ERC FUNDED PROJECTS

The overall goal of 14Constraint is to enhance the availability and use of radiocarbon data as constraints for process-based understanding of the age distribution of carbon in and respired by soils and ecosystems. Carbon enters ecosystems by a single process, photosynthesis. It returns by a range of processes that depend on plant allocation and turnover, the efficiency and rate of litter decomposition and the mechanisms stabilizing C in soils. Thus the age distribution of respired CO2 and the age of C residing in plants, litter and soils are diagnostic properties of ecosystems that provide key constraints for testing carbon cycle models. Radiocarbon, especially the transit of ‘bomb’ 14C created in the 1960s, is a powerful tool for tracing C exchange on decadal to centennial timescales. 14Constraint will assemble a global database of existing radiocarbon data (WP1) and demonstrate how they can constrain and test ecosystem carbon cycle models. WP2 will fill data gaps and add new data from sites in key biomes that have ancillary data sufficient to construct belowground C and 14C budgets. These detailed investigations will focus on the role of time lags caused in necromass and fine roots, as well as the dynamics of deep soil C. Spatial extrapolation beyond the WP2 sites will require sampling along global gradients designed to explore the relative roles of mineralogy, vegetation and climate on the age of C in and respired from soil (WP3). Products of this 14Constraint will include the first publicly available global synthesis of terrestrial 14C data, and will add over 5000 new measurements. This project is urgently needed before atmospheric 14C levels decline to below 1950 levels as expected in the next decade.

2 283 747 €

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

This proposal will determine the technical and economic viability of scaling up ultra-thin film deposition processes for exfoliated single atomic layers. The PI has developed methods to produce exfoliated nanosheets from a range of layered materials such as graphene, transition metal chalcogenides and transition metal oxides. These 2D materials have immediate and far-reaching potential in several high-impact technological applications such as microelectronics, composites and energy harvesting and storage. 2DNanoCaps (ERC ref: 278516) has already demonstrated that lab-scale ultra-thin graphene-based supercapacitor electrodes for energy storage result in unusually high power performance and extremely long device life-time (100% capacitance retention for 5000 charge-discharge cycles at the high power scan rate of 10,000 mV/s). This performance is remarkable- an order of magnitude better than similar systems produced with more conventional methods, which cause materials restacking and aggregation. 2D nanosheets also offer the chance of exploring the unique possibility of manufacturing conductive, robust, thin, easily assembled electrode and solid electrolytes to realize highly flexible and all-solid-state supercapacitors. This opportunity is particularly relevant from the industrial point of view especially in relation to the flammability issues of the electrolytes used for commercial energy storage devices at present. In order to develop and exploit any of the applications listed above, it will be imperative to develop deposition methods and techniques capable of obtaining industrial-scale “sheet-like” coverage, where flake re-aggregation is avoided. We believe our combination of unique material properties and cost effective, robust and production-scalable process of ultra-thin deposition will enable us to compete for significant global market opportunities in the energy-storage space

148 021 €

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

"Two-dimensional (2D) nanosheets, which possess a high degree of anisotropy with nanoscale thickness and infinite length in other dimensions, hold enormous promise as a novel class of ultrathin 2D nanomaterials with various unique functionalities and properties, and exhibit great potential in energy storage and conversion systems that are substantially different from their respective 3D bulk forms. Here I propose a strategy for the synthesis and processing of various 2D nanosheets across a broad range of inorganic, organic and polymeric materials with molecular-level or thin thickness through both the top-down exfoliation of layered materials and the bottom-up assembly of available molecular building blocks. Further, I aim to develop the synthesis of various 2D-nanosheet based composite materials with thickness of less than 100 nm and the assembly of 2D nanosheets into novel hierarchal superstrucutures (like aerogels, spheres, porous particles, nanotubes, multi-layer films). The structural features of these 2D nanomaterials will be controllably tailored by both the used layered precursors and processing methodologies. The consequence is that I will apply and combine defined functional components as well as assembly protocols to create novel 2D nanomaterials for specific purposes in energy storage and conversion systems. Their unique characters will include the good electrical conductivity, excellent mechanical flexibility, high surface area, high chemical stability, fast electron transport and ion diffusion etc. Applications will be mainly demonstrated for the construction of lithium ion batteries (anode and cathode), supercapacitors (symmetric and asymmetric) and fuel cells. As the key achievements, I expect to establish the delineation of reliable structure-property relationships and improved device performance of 2D nanomaterials."

1 500 000 €

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

We propose to develop truly two-dimensional continuous materials and two-dimensional monolayer films composed of individual nanocrystals by the comparatively fast, inexpensive, and scalable colloidal synthesis method. The materials’ properties will be studied in detail, especially regarding their (photo-) electrical transport. This will allow developing new types of device structures, such as Coulomb blockade and field enhancement based transistors. Recently, we demonstrated the possibility to synthesize in a controlled manner truly two-dimensional colloidal nanostructures. We will investigate their formation mechanism, synthesize further materials as “nanosheets”, develop methodologies to tune their geometrical properties, and study their (photo-) electrical properties. Furthermore, we will use the Langmuir-Blodgett method to deposit highly ordered monolayers of monodisperse nanoparticles. Such structures show interesting transport properties governed by Coulomb blockade effects known from individual nanoparticles. This leads to semiconductor-like behavior in metal nanoparticle films. The understanding of the electric transport in such “multi-tunnel devices” is still very limited. Thus, we will investigate this concept in detail and take it to its limits. Beside improvement of quality and exchange of material we will tune the nanoparticles’ size and shape in order to gain a deeper understanding of the electrical properties of supercrystallographic assemblies. Furthermore, we will develop device concepts for diode and transistor structures which take into account the novel properties of the low-dimensional assemblies. Nanosheets and monolayers of nanoparticles truly follow the principle of building devices by the bottom-up approach and allow electric transport measurements in a 2D regime. Highly ordered nanomaterial systems possess easy and reliably to manipulate electronic properties what make them interesting for future (inexpensive) electronic devices.

1 497 200 €

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

Topological insulators constitute a novel class of materials where the topological details of the bulk band structure induce a robust surface state on the edges of the material. While transport data for 2-dimensional topological insulators have recently become available, experiments on their 3-dimensional counterparts are mainly limited to photoelectron spectroscopy. At the same time, a plethora of interesting novel physical phenomena have been predicted to occur in such systems. In this proposal, we sketch an approach to tackle the transport and magnetic properties of the surface states in these materials. This starts with high quality layer growth, using molecular beam epitaxy, of bulk layers of HgTe, Bi2Se3 and Bi2Te3, which are the prime candidates to show the novel physics expected in this field. The existence of the relevant surface states will be assessed spectroscopically, but from there on research will focus on fabricating and characterizing nanostructures designed to elucidate the transport and magnetic properties of the topological surfaces using electrical, optical and scanning probe techniques. Apart from a general characterization of the Dirac band structure of the surface states, research will focus on the predicted magnetic monopole-like response of the system to an electrical test charge. In addition, much effort will be devoted to contacting the surface state with superconducting and magnetic top layers, with the final aim of demonstrating Majorana fermion behavior. As a final benefit, growth of thin high quality thin Bi2Se3 or Bi2Te3 layers could allow for a demonstration of the (2-dimensional) quantum spin Hall effect at room temperature - offering a road map to dissipation-less transport for the semiconductor industry.

2 419 590 €

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

Membranes are key materials in our life. Nature offers high performance membranes relying on a parallel local regulation of nanopore structure, functional placement, membrane composition and architecture. Existing technological membranes are key materials in separation, recycling, sensing, energy conversion, being essential components for a sustainable future. But their performance is far away from their natural counterparts. One reason for this performance gap is the lack of 3D nanolocal control in membrane design. This applies to each individual nanopore but as well to the membrane architecture. This proposal aims to implement 3D printing (additive manufacturing, top down) and complex near-field and total internal reflection (TIR) high resolution microscopy induced polymer writing (bottom up) to nanolocally control in hierarchical nanoporous membranes spatially and independent of each other: porosity, pore functionalization, membrane architecture, composition. This disruptive technology platform will make accessible to date unachieved, highly accurate asymmetric nanopores and multifunctional, hierarchical membrane architecture/ composition and thus highly selective, directed, transport with tuneable rates. 3D-FNPWriting will demonstrate this for the increasing class of metal nanoparticle/ salt pollutants aiming for tuneable, selective, directed transport based monitoring and recycling instead of size-based filtration, accumulation into sewerage and distribution into nature. Specifically, the potential of this disruptive technology with respect to transport design will be demonstrated for a) a 3D-printed in-situ functionalized nanoporous fiber architecture and b) a printed, nanolocally near-field and TIR-microscopy polymer functionalized membrane representing a thin separation layer. This will open systematic understanding of nanolocal functional control on transport and new perspectives in water/ energy management for future smart industry/ homes.

1 499 844 €

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

Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism. The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression. I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen. The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.

1 498 175 €

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

This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm. Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.

1 228 125 €

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

Optics is abundant in today’s world. Smartphone cameras, optical sensors for autonomous driving, virtual and augmented reality, medical imaging technology, and many more areas all require tailored optical sensors. In most cases, the optical sensors are still based on classical optical systems. For instance, high-end cameras or high-quality endoscopes still utilize classical glass optics. The related markets have sizes of several tens of billion USD and grow with double digit rates. For all applications, size is the limiting factor. There is a tremendous demand for imaging capabilities using optics at sizes below 1 mm, with the quality of classical optics, i.e., correction of aberrations, extremely high transmission, and broadband operation. Key features include also zooming, focusing, and f-number variation, as well as customized fields of view to realize foveated imaging and multi-aperture, multi-lens systems. Ideally, such optical systems provide 180° field of view with simultaneous zooming capabilities. Here, we propose a novel type of micro-optics that is extremely flexible, can be created at demand, possesses unprecedented functionality, and delivers solutions to problems that could not be solved before. The basic building block at the heart of our problem solution is the use of 3D printed microoptics by femtosecond direct laser writing. This method has all features to fulfil the above-mentioned requirements: It takes only a day from the idea to concept, optical design and simulation, and to manufacturing and testing, i.e., to generate a working prototype. Our method will create a new class of optical elements, which enable the smallest microscope objective in the world on the tip of an optical fiber with unprecedented imaging accuracy and functionality, such as focusing and zooming capability.

150 000 €

Start date: 2019-06-01, End date: 2020-11-30

Due to Europe's ageing society, there has been a dramatic increase in the occurrence of osteoporosis (OP) and related diseases. Sufferers have an impaired quality of life, and there is a considerable cost to society associated with the consequent loss of productivity and injuries. The current understanding of this disease needs to be revolutionized, but study has been hampered by a lack of means to properly characterize bone structure, remodeling dynamics and vascular activity. This project, 4D nanoSCOPE, will develop tools and techniques to permit time-resolved imaging and characterization of bone in three spatial dimensions (both in vitro and in vivo), thereby permitting monitoring of bone remodeling and revolutionizing the understanding of bone morphology and its function. To advance the field, in vivo high-resolution studies of living bone are essential, but existing techniques are not capable of this. By combining state-of-the art image processing software with innovative 'precision learning' software methods to compensate for artefacts (due e.g. to the subject breathing or twitching), and innovative X-ray microscope hardware which together will greatly speed up image acquisition (aim is a factor of 100), the project will enable in vivo X-ray microscopy studies of small animals (mice) for the first time. The time series of three-dimensional X-ray images will be complemented by correlative microscopy and spectroscopy techniques (with new software) to thoroughly characterize (serial) bone sections ex vivo. The resulting three-dimensional datasets combining structure, chemical composition, transport velocities and local strength will be used by the PIs and international collaborators to study the dynamics of bone microstructure. This will be the first time that this has been possible in living creatures, enabling an assessment of the effects on bone of age, hormones, inflammation and treatment.

12 366 635 €

Start date: 2019-04-01, End date: 2025-03-31

State-of-the-art microscopy and diffraction imaging provides insight into the atomic and sub-atomic structure of matter. They permit determination of the positions of atoms in a crystal lattice or in a molecule as well as the distribution of electrons inside atoms. State-of-the-art time-resolved spectroscopy with femtosecond and attosecond resolution provides access to dynamic changes in the atomic and electronic structure of matter. Our proposal aims at combining these two frontier techniques of XXI century science to make a long-standing dream of scientist come true: the direct observation of atoms and electrons in their natural state: in motion. Shifts in the atoms positions by tens to hundreds of picometers can make chemical bonds break apart or newly form, changing the structure and/or chemical composition of matter. Electronic motion on similar scales may result in the emission of light, or the initiation of processes that lead to a change in physical or chemical properties, or biological function. These motions happen within femtoseconds and attoseconds, respectively. To make them observable, we need a 4-dimensional (4D) imaging technique capable of recording freeze-frame snapshots of microscopic systems with picometer spatial resolution and femtosecond to attosecond exposure time. The motion can then be visualized by slow-motion replay of the freeze-frame shots. The goal of this project is to develop a 4D imaging technique that will ultimately offer picometer resolution is space and attosecond resolution in time.

2 500 000 €

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

The sub-cellular processes that control the most critical aspects of life occur in three-dimensions (3D), and are intrinsically dynamic. While super-resolution microscopy has revolutionized cellular imaging in recent years, our current capability to observe the dynamics of life on the nanoscale is still extremely limited, due to inherent trade-offs between spatial, temporal and spectral resolution using existing approaches. We propose to develop and demonstrate an optical microscopy methodology that would enable live sub-cellular observation in unprecedented detail. Making use of multicolor 3D point-spread-function (PSF) engineering, a technique I have recently developed, we will be able to simultaneously track multiple markers inside live cells, at high speed and in five-dimensions (3D, time, and color). Multicolor 3D PSF engineering holds the potential of being a uniquely powerful method for 5D tracking. However, it is not yet applicable to live-cell imaging, due to significant bottlenecks in optical engineering and signal processing, which we plan to overcome in this project. Importantly, we will also demonstrate the efficacy of our method using a challenging biological application: real-time visualization of chromatin dynamics - the spatiotemporal organization of DNA. This is a highly suitable problem due to its fundamental importance, its role in a variety of cellular processes, and the lack of appropriate tools for studying it. The project is divided into 3 aims: 1. Technology development: diffractive-element design for multicolor 3D PSFs. 2. System design: volumetric tracking of dense emitters. 3. Live-cell measurements: chromatin dynamics. Looking ahead, here we create the imaging tools that pave the way towards the holy grail of chromatin visualization: dynamic observation of the 3D positions of the ~3 billion DNA base-pairs in a live human cell. Beyond that, our results will be applicable to numerous 3D micro/nanoscale tracking applications.

1 802 500 €

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

Nature has evolved ultimate chemical functions based on controlling and altering conformation of its molecular machinery. Prominent examples include enzyme catalysis and information storage/duplication in nucleic acids. These achievements are based on large and complex yet remarkably defined structures obtained through folding of polymeric chains and a subtle interplay of non-covalent forces. Nature uses a limited set of building blocks – e.g. twenty amino-acids and four nucleobases – with specific abilities to impart well-defined folds. In the last decade, chemists have discovered foldamers: non-natural oligomers and polymers also prone to adopt folded structures. The emergence of foldamers has far reaching implications. A new major long term prospect is open to chemistry: the de novo synthesis of artificial objects resembling biopolymers in terms of their size, complexity, and efficiency at achieving defined functions, yet having chemical structures beyond the reach of biopolymers amenable to new properties and functions. The PI of this project has shown internationally recognized leadership in the development of a class of foldamers, aromatic oligoamides, whose features arguably make them the most suitable candidates to systematically explore what folded structures beyond biopolymers give access to. This project aims at developing methods to allow the routine fabrication of 20-40 units long aromatic oligoamide foldamers (6-15 kDa) designed to fold into artificial molecular containers having engineerable cavities and surfaces for molecular recognition of organic substrates, in particular large peptides and saccharides, polymers, and proteins. The methodology rests on modelling based design, multistep organic synthesis of heterocyclic monomers and their assembly into long sequences, structural elucidation using, among other techniques, x-ray crystallography, and the physico-chemical characterization of molecular recognition events.

2 496 216 €

Start date: 2013-06-01, End date: 2018-05-31

Chronic Obstructive Pulmonary Disease (COPD) is a group of chronic diseases characterized by airflow limitations in the lung. COPD is a critical international health problem. It is estimated to affect up to 600 million people worldwide and by 2020 it will become the third most frequent cause of death. In Europe alone, COPD affects up to 10% of people (i.e. more people than breast cancer and diabetes) and it takes the life of around 300,000 Europeans each year. Up to date, COPD has no cure as current treatments fail to halt the long-term decline in lung function. They are only able to delay its progression. Those treatments however, are associated with a variety of side effects some of which can be acute and even life threatening. Thus, COPD remains a disease with a significant unmet medical need. In this project (acronymed AbCURE_COPD) we intend to carry out a set of necessary activities for the evaluation of a potentially groundbreaking approach for treating COPD. Our approach is focusing on antibody-mediated clearance of senescent cells which accumulate in tissues with age and contribute to multiple age-related diseases, including COPD. The goal of the PoC project is two-fold. (1) The first goal is to establish the technical feasibility of our idea by testing the effect of senescence-specific antibodies on COPD development and progression by implementing COPD mouse model we developed. (2) The second goal is to establish the business feasibility of our revolutionary approach by taking the necessary steps towards its commercialization, focusing on the creation of strategic alliances with key private sector companies. We firmly believe that with our approach we can significantly extend the health span and improve the quality of life of COPD patients. Equally important, our approach will pave the way for the development of novel treatment strategies applicable to other age-related diseases, such as osteoarthritis, cardiovascular, and neurodegenerative diseases.

150 000 €

Start date: 2018-11-01, End date: 2020-04-30

Antibiotics have contributed to a tremendous increase in human well-being, saving many millions of lives. However, antibiotics become obsolete the more they are used as selection pressure promotes the development of resistant bacteria. The World Health Organization has proclaimed antibiotic resistance as a major global threat to public health. Today, 700,000 deaths per year are due to untreatable infections. To win the battle against antibiotic resistance, new policies affecting the supply and demand of existing and new drugs must be designed. I propose new research to identify and evaluate feasible and effective demand-side policy interventions targeting the relevant decision makers: physicians and patients. ABRSEIST will make use of a broad econometric toolset to identify mechanisms linking antibiotic resistance and consumption exploiting a unique combination of physician-patient-level antibiotic resistance, treatment, and socio-economic data. Using machine learning methods adapted for causal inference, theory-driven structural econometric analysis, and randomization in the field it will provide rigorous evidence on effective intervention designs. This research will improve our understanding of how prescribing, resistance, and the effect of antibiotic use on resistance, are distributed in the general population which has important implications for the design of targeted interventions. It will then estimate a structural model of general practitioners’ acquisition and use of information under uncertainty about resistance in prescription choice, allowing counterfactual analysis of information-improving policies such as mandatory diagnostic testing. The large-scale and structural econometric analyses allow flexible identification of physician heterogeneity, which ABRSEIST will exploit to design and evaluate targeted, randomized information nudges in the field. The result will be improved rational use and a toolset applicable in contexts of antibiotic prescribing.

1 498 920 €

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

The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.

3 375 693 €

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

Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity. We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome. Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown. Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.

1 902 500 €

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

Formation of the Earth and the other terrestrial planets of our Solar System (Mercury, Venus and Mars) commenced 4.568 billion years ago and occurred on a time scale of about 100 million years. These planets grew by the process of accretion, which involved numerous collisions with smaller (Moon- to Mars-size) bodies. Impacts with such bodies released sufficient energy to cause large-scale melting and the formation of deep “magma oceans”. Such magma oceans enabled liquid metal to separate from liquid silicate, sink and accumulate to form the metallic cores of the planets. Thus core formation in terrestrial planets was a multistage process, intimately related to the major impacts during accretion, that determined the chemistry of planetary mantles. However, until now, accretion, as modelled by astrophysicists, and core formation, as modelled by geochemists, have been treated as completely independent processes. The fundamental and crucial aim of this ambitious interdisciplinary proposal is to integrate astrophysical models of planetary accretion with geochemical models of planetary differentiation together with cosmochemical constraints obtained from meteorites. The research will involve integrating new models of planetary accretion with core formation models based on the partitioning of a large number of elements between liquid metal and liquid silicate that we will determine experimentally at pressures up to about 100 gigapascals (equivalent to 2400 km deep in the Earth). By comparing our results with the known physical and chemical characteristics of the terrestrial planets, we will obtain a comprehensive understanding of how these planets formed, grew and evolved, both physically and chemically, with time. The integration of chemistry and planetary differentiation with accretion models is a new ground-breaking concept that will lead, through synergies and feedback, to major new advances in the Earth and planetary sciences.

1 826 200 €

Start date: 2012-05-01, End date: 2018-04-30

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

1 148 000 €

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

Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.

1 499 375 €

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

Sensory perception involves the discrimination and binding of multiple modalities of sensory input. This is especially evident in the somatosensory system where different modalities of sensory input, including thermal and mechanosensory, are combined to generate a unified percept. The neural mechanisms of multisensory binding are unknown, in part because sensory perception is typically studied within a single modality in a single brain region. I propose a multi-level approach to investigate thermo-tactile processing in the mouse forepaw system from the primary sensory afferent neurons to thalamo-cortical circuits and behaviour. The mouse forepaw system is the ideal system to investigate multisensory binding as the sensory afferent neurons are well investigated, cell type-specific lines are available, in vivo optogenetic manipulation is possible both in sensory afferent neurons and central circuits and we have developed high-resolution somatosensory perception behaviours. We have previously shown that mouse primary somatosensory forepaw cortical neurons respond to both tactile and thermal stimuli and are required for non-noxious cooling perception. With multimodal neurons how, then, is it possible to both discriminate and bind thermal and tactile stimuli? I propose 3 objectives to address this question. We will first, perform functional mapping of the thermal and tactile pathways to cortex; second, investigate the neural mechanisms of thermo-tactile discrimination in behaving mice; and third, compare neural processing during two thermo-tactile binding tasks, the first using passively applied stimuli, and the second, active manipulation of thermal objects. At each stage we will perform cell type-specific neural recordings and causal optogenetic manipulations in awake and behaving mice. Our multi-level approach will provide a comprehensive investigation into how the brain performs multisensory perceptual binding: a fundamental yet unsolved problem in neuroscience.

1 999 877 €

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

"Digital 3D models are gaining more and more importance in diverse application fields ranging from computer graphics, multimedia and simulation sciences to engineering, architecture, and medicine. Powerful technologies to digitize the 3D shape of real objects and scenes are becoming available even to consumers. However, the raw geometric data emerging from, e.g., 3D scanning or multi-view stereo often lacks a consistent structure and meta-information which are necessary for the effective deployment of such models in sophisticated down-stream applications like animation, simulation, or CAD/CAM that go beyond mere visualization. Our goal is to develop new fundamental algorithms which transform raw geometric input data into augmented 3D models that are equipped with structural meta information such as feature aligned meshes, patch segmentations, local and global geometric constraints, statistical shape variation data, or even procedural descriptions. Our methodological approach is inspired by the human perceptual system that integrates bottom-up (data-driven) and top-down (model-driven) mechanisms in its hierarchical processing. Similarly we combine algorithms operating on different levels of abstraction into reconstruction and modeling networks. Instead of developing an individual solution for each specific application scenario, we create an eco-system of algorithms for automatic processing and interactive design of highly complex 3D models. A key concept is the information flow across all levels of abstraction in a bottom-up as well as top-down fashion. We not only aim at optimizing geometric representations but in fact at bridging the gap between reconstruction and recognition of geometric objects. The results from this project will make it possible to bring 3D models of real world objects into many highly relevant applications in science, industry, and entertainment, greatly reducing the excessive manual effort that is still necessary today."

2 482 000 €

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

During the 20th century computer technology evolved from bulky, slow, special purpose mechanical engines to the now ubiquitous silicon chips and software that are one of the pinnacles of human ingenuity. The goal of the field of molecular programming is to take the next leap and build a new generation of matter-based computers using DNA, RNA and proteins. This will be accomplished by computer scientists, physicists and chemists designing molecules to execute ``wet'' nanoscale programs in test tubes. The workflow includes proposing theoretical models, mathematically proving their computational properties, physical modelling and implementation in the wet-lab. The past decade has seen remarkable progress at building static 2D and 3D DNA nanostructures. However, unlike biological macromolecules and complexes that are built via specified self-assembly pathways, that execute robotic-like movements, and that undergo evolution, the activity of human-engineered nanostructures is severely limited. We will need sophisticated algorithmic ideas to build structures that rival active living systems. Active-DNA, aims to address this challenge by achieving a number of objectives on computation, DNA-based self-assembly and molecular robotics. Active-DNA research work will range from defining models and proving theorems that characterise the computational and expressive capabilities of such active programmable materials to experimental work implementing active DNA nanostructures in the wet-lab.

2 349 603 €

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

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

1 500 000 €

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

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

2 000 000 €

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

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

1 088 386 €

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

Amorphous and evolutionary DNA nanotechnology (AEDNA) explores novel conceptual directions and applications for DNA nanotechnology, which are based on intelligent, DNA-programmed soft hybrid materials, and the utilization of evolutionary principles for the optimization of nucleic acid nanocomponents. Amorphous DNA nanotechnology first aims at the creation of cell-sized, DNA-programmed microgels – DNA cells – with sensor, computation, communication, and actuator functions. Interacting DNA cells will be arranged into chemical cell consortia and artificial tissues using microfluidics, micromanipulation and 3D bioprinting techniques. Spatially distributed chemical circuits will then be utilized to establish collective behaviors such as quorum sensing, pattern formation, and self-differentiation within these consortia and tissues. The approach will be further scaled up to produce multicomponent DNA gel compositions that become active and differentiate upon mixing. In evolutionary nanotechnology, techniques derived from directed molecular evolution experiments will be applied to optimize the arrangement of functional nucleic acids on DNA and RNA nanoscaffolds. Compartmentalization and microfluidics will be utilized to screen for nucleic acid nanostructures capable of superstructure formation, and also for the development of ligand-sensitive components for molecular programming. An evolutionary approach will then be applied to amorphous DNA cells, resulting in DNA cell populations which contain individuals with different molecular identities. The proposal will pave the way for the creation of macroscopic materials with DNA-programmed intelligence, resulting in novel applications for DNA nanotechnology and molecular programming in diverse fields such as environmental and biological sensing, biocatalysis, smart adaptive materials, and soft robotics.

2 157 698 €

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

"AEROCAT aims at the elucidation of the potential of nanoparticle derived aerogels in catalytic applications. The materials will be produced from a variety of nanoparticles available in colloidal solutions, amongst which are metals and metal oxides. The evolving aerogels are extremely light, highly porous solids and have been demonstrated to exhibit in many cases the important properties of the nanosized objects they consist of instead of simply those of the respective bulk solids. The resulting aerogel materials will be characterized with respect to their morphology and composition and their resulting (electro-)catalytic properties examined in the light of the inherent electronic nature of the nanosized constituents. Using the knowledge gained within the project the aerogel materials will be further re-processed in order to exploit their full potential relevant to catalysis and electrocatalysis. From the vast variety of possible applications of nanoparticle-based hydro- and aerogels like thermoelectrics, LEDs, pollutant clearance, sensorics and others we choose our strictly focused approach (i) due to the paramount importance of catalysis for the Chemical Industry, (ii) because we have successfully studied the Ethanol electrooxidation on a Pd-nanoparticle aerogel, (iii) we have patented on the oxygen reduction reaction in fuel cells with bimetallic aerogels, (iv) and we gained first and extremely promising results on the semi-hydrogenation of Acetylene on a mixed Pd/ZnO-nanoparticle aerogel. With this we are on the forefront of a research field which impact might not be overestimated. We should quickly explore its potentials and transfer on a short track the knowledge gained into pre-industrial testing."

2 194 000 €

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

1.2 billion people worldwide lack access to safe drinking water. Drinking water quality is threatened by newly emerging organic micro-pollutants (pesticides, pharmaceuticals, industrial chemicals) in source waters. Nanofiltration is a technology that is expected to play a key role in future water treatment processes due to its effectiveness in removal of micropollutants. However, the loss of membrane flux due to fouling is one of the main impediments in the development of membrane processes for use in drinking water treatment. Currently there is a wholly inadequate mechanistic understanding of the role of biofilm on the fouling of nanofiltration membranes. Applying techniques including confocal microscopy, force spectroscopy, and infrared spectroscopy using an experimental programme informed by a technique known as scale-down together with mathematical modelling, it is confidently expected that significant advances will be gained in the mechanistic understanding of nanofiltration biofouling. The specific objectives are 1. How is the rate of formation and extent of such biofilms influenced by the biological response to the local microenvironment? 2 Elucidate the effect of extracellular polysaccharide substances on physical properties, composition and structure of these biofilms. 3: Investigate mechanisms to enhance biofilm removal by a physical detachment process complemented by techniques that alter biofilm material properties. A more fundamental insight into the mechanisms of nanofiltration operation will help in further development of this treatment method in future water treatment processes.

1 468 987 €

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

Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases. This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function. Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues. Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches. Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.

1 496 444 €

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

"By 2040, the European population aged over 60 will rise to 290 million, with those estimated to have dementia to 15.9 million. These dramatic demographic changes will pose huge challenges to health care systems, hence a detailed understanding of age-related cognitive and neurobiological changes is essential for helping elderly populations maintain independence. However, while existing research into cognitive ageing has carefully characterised developmental trajectories of functions such as memory and processing speed, one key cognitive ability that is particularly relevant to everyday functioning has received very little attention: In surveys, elderly people often report substantial declines in navigational abilities such as problems with finding one’s way in a novel environment. Such deficits severely restrict the mobility of elderly people and affect physical activity and social participation, but the underlying behavioural and neuronal mechanisms are poorly understood. In this proposal, I will take a new approach to cognitive ageing that will bridge the gap between animal neurobiology and human cognitive neuroscience. With support from the ERC, I will create a team that will characterise the mechanisms mediating age-related changes in navigational processing in humans. The project will focus on three structures that perform key computations for spatial navigation, form a closely interconnected triadic network, and are particularly sensitive to the ageing process. Crucially, the team will employ an interdisciplinary methodological approach that combines mathematical modelling, brain imaging and innovative data analysis techniques with novel virtual environment technology, which allows for rigorous testing of predictions derived from animal findings. Finally, the proposal also incorporates a translational project aimed at improving spatial mnemonic functioning with a behavioural intervention, which provides a direct test of functional relevance and societal impact."

1 318 990 €

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

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

1 727 920 €

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

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

2 493 600 €

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

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

1 498 175 €

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

"The first decade of Algorithmic Mechanism Design (AMD) concentrated, very successfully, on the design of truthful mechanisms for the allocation of resources among agents with private preferences. Truthful mechanisms are ones that incentivize rational users to report their preferences truthfully. Truthfulness, however, for all its theoretical appeal, suffers from several inherent limitations, mainly its high communication and computation complexities. It is not surprising, therefore, that practical applications forego truthfulness and use simpler mechanisms instead. Simplicity in itself, however, is not sufficient, as any meaningful mechanism should also have some notion of fairness; otherwise agents will stop using it over time. In this project I plan to develop an innovative AMD theoretical framework that will go beyond truthfulness and focus instead on the natural themes of simplicity and fairness, in addition to computational tractability. One of my primary goals will be the design of simple and fair poly-time mechanisms that perform at near optimal levels with respect to important economic objectives such as social welfare and revenue. To this end, I will work toward providing precise definitions of simplicity and fairness and quantifying the effects of these restrictions on the performance levels that can be obtained. A major challenge in the evaluation of non-truthful mechanisms is defining a reasonable behavior model that will enable their evaluation. The success of this project could have a broad impact on Europe and beyond, as it would guide the design of natural mechanisms for markets of tens of billions of dollars in revenue, such as online advertising, or sales of wireless frequencies. The timing of this project is ideal, as the AMD field is now sufficiently mature to lead to a breakthrough and at the same time young enough to be receptive to new approaches and themes."

1 394 600 €

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

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

1 925 250 €

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

This project focuses on developing quantum field theory methods and applying them to the phenomenology of elementary particles. At the Large Hadron Collider (LHC) our current best theoretical understanding of particle physics is being tested against experiment by measuring e.g. properties of the recently discovered Higgs boson. With run two of the LHC, currently underway, the experimental accuracy will further increase. Theoretical predictions matching the latter are urgently needed. Obtaining these requires extremely difficult calculations of scattering amplitudes and cross sections in quantum field theory, including calculations to correctly describe large contributions due to long-distance physics in the latter. Major obstacles in such computations are the large number of Feynman diagrams that are difficult to handle, even with the help of modern computers, and the computation of Feynman loop integrals. To address these issues, we will develop innovative methods that are inspired by new structures found in supersymmetric field theories. We will extend the scope of the differential equations method for computing Feynman integrals, and apply it to scattering processes that are needed for phenomenology, but too complicated to analyze using current methods. Our results will help measure fundamental parameters of Nature, such as, for example, couplings of the Higgs boson, with unprecedented precision. Moreover, by accurately predicting backgrounds from known physics, our results will also be invaluable for searches of new particles.

2 000 000 €

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

Prospective biosensing technologies will need to tackle the grand challenges arising from the global demographic changes. Among the most crucial tasks is the monitoring of food and environmental quality as well as the medical diagnosis. Digital fluidics offers vast advantages in performing these tasks relying on tiny containers with reacting biochemical species and allowing massively parallelized assays and high throughput screening using optical detection approaches. I envision that adding not-optical detectors, which electrically probe the analyte responses, will provide a source of new but complementary information, obtained in a label-free and contactless manner. Hence, these all-electric platforms enable monitoring the kinetics of chemical reactions in lab-on-chip format, as well as take over auxiliary tasks, e.g. indexing, counting of droplets, flow monitoring. In frame of the ERC project SMaRT, my team developed a unique detection platform -millifluidic resonance detector- that inductively couples to an analyte and assesses its physico-chemical properties. The unique selling points are (i) non-invasiveness to analyte, (ii) unnecessity of a transparent fluidic channel, (iii) cost efficiency and (iv) portability. Implementing the input from the partner companies, here I aim to reach the commercialization stage pursuing a number of key milestones, i.e. enhance the screening throughput, realize a platform independent of external electronic devices, provide a temperature stabilization of the response, and develop the app. Societal benefits: We demonstrated that the device provides an access to the metabolic activity of living organisms in droplets. This is way beyond the capabilities of the state-of-the-art optical detection. With this feature, the device can address the issue of increasing antibiotic resistance of bacteria and thus help to optimize the antibiotic policy in hospitals and households and to test new drugs in a time- and cost-efficient way.

150 000 €

Start date: 2017-09-01, End date: 2019-02-28

"Traditionally, natural products are classified into ""natural product families"". Within a family all congeners display specific structure elements, owing to their common biosynthetic pathway. This suggests a bio-inspired or ""collective synthesis"", as has been devised by D: W. MacMillan. However, a biosynthetic pathway is confined to these structure elements, thus limiting synthesis with regard to structure diversification. In this research proposal the applicant exemplarily devises a strategic concept to overcome these limitations, by replacing the dogma of ""retrosynthetic analysis"" with ""structure pattern recognition"". This concept is termed ""Artificial Natural Product Systems Synthesis — ANaPSyS"", and aims to supersede the current ""logic of chemical synthesis"" as a standard practice in this field. ANaPSyS exclusively categorizes natural products based on structural relationships — regardless of biogenetic origin. The structure pattern analysis groups natural products according to their shared core structure, and thereof creates a common precursor called ""privileged intermediate (PI)"". This intermediate is resembled in each of these natural products and is architecturally less complex. As a result every member of this natural product group can originate from a different natural product family and is obtained via this ""privileged intermediate"", which serves as basis for the artificial synthetic network. With ANaPSyS a synthetic route is not restricted to a single target structure anymore (as in conventional synthesis). In comparison with bio-inspired synthesis, which is limited to a single natural product family, ANaPSyS enables the synthesis of a whole set of natural product families. With every synthesis accomplished, the network is upgraded — hence diversification leads to a rise in revenue. As a consequence, synthetic efficiency is drastically enhanced, therefore profoundly boosting and facilitating lead structure development. "

1 497 000 €

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

The last two decades have seen fascinating attempts to establish new narratologies, basing narratology on cognitive science or coupling it with other approaches such as postcolonial studies. While appreciating that these attempts have raised questions beyond the limits of structuralist narratology, critics have noted that by doing so they tend to abandon narratology’s strength, that is its analytical tools. In many cases, narratology has become a label that is as empty as it is fashionable. The project as outlined here, on the other hand, develops a new approach that combines the analytical arsenal of structuralist narratology with a phenomenological take on time in order to provide new answers as to the question of narrative’s function. By exploring the tension between experience and teleology in ancient literature, it sets out to demonstrate how narrative serves as a mode of coming to grips with time. Besides offering a new narratology that cross-fertilizes the strengths of different disciplines and pioneering a new approach to ancient literature, the project will steer the current debate on experience and presence into a new direction across disciplines in the humanities.

1 383 840 €

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

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

2 478 750 €

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

"Blood vessels pervade all tissues in the body to supply nutrients and oxygen. Aberrant vessel growth and function are hallmarks of cancer and cardiovascular diseases and they contribute to disease pathogenesis. Antiangiogenic therapeutics have reached the clinic, but limited efficacy and resistance raise unresolved challenges. The current limitations of angiogenic medicine call for a more integrated understanding of the angiogenic process that focuses not only on the instigators of vessel branching but also on mechanisms that sustain vessel growth. Recent insights into fundamental aspects of cell growth move metabolism into spotlight and establish how proliferating cells reprogram their metabolism to provide energy and building blocks for cell replication. During angiogenesis, endothelial cells (ECs) also convert between growth states: although mostly quiescent in adult tissues, ECs divide and migrate rapidly upon angiogenic stimulation. To allow growth of new vessel branches, ECs therefore need to adjust their metabolism to increase energy production and biosynthetic activity. However, the molecular mechanisms that coordinate EC metabolism with angiogenic signalling are not known to date. In this proposal, we put forth the hypothesis that metabolic regulation is a key component of the endothelial angiogenic machinery that is required to sustain vessel growth. Thus, this proposal aims (I) to define transcriptional circuits that link EC growth with metabolism, (II) to explore the regulation of these transcriptional networks by lysine acetylation, a nutrient-regulated protein modification with key functions in metabolism, and (III) to assess the role of sirtuin deacetylases for sensing endothelial energetics during vascular growth. Understanding the principles of angiogenesis-metabolism crosstalk will not only yield novel insights into the basic mechanisms of vessel formation but will also provide unprecedented opportunities for future drug development."

1 487 920 €

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

AnonymClassic is the first ever comprehensive study of Kalila and Dimna (a book of wisdom in fable form), a text of premodern world literature. Its spread is comparable to that of the Bible, except that it passed from Hinduism and Buddhism via Islam to Christianity. Its Arabic version, produced in the 8th century, when this was the lingua franca of the Near East, became the source of all further translations up to the 19th century. The work’s multilingual history involving circa forty languages has never been systematically studied. The absence of available research has made world literature ignore it, while scholars of Arabic avoided it because of its widely diverging manuscripts, so that the actual shape of the Arabic key version is still in need of investigation. AnonymClassic tests a number of ‘high-risk’ propositions, including three key hypotheses: 1) The anonymous Arabic copyists of Kalila and Dimna are de facto co-authors, 2) their agency is comparable to that of the named medieval translators, and 3) the fluctuation of the Arabic versions is conditioned by the work’s fictional status. AnonymClassic’s methodology relies on a cross-lingual narratological analysis of the Arabic versions and all medieval translations (supported by a synoptic digital edition), which takes precisely the interventions at each stage of transmission (redaction, translation) as its subject. Considering the work’s paths of dissemination from India to Europe, AnonymClassic will challenge the prevalent Western theoretical lens on world literature conceived ‘from above’ with the view ‘from below,’ based on the attested cross-cultural network constituted by its versions. AnonymClassic will introduce a new paradigm of an East-Western literary continuum with Arabic as a cultural bridge. Against the current background of Europe’s diversifying and multicultural society, AnonymClassic purposes to integrate pre-modern Near Eastern literature and culture into our understanding of Global Culture.

2 435 113 €

Start date: 2018-01-01, End date: 2022-12-31

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

1 004 000 €

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

After decades of successful treatment of bacterial infections with antibiotics, formerly treatable bacteria have developed drug resistance and consequently pose a major threat to public health. To address the urgent need for effective antibacterial drugs we will develop a streamlined chemical-biology platform that facilitates the consolidated identification and structural elucidation of natural products together with their dedicated cellular targets. This innovative concept overcomes several limitations of classical drug discovery processes by a chemical strategy that focuses on a directed isolation, enrichment and identification procedure for certain privileged natural product subclasses. This proposal consists of four specific aims: 1) synthesizing enzyme active site mimetics that capture protein reactive natural products out of complex natural sources, 2) designing natural product based probes to identify their cellular targets by a method called activity based protein profiling , 3) developing a traceless photocrosslinking strategy for the target identification of selected non-reactive natural products, and 4) application of all probes to identify novel enzyme activities linked to viability, resistance and pathogenesis. Moreover, the compounds will be used to monitor the infection process during invasion into eukaryotic cells and will reveal host specific targets that promote and support bacterial pathogenesis. Inhibition of these targets is a novel and so far neglected approach in the treatment of infectious diseases. We anticipate that these studies will provide a powerful pharmacological platform for the development of potent natural product derived antibacterial agents directed toward novel therapeutic targets.

1 500 000 €

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

Even after three decades of research on human-computer interaction (HCI), current general-purpose user interfaces (UI) still lack the ability to attribute mental states to their users, i.e. they fail to understand users' intentions and needs and to anticipate their actions. This drastically restricts their interactive capabilities. ANTICIPATE aims to establish the scientific foundations for a new generation of user interfaces that pro-actively adapt to users' future input actions by monitoring their attention and predicting their interaction intentions - thereby significantly improving the naturalness, efficiency, and user experience of the interactions. Realising this vision of anticipatory human-computer interaction requires groundbreaking advances in everyday sensing of user attention from eye and brain activity. We will further pioneer methods to predict entangled user intentions and forecast interactive behaviour with fine temporal granularity during interactions in everyday stationary and mobile settings. Finally, we will develop fundamental interaction paradigms that enable anticipatory UIs to pro-actively adapt to users' attention and intentions in a mindful way. The new capabilities will be demonstrated in four challenging cases: 1) mobile information retrieval, 2) intelligent notification management, 3) Autism diagnosis and monitoring, and 4) computer-based training. Anticipatory human-computer interaction offers a strong complement to existing UI paradigms that only react to user input post-hoc. If successful, ANTICIPATE will deliver the first important building blocks for implementing Theory of Mind in general-purpose UIs. As such, the project has the potential to drastically improve the billions of interactions we perform with computers every day, to trigger a wide range of follow-up research in HCI as well as adjacent areas within and outside computer science, and to act as a key technical enabler for new applications, e.g. in healthcare and education.

1 499 625 €

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

Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems. We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes. This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.

2 000 000 €

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

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: 2024-04-30

Social bonding success in life impacts on health, survival and fitness. It is proposed that early and later social experience as well as heritable factors determine social bonding abilities in adulthood, although the relative influence of each is unclear. In humans, the resulting uncertainty likely impedes psychological and psychiatric assessment and therapy. One problem hampering progress for human studies is that social bonding success is hard to objectively quantify, particularly in adults. I propose to directly address this problem by determining the key influences on social bonding abilities in chimpanzees, our closest living relative, where social bonding success can be objectively quantified, and is defined as number of affiliative relationships maintained over time with high rates of affiliation. Objectives. This project will quantify the relative impact of early and later social experience as well as heritable factors on social hormone levels, social cognition and social bonding success in 270 wild and captive chimpanzees, using both cohort and longitudinal data. This will reveal the degree of plasticity in social cognition and bonding behaviour throughout life. Finally, it will evaluate the potential for using endogenous hormone levels as non-invasive biomarkers of social bonding success, as well as identifying social contexts that act as strong natural social hormone releasers. Outcomes. This project will expose what makes some better at social bonding than others. Specifically, it will show the extent to which later social experience can compensate for early social experience or heritable factors in terms of adult social bonding success, the latter being a key factor in determining health and happiness in life. This project also offers the potential for using hormonal biomarkers in clincial settings, as objective assessment of changes in relationships over time, and in therapy by engaging in social behaviours that act as strong social hormone releasers.

1 495 000 €

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