modelling, analysis, and design of these multidimensional transmit and receive schemes form the core of this research proposal. Ultimately, our research aims at developing the fundamental tools that will allow the design of wireless communication systems with an order-of-magnitude higher capacity at a lower cost than today; of ultrasound therapy systems maximizing delivered power while reducing treatment duration and unwanted illumination; and of distributed aperture multi-beam radars allowing more effective target location, identification, and classification. Europe has several successful industries that are active in biomedical imaging/therapy, radar systems, and wireless communications. The future success of these sectors critically depends on the ability to innovate and integrate new technology.

1 872 720 €

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

Understanding the molecular mechanisms underlying adipose blood vessel growth or regression opens new fundamentally insight into novel therapeutic options for the treatment of obesity and its related metabolic diseases such as type 2 diabetes and cancer. Unlike any other tissues in the body, the adipose tissue constantly experiences expansion and shrinkage throughout the adult life. Adipocytes in the white adipose tissue have the ability to switch into metabolically highly active brown-like adipocytes. Brown adipose tissue (BAT) contains significantly higher numbers of microvessels than white adipose tissue (WAT) in order to adopt the high rates of metabolism. Thus, an angiogenic phenotype has to be switched on during the transition from WAT into BAT. We have found that acclimation of mice in cold could induce transition from inguinal and epidedymal WAT into BAT by upregulation of angiogenic factor expression and down-regulations of angiogenesis inhibitors (Xue et al, Cell Metabolism, 2009). The transition from WAT into BAT is dependent on vascular endothelial growth factor (VEGF) that primarily targets on vascular endothelial cells via a tissue hypoxia-independent mechanism. VEGF blockade significantly alters adipose tissue metabolism. In another genetic model, we show similar findings that angiogenesis is crucial to mediate the transition from WAT into BAT (Xue et al, PNAS, 2008). Here we propose that the vascular tone determines the metabolic switch between WAT and BAT. Characterization of these novel angiogenic pathways may reveal new mechanisms underlying development of obesity- and metabolism-related disease complications and may define novel therapeutic targets. Thus, the benefit of this research proposal is enormous and is aimed to treat the most common and highly risk human health conditions in the modern time.

2 411 547 €

Start date: 2010-03-01, End date: 2015-02-28

Since their discovery, Quantum Hall Effects have unfolded intriguing avenues of research, exhibiting a multitude of unexpected exotic states: accurate quantized conductance states; particle-like and hole-conjugate fractional states; counter-propagating charge and neutral edge modes; and fractionally charged quasiparticles - abelian and (predicted) non-abelian. Since the sought-after anyonic statistics of fractional states is yet to be verified, I propose to launch a thorough search for it employing new means. I believe that our studies will serve the expanding field of the emerging family of topological materials. Our on-going attempts to observe quasiparticles (qp’s) interference, in order to uncover their exchange statistics (under ERC), taught us that spontaneous, non-topological, ‘neutral edge modes’ are the main culprit responsible for qp’s dephasing. In an effort to quench the neutral modes, we plan to develop a new class of micro-size interferometers, based on synthetically engineered fractional modes. Flowing away from the fixed physical edge, their local environment can be controlled, making it less hospitable for the neutral modes. Having at hand our synthetized helical-type fractional modes, it is highly tempting to employ them to form localize para-fermions, which will extend the family of exotic states. This can be done by proximitizing them to a superconductor, or gapping them via inter-mode coupling. The less familiar thermal conductance measurements, which we recently developed (under ERC), will be applied throughout our work to identify ‘topological orders’ of exotic states; namely, distinguishing between abelian and non-abelian fractional states. The proposal is based on an intensive and continuous MBE effort, aimed at developing extremely high purity, GaAs based, structures. Among them, structures that support our new synthetic modes that are amenable to manipulation, and others that host rare exotic states, such as v=5/2, 12/5, 19/8, and 35/16.

1 801 094 €

Start date: 2019-05-01, End date: 2024-10-31

The proposed project aims to create a center of excellence that aims at understanding the approximability of NP-hard optimization problems. In particular, for central problems like vertex cover, coloring of graphs, and various constraint satisfaction problems we want to study upper and lower bounds on how well they can be approximated in polynomial time. Many existing strong results are based on what is known as the Unique Games Conjecture (UGC) and a significant part of the project will be devoted to studying this conjecture. We expect that a major step needed to be taken in this process is to further develop the understanding of Boolean functions on the Boolean hypercube. We anticipate that the tools needed for this will come in the form of harmonic analysis which in its turn will rely on the corresponding results in the analysis of functions over the domain of real numbers.

2 376 000 €

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

Our aim is to provide a theoretical framework for studies of dynamical aspects of magnetic materials and magnetisation reversal, which has potential for applications for magnetic data storage and magnetic memory devices. The project focuses on developing and using an atomistic spin dynamics simulation method. Our goal is to identify novel materials and device geometries with improved performance. The scientific questions which will be addressed concern the understanding of the fundamental temporal limit of magnetisation switching and reversal, and the mechanisms which govern this limit. The methodological developments concern the ability to, from first principles theory, calculate the interatomic exchange parameters of materials in general, in particular for correlated electron materials, via the use of dynamical mean-field theory. The theoretical development also involves an atomistic spin dynamics simulation method, which once it has been established, will be released as a public software package. The proposed theoretical research will be intimately connected to world-leading experimental efforts, especially in Europe where a leading activity in experimental studies of magnetisation dynamics has been established. The ambition with this project is to become world-leading in the theory of simulating spin-dynamics phenomena, and to promote education and training of young researchers. To achieve our goals we will build up an open and lively environment, where the advances in the theoretical knowledge of spin-dynamics phenomena will be used to address important questions in information technology. In this environment the next generation research leaders will be fostered and trained, thus ensuring that the society of tomorrow is equipped with the scientific competence to tackle the challenges of our future.

2 130 000 €

Start date: 2010-01-01, End date: 2014-12-31

"This project will develop the use of relict, extraterrestrial minerals in Archean to Cenozoic slowly formed sediments as tracers of events in the solar system and cosmos, and to decipher the possible relation between such events and evolution of life and environmental change on Earth. There has been consensus that it would not be possible to reconstruct variations in the flux of different types of meteorites to Earth through the ages. Meteorite falls are rare and meteorites weather and decay rapidly on the Earth surface. However, the last years we have developed the first realistic approach to circumvent these problems. Almost all meteorite types contain a small fraction of spinel minerals that survives weathering and can be recovered from large samples of condensed sediments of any age. Inside the spinels we can locate by synchrotron-light X-ray tomography 1-30 micron sized inclusions of most of the other minerals that made up the original meteorite. With cutting-edge frontier microanalyses such as Ne-21 (solar wind, galactic rays), oxygen isotopes (meteorite group and type) and cosmic ray tracks (supernova densities) we will be able to unravel from the geological record fundamental new information about the solar system at specific times through the past 3.8 Gyr. Variations in flux and types of meteorites may reflect solar-system and galaxy gravity disturbances as well as the sequence of disruptions of the parent bodies for meteorite types known and not yet known. Cosmic-ray tracks in spinels may identify the galactic year (230 Myr) in the geological record. For the first time it will be possible to systematically relate major global biotic and tectonic events, changes in sea-level, climate and asteroid and comet impacts to what happened in the larger astronomical realm. In essence, the project is a robust approach to establish a pioneer ""astrostratigraphy"" for Earth's geological record, complementing existing bio-, chemo-, and magnetostratigraphies."

1 950 000 €

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

Atmospheric Gas-to-Particle conversion (ATM-GTP) is a 5-year project focusing on one of the most critical atmospheric processes relevant to global climate and air quality: the first steps of atmospheric aerosol particle formation and growth. The project will concentrate on the currently lacking environmentally-specific knowledge about the interacting, non-linear, physical and chemical atmospheric processes associated with nano-scale gas-to-particle conversion (GTP). The main scientific objective of ATM-GTP is to create a deep understanding on atmospheric GTP taking place at the sub-5 nm size range, particularly in heavily-polluted Chinese mega cities like Beijing and in pristine environments like Siberia and Nordic high-latitude regions. We also aim to find out how nano-GTM is associated with air quality-climate interactions and feedbacks. We are interested in quantifying the effect of nano-GTP on the COBACC (Continental Biosphere-Aerosol-Cloud-Climate) feedback loop that is important in Arctic and boreal regions. Our approach enables to point out the effective reduction mechanisms of the secondary air pollution by a factor of 5-10 and to make reliable estimates of the global and regional aerosol loads, including anthropogenic and biogenic contributions to these loads. We can estimate the future role of Northern Hemispheric biosphere in reducing the global radiative forcing via the quantified feedbacks. The project is carried out by the world-leading scientist in atmospheric aerosol science, being also one of the founders of terrestrial ecosystem meteorology, together with his research team. The project uses novel infrastructures including SMEAR (Stations Measuring Ecosystem Atmospheric Relations) stations, related modelling platforms and regional data from Russia and China. The work will be carried out in synergy with several national, Nordic and EU research-innovation projects: Finnish Center of Excellence-ATM, Nordic CoE-CRAICC and EU-FP7-BACCHUS.

2 500 000 €

Start date: 2017-06-01, End date: 2022-05-31

Gauge theories play a central role in particle and condensed matter physics. Heavy-ion collisions explore the strong dynamics of quarks and gluons, which also governs the deep interior of neutron stars, while strongly correlated electrons determine the physics of high-temperature superconductors and spin liquids. Numerical simulations of such systems are often hindered by sign problems. In quantum link models - an alternative formulation of gauge theories developed by the applicant - gauge fields emerge from discrete quantum variables. In the past year, in close collaboration with atomic physicists, we have established quantum link models as a framework for the atomic quantum simulation of dynamical gauge fields. Abelian gauge theories can be realized with Bose-Fermi mixtures of ultracold atoms in an optical lattice, while non-Abelian gauge fields arise from fermionic constituents embodied by alkaline-earth atoms. Quantum simulators, which do not suffer from the sign problem, shall be constructed to address non-trivial dynamics, including quantum phase transitions in spin liquids, the real-time dynamics of confining strings as well as of chiral symmetry restoration at finite temperature and baryon density, baryon superfluidity, or color-flavor locking. New classical simulation algorithms shall be developed in order to solve severe sign problems, to investigate confining gauge theories, and to validate the proposed quantum simulators. Starting from U(1) and SU(2) gauge theories, an atomic physics tool box shall be developed for quantum simulation of gauge theories of increasing complexity, ultimately aiming at 4-d Quantum Chromodynamics (QCD). This project is based on innovative ideas from particle, condensed matter, and computational physics, and requires an interdisciplinary team of researchers. It has the potential to drastically increase the power of simulations and to address very challenging problems that cannot be solved with classical simulation methods.

1 975 242 €

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

The attoclock is a powerful, new, and unconventional tool to study fundamental attosecond dynamics on an atomic scale. We established its potential by using the first attoclock to measure the tunneling delay time in laser-induced ionization of helium and argon atoms, with surprising results. Building on these first proof-of-principle measurements, I propose to amplify and expand this tool concept to explore the following key questions: How fast can light liberate electrons from a single atom, a single molecule, or a solid-state system? Related are more questions: How fast can an electron tunnel through a potential barrier? How fast is a multi-photon absorption process? How fast is single-photon photoemission? Many of these questions will undoubtedly spark more questions – revealing deeper and more detailed insights on the dynamics of some of the most fundamental and relevant optoelectronic processes. There are still many unknown and unexplored areas here. Theory has failed to offer definitive answers. Simulations based on the exact time-dependent Schrödinger equation have not been possible in most cases. Therefore one uses approximations and simpler models to capture the essential physics. Such semi-classical models potentially will help to understand attosecond energy and charge transport in larger molecular systems. Indeed the attoclock provides a unique tool to explore different semi-classical models. For example, the question of whether electron tunneling through an energetically forbidden region takes a finite time or is instantaneous has been subject to ongoing debate for the last sixty years. The tunnelling process, charge transfer, and energy transport all play key roles in electronics, energy conversion, chemical and biological reactions, and fundamental processes important for improved information, health, and energy technologies. We believe the attoclock can help refine and resolve key models for many of these important underlying attosecond processes.

2 319 796 €

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

NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.

2 499 800 €

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

We use IR spectroscopy of trapped ions in a cryogenic FT-ICR spectrometer to probe non-covalent, “dispersion” interactions in large, gas-phase molecular ions. We will measure conformational equilibria by N-H frequency shifts, and correlate gas-phase IR frequency to the N-H-N bond angle in an ionic H-bond. Substituents on “onium” cations can adopt various conformations, whose energies map interaction potentials. Substituents on their proton-bound dimers interact non-covalently through dispersion forces, whose quantitative evaluation in large molecules has remained difficult despite dispersion becoming increasingly cited as a design principle in the construction of catalysts and materials. The non-covalent interactions bend the N-H-N bond, leading to large shifts in the IR frequency. The proton-bound dimer acts like a molecular balance where the non-covalent interaction, is set against the bending potential in an ionic hydrogen bond. Despite encouragingly accurate calculations for small molecules, experimental benchmarks for large molecules in the gas phase remain scarce, and there is evidence that the good results for small molecules may not extrapolate reliably to large molecules. The present proposal introduces a new experimental probe of non-covalent interactions, providing a sensitive test of the diverging results coming from various computational methods and other experiments. The experiment must be done on isolated molecules in the gas phase, as previous work has shown that solvation substantially cancels out the attractive potential. Accordingly, the proposed experimental design, which involves a custom-built spectrometer, newly available tunable IR sources, chemical synthesis of custom substrates, and quantum calculations up to coupled-cluster levels of theory, showcases how an interdisciplinary approach combining physical and organic chemistry can solve a fundamental problem that impacts how we understand steric effects in organic chemistry.

2 446 125 €

Start date: 2019-05-01, End date: 2024-04-30

A major aim in genome research is to reveal how genetic variation affects phenotypic variation. Here I propose to use high-throughput genomics (whole genome sequencing, transcriptome and epigenome analysis) to screen carefully selected study populations where the chances are particularly favourable to obtain novel insight into genotype-phenotype relationships. The ambition is to take discoveries all the way from phenotypic characterization to the identification of the genes and the actual genetic variant causing a phenotypic effect and to understanding the underlying functional mechanisms. The program will involve a fish (the Atlantic herring), a bird (the domestic chicken) and a mammal (the European rabbit). The Atlantic herring will be studied because it provides unique opportunities to study the genetics of adaptation in a natural population and because of the possibilities to revolutionize the fishery management of this economically important marine fish. We will generate a draft assembly of the herring genome and then perform whole genome resequencing of different populations to reveal the population structure and the loci underlying genetic adaptation. The European rabbit is an excellent model for studying the genetics of speciation due to the presence of two distinct subspecies on the Iberian Peninsula. The domestication of the rabbit is also particularly interesting because it is a recent event (about 1500 years ago) and it is well established that domestication happened from the wild rabbit population in southern France. Finally, the domestic chicken provides excellent opportunities for in depth functional studies since it is both a domestic animal harbouring a rich genetic diversity and an experimental organism. (BATESON is the acronym for this proposal because Bateson (1902) pioneered the study of genotype-phenotype relationships in animals and used the chicken for this work.)

2 300 000 €

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

"I propose to lead an international observational effort to characterize the population of massive planets, brown dwarf and stellar secondaries orbiting their parent stars with short periods, up to 10-30 days. The effort will utilize the superb, accurate, continuous lightcurves of more than hundred thousand stars obtained recently by two space missions – CoRoT and Kepler. I propose to use these lightcurves to detect non-transiting low-mass companions with a new algorithm, BEER, which I developed recently together with Simchon Faigler. BEER searches for the beaming effect, which causes the stellar intensity to increase if the star is moving towards the observer. The combination of the beaming effect with other modulations induced by a low-mass companion produces periodic modulation with a specific signature, which is used to detect small non-transiting companions. The accuracy of the space mission lightcurves is enough to detect massive planets with short periods. The proposed project is equivalent to a radial-velocity survey of tens of thousands of stars, instead of the presently active surveys which observe only hundreds of stars. We will use an assortment of telescopes to perform radial velocity follow-up observations in order to confirm the existence of the detected companions, and to derive their masses and orbital eccentricities. We will discover many tens, if not hundreds, of new massive planets and brown dwarfs with short periods, and many thousands of new binaries. The findings will enable us to map the mass, period, and eccentricity distributions of planets and stellar companions, determine the upper mass of planets, understand the nature of the brown-dwarf desert, and put strong constrains on the theory of planet and binary formation and evolution."

1 737 600 €

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

In this project, we will develop and use technology that combines synthetic genomics and live-cell imaging. These methods make it possible to study the intracellular biophysics at single-molecule detail in thousands of genetically different bacterial strains in parallel. Our approach is based on in situ genotyping of a barcoded strain library after phenotyping has been performed by live-cell imaging. Within the scope of the proposed project, the new technology will be used to solve mechanistic and structural questions of the bacterial cell cycle. To this end, we will explore two parallel but complementary applications. In the first application, we will determine the dynamic 3D structure of the E. coli chromosome at 1kb resolution throughout the cell cycle. The structure determination can be seen as a live-cell version of chromatin conformation capture, where we will follow the 3D distances of 10 000 pairs of chromosomal loci over the cell cycle at high resolution. In the second application, we will make a complete CRISPRi knockdown strain library where we can follow the replication forks of the E. coli chromosome and septum formation over the cell cycle in individual cells. Using this strategy, we will resolve how individual gene products contribute to the cell-to-cell accuracy in replication initiation and cell division. In particular, this approach allows us to address the challenging question of size sensing at replication initiation. How the cell can decide that it is large enough to initiate replication is still an open question despite decades of investigations. The general principles for high-end imaging of pool-synthesized cell libraries have nearly unlimited applications throughout cell biology. The specific applications explored in this project will take the understanding of the bacterial cell cycle to a new level and answer general questions about the chromosomal organization and cell size sensing.

2 411 410 €

Start date: 2021-01-01, End date: 2025-12-31

BioELCell will deliver ground-breaking approaches to create next material generation based on renewable resources, mainly cellulose and lignin micro- and nano-particles (MNC, MNL). Our action will disassemble and re-engineer these plant-based polymers into functional materials that will respond to the demands of the bioeconomy of the future, critically important to Europe and the world. My ambitious, high gain research plan is underpinned in the use of multiphase systems with ultra-low interfacial tension to facilitate nanocellulose liberation and atomization of lignin solution streams into spherical particles. BioELCell will design novel routes to control MNC and MNL reassembly in new 1-D, 2-D and 3-D structures. The systematic methodologies that I propose will address the main challenges for lignocellulose processing and deployment, considering the important effects of interactions with water. This BioELCell action presents a transformative approach by integrating complementary disciplines that will lead to a far-reaching understanding of lignocellulosic biopolymers and solve key challenges in their use, paving the way to functional product development. Results of this project permeates directly or indirectly in the grand challenges for engineering, namely, water use, carbon sequestration, nitrogen cycle, food and advanced materials. Indeed, after addressing the key fundamental elements of the research lines, BioELCell vindicates such effects based on rational use of plant-based materials as a sustainable resource, making possible the generation of new functions and advanced materials. BioELCell goes far beyond what is known today about cellulose and lignin micro and nano-particles, some of the most promising materials of our century, which are emerging as key elements for the success of a sustainable society.

2 486 182 €

Start date: 2018-08-01, End date: 2023-07-31

Identifying risk factors for diseases that can be prevented or delayed by early intervention is of major importance, and numerous genetic, lifestyle, anthropometric and clinical risk factors were found for many different diseases. Another source of potentially pertinent disease risk factors is the human microbiome - the collective genome of trillions of bacteria, viruses, fungi, and parasites that reside in the human gut. However, very few microbiome disease markers were found to date. Here, we aim to develop risk prediction tools based on the human microbiome that predict the likelihood of an individual to develop a particular condition or disease within 5-10 years. We will use a cohort of >2200 individuals that my group previously assembled, for whom we have clinical profiles, gut microbiome data, and banked blood and stool samples. We will invite people 5-10 years after their initial recruitment time, profile disease status and blood markers, and develop algorithms for predicting 5-10 year onset of Type 2 diabetes, cardiovascular disease, and obesity, using microbiome data from recruitment time. To increase the likelihood of finding microbiome markers predictive of disease onset, we will develop novel experimental and computational methods for in-depth characterization of microbial gene function, the metabolites produced by the microbiome, the underexplored fungal microbiome members, and the interactions between the gut microbiota and the host adaptive immune system. We will then apply these methods to >2200 banked samples from cohort recruitment time and use the resulting data in devising our microbiome-based risk prediction tools. In themselves, these novel assays and their application to >2200 samples should greatly advance the microbiome field. If successful, our proposal will identify new disease risk factors and risk prediction tools based on the microbiome, paving the way towards using the microbiome in early disease detection and prevention.

2 500 000 €

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

During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.

1 320 000 €

Start date: 2008-11-01, End date: 2014-09-30

Early vertebrate evolution involved a series of drastic structural reorganisations as new features were added and elaborated. The fossil record illuminates this evolutionary history more directly than inferences from the diversity of living forms, but the fossils usually consist only of bones whereas many of the most important and interesting changes occurred in the soft anatomy. Traditional approaches to reconstructing the musculature and other soft tissues of fossil vertebrates rely on subjective tools, like the visual identification of rough bone textures thought to indicate muscle attachments, and generally leave a lot to be desired. Here I propose a wholly novel and radically more objective approach to the identification of soft-tissue contacts, using holotomographic synchrotron CT at sub-micron resolutions to identify these contacts by the three-dimensional micro-architecture of the bone. A pilot study has already shown that such scans (performed at the ESRF synchrotron facility in Grenoble) are capable of imaging key features such as arrested growth surfaces and probable Sharpey s fibres in 380 million year old fossils. We will undertake a systematic review of the three-dimensional bone micro-architectures associated with different soft-tissue contacts in living vertebrates, and the use this as a key to reconstruct the soft-tissue contacts on fossil bones with unprecedented accuracy. This will permit us to produce far more reliable reconstructions of the soft anatomy than has hitherto been possible. Our findings will inform other areas of palaentology, particularly functional morphology, and will also be of great importance to evolutionary developmental biology.

1 046 782 €

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

Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.

2 489 643 €

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

My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research. Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards. Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear. Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information. I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.

2 135 385 €

Start date: 2012-04-01, End date: 2017-07-31

Elementary particle physics is entering a spectacular new era in which experiments at the Large Hadron Collider (LHC) at CERN will soon start probing some of the deepest questions in physics, such as: Why is gravity so weak? Do elementary particles have substructure? What is the origin of mass? Are there new dimensions? Can we produce black holes in the lab? Could there be other universes with different physical laws? While the LHC pushes the energy frontier, the unprecedented precision of Atom Interferometry, has pointed me to a new tool for fundamental physics. These experiments based on the quantum interference of atoms can test General Relativity on the surface of the Earth, detect gravity waves, and test short-distance gravity, charge quantization, and quantum mechanics with unprecedented precision in the next decade. This ERC Advanced grant proposal is aimed at setting up a world-leading European center for development of a deeper theory of fundamental physics. The next 10 years is the optimal time for such studies to benefit from the wealth of new data that will emerge from the LHC, astrophysical observations and atom interferometry. This is a once-in-a-generation opportunity for making ground-breaking progress, and will open up many new research horizons.

2 200 000 €

Start date: 2009-05-01, End date: 2014-04-30

Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab’s main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs). In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation. In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair. Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.

2 268 750 €

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

Understanding cause-effect relationships between variables is of great interest in many fields of science. However, causal inference from data is much more ambitious and difficult than inferring (undirected) measures of association such as correlations, partial correlations or multivariate regression coefficients, mainly because of fundamental identifiability problems. A main objective of the proposal is to exploit advantages from large-scale heterogeneous data for causal inference where heterogeneity arises from different experimental conditions or different unknown sub-populations. A key idea is to consider invariance or stability across different experimental conditions of certain conditional probability distributions: the invariants correspond on the one hand to (properly defined) causal variables which are of main interest in causality; andon the other hand, they correspond to the features for constructing powerful predictions for new scenarios which are unobserved in the data (new probability distributions). This opens novel perspectives: causal inference can be phrased as a prediction problem of a certain kind, and vice versa, new prediction methods which work well across different scenarios (unobserved in the data) should be based on or regularized towards causal variables. Fundamental identifiability limits will become weaker with increased degree of heterogeneity, as we expect in large-scale data. The topic is essentially unexplored, yet it opens new avenues for causal inference, structural equation and graphical modeling, and robust prediction based on large-scale complex data. We will develop mathematical theory, statistical methodology and efficient algorithms; and we will also work and collaborate on major application problems such as inferring causal effects (i.e., total intervention effects) from gene knock-out or RNA interference perturbation experiments, genome-wide association studies and novel prediction tasks in economics.

2 184 375 €

Start date: 2018-10-01, End date: 2023-09-30

"The CCICO project will build a comprehensive understanding of how proximity to previously unexplored combinations of instabilities, as well as previously unidentified types of ordering, manifest in novel behaviors, and will develop design guidelines for practical realization of new materials with such behaviors. Taking transition-metal oxides as our model systems, we will develop and apply first-principles electronic structure theory methods to explore an extensive array of new combinations of orderings, with a focus on interactions between the electronic -- Jahn-Teller, orbital and charge -- and structural -- rotations, ferroelectric and other distortions -- degrees of freedom. Our goal is to spawn a new field of study based on a novel combination of orderings in the same way that the field of multiferroics was jump-started ten years ago by our work understanding the coexistence of ferroelectricity and magnetism. Conversely, we will apply the computational tools developed in our history of studying multiferroics, particularly descriptions of proximity to structural and magnetic phase transitions, to characterizing observed behaviors such as exotic superconductivity in existing materials. In the process we will search for and characterize elusive or poorly characterized forms of order in solids, with a focus on ferrotoroidicity and emergent local dipoles. A final application is to create designer materials for solid-state experiments relevant to high-energy physics and cosmology. Promising compounds that are amenable to bulk synthesis will be made in our new oxide single-crystal growth laboratory; materials that require thin-film routes will be pursued in collaboration with colleagues."

2 000 000 €

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

Each cell in our body has a specific biography that is defined by its pedigree relationship with other cells (lineage) and by its history of gene expression (trajectory). A fundamental question in cellular and developmental biology has been how the lineage and trajectory of a cell lead to its specification and differentiation. Remarkable progress in genome editing and single-cell sequencing has generated the opportunity to understand this process at global scales and single-cell resolution. We have recently developed methods to reconstruct the cellular ancestry and transcriptional trajectories of cells during embryogenesis. The resulting lineage and trajectory trees can be analyzed to gain comprehensive views of how cellular diversity arises and how differentiation leads to physiologically specialized cell types. To generate such global views of cellular development, we will: 1. Define the cellular diversity and gene expression trajectories during zebrafish embryogenesis and organogenesis. Trajectory trees will be generated from scRNA-seq data and analyzed to reconstruct the gene expression pathways underlying fate specification. 2. Reveal the relationships between lineage and transcriptional trajectories during fate specification. Lineage trees will be generated by marking cells via genome editing and combined with trajectory trees to reveal the cellular paths towards fate specification. 3. Discover the gene expression cascades that remodel cells into physiologically functional types. Cell biological modules will be identified by comparing gene enrichment in differentiation trajectories and reveal the specialized and shared mechanisms of differentiation. These studies will help provide the first comprehensive and global view of the trajectories and lineages underlying vertebrate development. Our focus is on the zebrafish model system, but the data and concepts developed in this project will be applicable to other developmental and cellular systems.

2 411 440 €

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

Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process

2 004 155 €

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

Deciphering and engineering the assembly of cellular organelles is a key pursuit in biology. The centriole is an evolutionarily conserved organelle well suited for this goal, and which is crucial for cell signaling, motility and division. The centriole exhibits a striking 9-fold radial symmetry of microtubules around a likewise symmetrical cartwheel containing stacked ring-bearing structures. Components essential for generating this remarkable architecture from alga to man have been identified. A next critical step is to engineer assays to probe the dynamics of centriole assembly with molecular precision to fully understand how these components together build a functional organelle. Our ambitious research proposal aims at taking groundbreaking steps in this direction through four specific aims: 1) Reconstituting cartwheel ring assembly dynamics. We will use high-speed AFM (HS-AFM) to dissect the biophysics of SAS-6 ring polymer dynamics at the root of cartwheel assembly. We will also use HS-AFM to analyze monobodies against SAS-6, as well as engineer surfaces and DNA origamis to further dissect ring assembly. 2) Deciphering ring stacking mechanisms. We will use cryo-ET to identify SAS-6 features that direct stacking of ring structures and set cartwheel height. Moreover, we will develop an HS-AFM stacking assay and a reconstituted stacking assay from human cells. 3) Understanding peripheral element contributions to centriole biogenesis. We will dissect the function of the peripheral centriole pinhead protein Cep135/Bld10p, as well as identify and likewise dissect peripheral A-C linker proteins. Furthermore, we will further engineer the HS-AFM assay to include such peripheral components. 4) Dissecting de novo centriole assembly mechanisms. We will dissect de novo centriole formation in human cells and water fern. We will also explore whether de novo formation involves a phase separation mechanism and repurpose the HS-AFM assay to probe de novo organelle biogenes

2 500 000 €

Start date: 2019-09-01, End date: 2024-08-31

Bullying in schools is widespread, with adverse effects on youth and high costs for societies. Research on bullying prevention has so far focused on average effects of anti-bullying programs and mainly concerned universal, preventive measures. While important, this has overshadowed attempts to uncover how exactly school personnel intervene in particular bullying cases and when and why that fails. CHALLENGE will open up new research horizons by shifting the focus from average program effects to the characteristics and conditions of youth who remain victimized or continue bullying despite targeted interventions. The next big questions in the field are tackled in four work packages: WP1 uncovers the key features of persistent bullying, such as the extent to which it is due to school-level factors or rather varies across bullying cases (within schools). WP2 elucidates the plight of persistent victims by testing why victimized youth are most maladjusted in contexts where the overall level of victimization is decreasing (healthy context paradox, Garandeau & Salmivalli, 2019). WP3 tests the efficacy of different targeted interventions in real-life conditions, uncovering challenge factors that increase the risk of a bullying case remaining unresolved. Moreover, it tests how youth characteristics affect their cognitive, emotional and motivational responses to different interventions. WP4 utilizes molecular genetics to test genetic susceptibility to intervention effects at the individual level. CHALLENGE uses quantitative, qualitative, and DNA analyses, combines longitudinal and experimental designs, and harnesses novel tools to collect real-time intervention data and to register children’s responses to interventions. It bridges the perspectives of developmental and social psychology, child psychiatry, and genetics, builds theory on persistent bullying and enables the development of tailored measures for specific target groups where available interventions have failed

2 424 001 €

Start date: 2020-10-01, End date: 2025-09-30

"Among the various toxins isolated, the chlorosulfolipids are particularly intriguing because of their structural and stereochemical complexity. The mechanism of biological activity remains unknown. The lack of availability of the natural products has impaired more in-depth studies aimed at pharmacological, biological, and chemical characterization for proper evaluation of the risk for human health and their role in nature. The proposal takes as its basis this unusual class of natural products and delineates a multifaceted program of inquiry involving: (1) structural characterization of the most complex chlorosulfolipid isolated to date, (2) conformational studies in solution of chlorinated lipids, (3) synthesis and study of brominated lipid analogs, (4) development of analytical methods for detection of these toxins in the environment, (5) the discovery and development of reagents and catalysts for asymmetric chlorination of olefins, (6) examination of lipid conformation in constrained media, (7) examination of the mechanism of anchimeric assistance by chlorides, and (8) applications to drug discovery."

2 233 240 €

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

Epigenetic mechanisms play an important role in regulating and maintaining the functionality of cells and have been implicated in a wide range of human diseases. Histone proteins that form the protein core of nucleosomes are subject to a bewildering array of covalent and structural modifications, which can repress, permit, or promote transcription. These modifications can be added and removed by specialized complexes that are recruited by other covalent modifications, by transcription factors, or by the transcriptional machinery. Advances in genomics led to comprehensive mapping of the ``epigenome'' in a range of tissues and organisms. These maps established the tight connection between histone modifications and transcription programs. These static charts, however, are less successful at uncovering the underlying mechanisms, logic, and function of histone modifications in establishing and maintaining transcriptional programs. Our premise is that we can answer these basic questions by observing the effect of genetic perturbations on the dynamics of both chromatin state and transcriptional activity. We aim to dissect the chromatin-transcription system in a systematic manner by building on our extensive experience in modeling and analysis, and a unique high-throughput experimental system we established in my lab. We plan to use the budding yeast model organism, which allows for efficient genetic and experimental manipulations. We will combine two technologies: (1) high-throughput measurements of single-cell transcriptional output using fluorescence reporters; and (2) high-throughput immunoprecipitation sequencing assays to map chromatin state. Measuring with these the dynamics of response to stimuli under different genetic backgrounds and using advanced stochastic network models, we will chart detailed mechanisms that are opaque to current approaches and elucidate the general principles that govern the interplay between chromatin and transcription.

2 396 450 €

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

The overall objective is to fully understand the Chiral Induced Spin Selectivity (CISS) effect, which was discovered recently. It was found that the transmission or conduction of electrons through chiral molecules is spin dependent. The CISS effect is a change in the pradigm that assumed that any spin manipulation requiers magnetic materials or materials with high spin-orbit coupling. These unexpected new findings open new possibilities for applying chiral molecules in spintronics applications and may provide new insights on electron transfer processes in Biology. The specific goals of the proposed research are (i) To establish the parameters that affect the magnitude of the CISS effect. (ii) To demonstrate spintronics devices (memory and transistors) that are based on the CISS effect. (iii) To investigate the role of CISS in electron transfer in biology related systems. The experiments will be performed applying a combination of experimental methods including photoelectron spectroscopy, single molecule conduction, light-induced electron transfer, and spin specific conduction through magneto-electric devices. The project has a potential to have very large impact on various fields from Physics to Biology. It will result in the establishment of chiral organic molecules as a new substrate for wide range of spintronics related applications including magnetic memory, and in determining whether spins play a role in electron transfer processes in biology.

2 499 998 €

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

This five years research proposal is focused on the development of novel information theoretic concepts and techniques and their usage, as to identify the ultimate communications limits and potential of different cloud radio network structures, in which the central signal processing is migrated to the cloud (remote central units), via fronthaul/backhaul infrastructure links. Moreover, it is also directed to introduce and study the optimal or close to optimal strategies for those systems that are to be motivated by the developed theory. We plan to address wireless networks, having future cellular technology in mind, but the basic tools and approaches to be built and researched are relevant to other communication networks as well. Cloud communication networks motivate novel information theoretic views, and perspectives that put backhaul/fronthaul connections in the center, thus deviating considerably from standard theoretical studies of communications links and networks, which are applied to this domain. Our approach accounts for the fact that in such networks information theoretic separation concepts are no longer optimal, hence isolating simple basic components of the network is essentially suboptimal. The proposed view incorporates, in a unified way, under the general cover of information theory: Multi-terminal distributed networks; Basic and timely concepts of distributed coding and communications; Network communications and primarily network coding, Index coding, as associated with interference alignment and caching; Information-Estimation relations and signal processing, addressing the impact of distributed channel state information directly; A variety of fundamental concepts in optimization and random matrix theories. This path provides a natural theoretical framework directed towards better understanding the potential and limitation of cloud networks on one hand and paves the way to innovative communications design principles on the other.

1 981 782 €

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

The creation of new molecular entities and subsequent exploitation of their properties is central to a broad spectrum of research disciplines from medicine to materials. Most –if not all- of the efforts of organic chemists were directed to the development of creative strategies to built carbon-carbon and carbon-heteroatom bonds in a predictable and efficient manner. But is the creation of new bonds the only approach that organic chemistry should follow? Could we design the synthesis of challenging molecular skeleton no more through the construction of carbon-carbon bonds but rather through selective cleavage of carbon-carbon bonds (C-C bond activation)? The goal of this work is to develop powerful synthetic approaches for the selective C-C bond activation and demonstrate that it has the potential to be a general principle in organic synthesis for the regio-, diastereo- and even enantiomerically enriched preparation of adducts despite that C-C single bonds belong among the least reactive functional groups in chemistry. The realization of this synthetic potential requires the ability to functionalize selectively one C-C bond in compounds containing many such bonds and an array of functional groups. This site selective C-C bond activation is one of the greatest challenges that must be met to be used widely in complex-molecular synthesis. To emphasize the practicality of C-C bond activation, we will prepare in a single-pot operation challenging molecular framework possessing various stereogenic centers from very simple starting materials through selective C-C bond activation. Ideally, alkenes will be in-situ transformed into alkanes that will subsequently undergo the C-C activation even in the presence of functional group. This work will lead to ground-breaking advances when non-strained cycloalkanes (cyclopentane, cyclohexane) will undergo this smooth C-C bond activation with friendly and non toxic organometallic species.

2 367 495 €

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

Computational learning theory has been highly successful over the last three decades, both in providing deep mathematical theories and in influencing the practice of machine learning. One of the great recent successes of computational learning theory has been the study of online learning and multi-arm bandits. This line of research has been highly successful, both theoretically and practically, addressing many important applications. Unfortunately, the recent theoretical progress in Markov Decision Process and reinforcement learning has been slower. Based on my fundamental contributions to reinforcement learning (e.g. policy gradient, sparse sampling and trajectory trees), to online learning and machine learning in general, I propose to take the theoretical and practical success of online learning to the “next level” by making significant breakthroughs in reinforcement learning. Our main aim is to advance the state of the art in the theory of reinforcement learning, and our research will revolve around three pillars: (1) compact representation, (2) efficient computation and (3) societal challenges, including fairness and privacy. A successful project will greatly impact reinforcement learning in all its stages. Modelling: Introducing new compact representation models, will enhance our understanding how to structure complex problems, which would greatly extend the applicability of reinforcement learning. Efficient computation: New algorithmic methodologies will give new insight for overcoming computational and statistical barriers both for planning and learning. Learning: New learning paradigms would address fundamental issues of copping with uncertainties in complex control environments of reinforcement learning. Societal challenges: Allowing the community to understand, assess, address and overcome societal challenges is of the greatest importance to the acceptance of AI methodologies by the general public.

1 878 125 €

Start date: 2020-10-01, End date: 2025-09-30

Self-assembly is the key construction principle that nature uses so successfully to fabricate its molecular machinery and highly elaborate structures. In this project we will follow nature’s strategies and make a concerted experimental and theoretical effort to study, understand and control self-assembly for a new generation of colloidal building blocks. Starting point will be recent advances in colloid synthesis strategies that have led to a spectacular array of colloids of different shapes, compositions, patterns and functionalities. These allow us to investigate the influence of anisotropy in shape and interactions on aggregation and self-assembly in colloidal suspensions and mixtures. Using responsive particles we will implement colloidal lock-and-key mechanisms and then assemble a library of “colloidal molecules” with well-defined and externally tunable binding sites using microfluidics-based and externally controlled fabrication and sorting principles. We will use them to explore the equilibrium phase behavior of particle systems interacting through a finite number of binding sites. In parallel, we will exploit them and investigate colloid self-assembly into well-defined nanostructures. Here we aim at achieving much more refined control than currently possible by implementing a protein-inspired approach to controlled self-assembly. We combine molecule-like colloidal building blocks that possess directional interactions and externally triggerable specific recognition sites with directed self-assembly where external fields not only facilitate assembly, but also allow fabricating novel structures. We will use the tunable combination of different contributions to the interaction potential between the colloidal building blocks and the ability to create chirality in the assembly to establish the requirements for the controlled formation of tubular shells and thus create a colloid-based minimal model of synthetic virus capsid proteins.

2 498 040 €

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

The goal of this project is to study conformally invariant fractal structures from the perspectives of analysis, dynamics, probability, geometry and physics, emphasizing interrelations of these fields. In the last two decades such structures emerged in several areas: continuum scaling limits of 2D critical models in statistical physics (percolation, Ising model); extremal configurations for various problems in complex analysis (multifractal harmonic measures, coefficient growth of univalent maps, Brennan's conjecture); chaotic sets for complex dynamical systems (Julia sets, Kleinian groups). Capitalizing on recent successes, I plan to continue my work in these areas, exploiting their interactions and connections to physics. I intend to achieve at least some of the following goals: * To establish that several critical lattice models have conformally invariant scaling limits, by building upon results on percolation and Ising models and finding discrete holomorphic observables. * To study geometric properties of arising fractal curves and random fields by connecting them to Schramm's SLE curves and Gaussian Free Fields. * To investigate massive scaling limits by describing them geometrically with generalizations of SLEs. * To lay mathematical framework behind relevant physical notions, such as Coulomb Gas (by relating height functions to GFFs) and Quantum Gravity (by identifying limits of random planar graphs with Liouville QGs). * To improve known bounds in several old questions in complex analysis by studying multifractal spectra of harmonic measures. * To estimate extremal behavior of such spectra by using holomorphic motions of (quasi) conformal maps and thermodynamic formalism. * To understand nature of extremal multifractals for harmonic measure by studying random and dynamical fractals. The topics involved range from century old to very young ones. Recently connections between them started to emerge, opening exciting possibilities for new developments in some long standing open problems.

1 278 000 €

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

Spectroscopic investigation of high (n >>20) molecular Rydberg states below and above the first adiabatic ionization threshold will be carried out with the aims of 1) obtaining fully resolved information on the vibrational, rotational, spin-orbit and hyperfine structures of these highly excited electronic states, 2) characterizing the role of nuclear spins in molecular photoionization, 3) determining the hyperfine structure of fundamental molecular cations at kHz resolution and accuracy by Rydberg series extrapolation, 4) measuring intervals between rovibrational levels of these molecular cations at sub MHz precision, 5) gaining a complete understanding, and providing an adequate description and classification, of angular momentum coupling (including nuclear spins) in high molecular Rydberg states, 6) testing theoretical predictions of the energy level structure of Rydberg molecules by ab initio multichannel quantum defect theory (MQDT) and of the rotational, vibrational and hyperfine levels of molecular cations by ab initio quantum chemistry and QED. The spectroscopic measurements using tunable narrow-band vacuum-ultraviolet and millimeter wave radiation sources will be performed on cold samples in supersonic beams as well as on trapped samples of translationally cold Rydberg atoms and molecules. To this end, our recent approach to trap H atoms in Rydberg states electrostatically (Hogan and Merkt, Phys. Rev. Lett. 100, 043001 (2008)) will be extended to molecules, and the possibility of transfering the trapped species from electrostatic traps to magnetic and optical traps will be explored.

1 192 395 €

Start date: 2008-11-01, End date: 2013-10-31

Coupling of atoms is the basis of chemistry, yielding the beauty and richness of molecules and materials. Herein I introduce nanocrystal chemistry: the use of semiconductor nanocrystals (NCs) as artificial atoms to form NC molecules that are chemically, structurally and physically coupled. The unique emergent quantum mechanical consequences of the NCs coupling will be studied and tailored to yield a chemical-quantum palette: coherent coupling of NC exciton states; dual color single photon emitters functional also as photo-switchable chromophores in super-resolution fluorescence microscopy; electrically switchable single NC photon emitters for utilization as taggants for neuronal activity and as chromophores in displays; new NC structures for lasing; and coupled quasi-1D NC chains manifesting mini-band formation, and tailored for a quantum-cascade effect for IR photon emission. A novel methodology of controlled oriented attachment of NC building blocks (in particular of core/shell NCs) will be presented to realize the coupled NCs molecules. For this a new type of Janus NC building block will be developed, and used as an element in a Lego-type construction of double quantum dots (dimers), heterodimers coupling two different types of NCs, and more complex NC coupled quantum structures. To realize this NC chemistry approach, surface control is essential, which will be achieved via investigation of the chemical and dynamical properties of the NCs surface ligands layer. As outcome I can expect to decipher NCs surface chemistry and dynamics, including its size dependence, and to introduce Janus NCs with chemically distinct and selectively modified surface faces. From this I will develop a new step-wise approach for synthesis of coupled NCs molecules and reveal the consequences of quantum coupling in them. This will inspire theoretical and further experimental work and will set the stage for the development of the diverse potential applications of coupled NC molecules.

2 499 750 €

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

The central dogma in biology often invokes a bottom-up picture of life. However, at different biological scales, new properties in form and function arise that have a superseding causal impact on the behaviour of the lower-scale components from which these new properties emerge. These top-down or reverse scale-crossing effects must be taken into account in order to make predictions about spatiotemporally controlled single-cell fates, activities, levels of gene expression, or the functional outcome of cellular signalling. They can stem from the multicellular, the cellular, and the intracellular scale, and can be quantified using multiscale and multiplexed RNA and protein state imaging in combination with computer vision and data-driven modelling. The ability to comprehensively map these reverse causal effects across multiple scales has the potential to revolutionize most, if not all domains of biology and medicine. In this project, we will establish the importance of reverse causal effects in human induced pluripotent stem cells and early D. rerio embryos. To achieve this, we will develop a quantitative imaging method beyond the diffraction limit of light without compromising scalability in temporal and spatial dimensions. We will also develop a method that achieves scalable, transcriptome-wide image-based multiplexing of mRNA transcripts, and we will extend our computer vision approaches to higher resolution and to three spatial dimensions. These methods will be systematically applied to stem cell collectives grown in 2D and 3D, as well as to early embryos, achieving comprehensive quantification of nuclear and chromatin states, gene expression, subcellular organization, cellular states, and tissue-scale organization across millions of individual cells within the same dataset. These datasets will be used to quantify how, at different scales, new properties in form and function arise that have a superseding causal impact on the behaviour of the lower-scale components

2 411 075 €

Start date: 2020-09-01, End date: 2025-08-31

Specificity in the ubiquitin-proteasome system is largely conferred by ubiquitin E3 ligases (E3s). Cullin-RING ligases (CRLs), constituting ~30% of all E3s in humans, mediate the ubiquitination of ~20% of the proteins degraded by the proteasome. CRLs are divided into seven families based on their cullin constituent. Each cullin binds a RING domain protein, and a vast repertoire of adaptor/substrate receptor modules, collectively creating more than 200 distinct CRLs. All CRLs are regulated by the COP9 signalosome (CSN), an eight-protein isopeptidase that removes the covalently attached activator, NEDD8, from the cullin. Independent of NEDD8 cleavage, CSN forms protective complexes with CRLs, which prevents destructive auto-ubiquitination. The integrity of the CSN-CRL system is crucially important for the normal cell physiology. Based on our previous work on CRL structures (Fischer, et al., Nature 2014; Fischer, et al., Cell 2011) and that of isolated CSN (Lingaraju et al., Nature 2014), We now intend to provide the underlying molecular mechanism of CRL regulation by CSN. Structural insights at atomic resolution, combined with in vitro and in vivo functional studies are designed to reveal (i) how the signalosome deneddylates and maintains the bound ligases in an inactive state, (ii) how the multiple CSN subunits bind to structurally diverse CRLs, and (iii) how CSN is itself subject to regulation by post-translational modifications or additional further factors. The ERC funding would allow my lab to pursue an ambitious interdisciplinary approach combining X-ray crystallography, cryo-electron microscopy, biochemistry and cell biology. This is expected to provide a unique molecular understanding of CSN action. Beyond ubiquitination, insight into this >13- subunit CSN-CRL assembly will allow examining general principles of multi-subunit complex action and reveal how the numerous, often essential, subunits contribute to complex function.

2 200 677 €

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

This proposal addresses high-risk, high-reward research of integrated sensing and computing architectures, as well as of models, methods and tools for their design and operation. Such architectures provide the bridge between bio-systems and information processing systems, where a bio-system is an abstraction of a human in terms of biophysical parameters. Breakthroughs in data acquisition, processing and decision making support will enable new smart-health applications. The essential research goals of this proposal are: biophysical data acquisition by novel programmable integrated sensor arrays and their design and test using a modular and structured architecture; data processing in situ and/or remotely using application-specific hardware and/or embedded software; a new robust synthesis methodology for data processing units based on a new logic structure; models, abstractions and software tools for reasoning about the acquired data, to validate health conditions and/or to provide remedies (i.e., therapy). The results of this research will be embodied in a demonstrator showing the effectiveness of these combined technologies in first-aid medical care. The outcome of this research will have a deep and broad impact on health care, because it will improve diagnosis and therapy in a variety of cases. Namely, it will boost the quality and quantity of the acquired biophysical data, possibly in real time, by leveraging multiple sensing modalities and dedicated computing architectures. The use of formal methods for design, data evaluation and decision making support will enhance the quality of the diagnostic platforms and will ease their qualification and adoption. Moreover, the integration of sensing and electronics and their in-field programmability will reduce production cost and lower the barrier of adoption, thus providing for better and more affordable health care means.

2 086 740 €

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

Organismal development requires proper timing of events such as cell fate choices, but the mechanisms that control temporal patterning remain poorly understood. In particular, we know little of the cyclical timers, or ‘clocks’, that control recurring events such as vertebrate segmentation or nematode molting. Furthermore, it is unknown how cyclical timers are coordinated with the global, or linear, timing of development, e.g. to ensure an appropriate number of cyclical repeats. We propose to elucidate the components, wiring, and properties of a prototypic developmental clock by studying developmental timing in the roundworm C. elegans. We build on our recent discovery that nearly 20% of the worm’s transcriptome oscillates during larval development – an apparent manifestation of a clock that times the various recurring events that encompass each larval stage. Our aims are i) to identify components of this clock using genetic screens, ii) to gain insight into the system’s architecture and properties by employing specific perturbations such as food deprivation, and iii) to understand the coupling of this cyclic clock to the linear heterochronic timer through genetic manipulations. To achieve our ambitious goals, we will develop tools for mRNA sequencing of individual worms and for their developmental tracking and microchamber-based imaging. These important advances will increase temporal resolution, enhance signal-to-noise ratio, and achieve live tracking of oscillations in vivo. Our combination of genetic, genomic, imaging, and computational approaches will provide a detailed understanding of this clock, and biological timing mechanisms in general. As heterochronic genes and rhythmic gene expression are also important for controlling stem cell fates, we foresee that the results gained will additionally reveal regulatory mechanisms of stem cells, thus advancing our fundamental understanding of animal development and future applications in regenerative medicine.

2 358 625 €

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

Atmospheric aerosol particles play a key role in regulating the climate, and particulate matter is responsible for most of the 7 million deaths per year attributed to air pollution. Lack of understanding of aerosol processes, especially the formation of ice crystals and secondary particles from condensable trace gases, hampers the development of air quality modelling, and remains one of the major uncertainties in predicting climate. The purpose of this project is to achieve a comprehensive understanding of atmospheric nanocluster and ice crystal formation based on fundamental physico-chemical principles. We will use a wide palette of theoretical methods including quantum chemistry, reaction kinetics, continuum solvent models, molecular dynamics, Monte Carlo simulations, Markov chain Monte Carlo methods, computational fluid dynamics, cluster kinetic and thermodynamic models. We will study non-equilibrium effects and kinetic barriers in atmospheric clustering, and use these to build cluster distribution models with genuine predictive capacity. Chemical ionization mass spectrometers can, unlike any other instruments, detect the elemental composition of many of the smallest clusters at ambient low concentrations. However, the charging process and the environment inside the instrument change the composition of the clusters in hitherto unquantifiable ways. We will solve this problem by building an accurate model for the fate of clusters inside mass spectrometers, which will vastly improve the amount and quality of information that can be extracted from mass spectrometric measurements in atmospheric science and elsewhere. DAMOCLES will produce reliable and consistent models for secondary aerosol and ice particle formation and growth. This will lead to improved predictions of aerosol concentrations and size distributions, leading to improved air quality forecasting, more accurate estimates of aerosol indirect climate forcing and other aerosol-cloud-climate interactions.

2 390 450 €

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

A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.

2 500 000 €

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

The recent anthropogenic global warming makes a detailed understanding of coupling processes between climate and biogeochemical cycles of pressing importance. The atmospheric archive of air bubbles enclosed in polar ice cores provides the only direct record of greenhouse gas changes in the past, and the key to understanding the related changes in biogeochemical cycles and climate/greenhouse gas feedbacks. Crucial questions about greenhouse gas variability on very short (decadal) and very long (orbital) time scales still remain open. To answer these questions, the ice core community has proposed new drilling projects with the goal of nearly doubling the time span of the available ice core record to the last 1.5 million years and of covering the entire Holocene greenhouse gas record in unprecedented decadal resolution. These goals have one thing in common: due to glacier flow most of this record will only be found in a very thin layer in the bottom-most ice of the cores. Completely new analytical approaches are needed to unlock the atmospheric archive in this ice in order to gain high-resolution, high-precision measurements, while at the same time drastically reducing sample consumption compared to established techniques. The deepSLice project will make such a step change in ice core analytics by developing a novel coupled Continuous Sublimation Extraction-Quantum Cascade Laser Spectrometer system. It will allow us to simultaneously measure CO2, CH4 and N2O concentrations as well as the isotopic composition of CO2 on air samples of only 1-2 ml at standard pressure and temperature, reducing the required sample size by one order of magnitude. This non-destructive analysis will make it also possible for the complete air sample to be recollected after analysis and used for other measurements. This method will be applied to existing and new ice cores in order to study past changes in greenhouse gases and the underlying biogeochemical cycles in unparalleled detail.

2 255 788 €

Start date: 2015-10-01, End date: 2021-03-31

Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.

2 261 440 €

Start date: 2010-03-01, End date: 2015-02-28